Upregulation of S100 Calcium-Binding Protein A9 levels in the lungs of patients with idiopathic pulmonary fibrosis

Upregulation of S100 Calcium-Binding Protein A9 levels in the lungs of patients with idiopathic pulmonary fibrosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Upregulation of S100 Calcium-Binding Protein A9 levels in the lungs of patients with idiopathic pulmonary fibrosis Jong-Uk Lee, Jong-Sook Park, Myung-Shin Kim, Jai-Seong Park, Eun-Suk Go, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-20772/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Neutrophilic inflammation is a predominant characteristic of idiopathic pulmonary fibrosis (IPF). S100 Calcium-Binding Protein A9 (S100A9) is a neutrophil-derived protein and is involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF has not been evaluated. Methods : S100A9 concentrations were measured by ELISA in the BAL fluid obtained from NCs (n = 33) and patients with IPF (n = 87), NSIP (n = 22), HP (n = 19), or sarcoidosis (n = 10). Results: The S100A9 levels in BALF were significantly higher in patients with IPF than in those with NC (0.4 [0.18–0.9] vs. 0 [0–0.5] ng/mL, p < 0.001), HP (0.19 [0.07–0.33] ng/mL, p = 0.043), or sarcoidosis (0.06 [0–0.11] ng/mL, p < 0.001) patients. A S100A9 level of 0.093 ng/mL had discriminating powers of 78.79% for specificity and 81.61% for sensitivity between IPF patients and NCs. S100A9 levels were also correlated with neutrophil numbers (r = 0.356, p = 0.0007) and S100A9 was expressed on neutrophils and macrophages in the BALF of IPF patients. Patients with S100A9 levels above 0.5535 ng/mL or a neutrophil percentage above 49.09% (n = 43) had significantly lower survival rates than those with S100A9 levels at or below 0.5535 ng/mL and a neutrophil percentage at or below 49.09% (n = 41) (HR, 9.28; p = 0.0004). Conclusion: S100A9 may participate in the development and progression of IPF. The levels of S100A9 in BALF may be a surrogate marker for diagnosing IPF and predicting its prognosis. Pulmonology IPF S100A9 BAL fluid Diagnosis Prognosis Figures Figure 1 Figure 2 Figure 3 Introduction Idiopathic interstitial pneumonia (IIP) is a group of lung diseases whose etiology is unknown. IIP is characterized by an accumulation of inflammatory cells in the pulmonary parenchyma and interstitium that leads to fibrosis. Idiopathic pulmonary fibrosis (IPF), the most common form of IIP, results in gradual deterioration with a diverse clinical course [ 1 , 2 ]. The poor prognosis of IPF is due to alveolar epithelial injury and abnormal repair mechanisms that ultimately develop into irreversible pulmonary fibrosis [ 3 ]. Abnormalities in multiple biological pathways lead to processes related to the pathogenesis of IPF, and affect inflammation and wound repair. The processes and factors include the clotting cascade, oxidant–antioxidant pathways, apoptosis, inflammatory cytokines, angiogenesis, vascular remodeling, growth factors, surfactants, and matrix regulatory factors [ 4 , 5 ]. Among the inflammatory patterns, neutrophilic inflammation is predominant in bronchoalveolar lavage fluid (BALF) of IPF patients [ 6 – 8 ] and is related to early mortality in these patients [ 6 , 9 ]. Levels of the neutrophil chemoattractant CXCL8 are higher in the BALF and serum of patients with IPF [ 10 ]. In addition, levels of the alveolar epithelial marker cytokeratin 19 are correlated with neutrophil infiltration, suggesting a relationship between epithelial injury and neutrophilic inflammation [ 11 ]. Neutrophilic inflammation was recently revealed as being related to fibrosis. In neutrophilic inflammation, neutrophil granules release neutrophil elastase (NE) and matrix-degrading proteins such as matrix metalloproteinases (MMPs), which are the main tissue destructive agents and are heavily involved in matrix degradation [ 12 ]. NE increases in the lungs of IPF patients [ 8 ] and regulates the degradation of the extracellular matrix (ECM) into collagens I, II, III, IV, fibronectin, laminin, and elastin. It also induces fibroblast proliferation and myofibroblast differentiation [ 13 , 14 ]. S100A9 is one of the main mediators of neutrophils and macrophages and is now considered a damage-associated molecular pattern protein (DAMP) because it exists intracellularly and is released upon activation or damage under conditions of cellular stress [ 15 ]. S100A9 has the potential to cause fibroblast proliferation [ 16 ], and to upregulate collagen type III α-smooth muscle actin and the receptor for advanced glycation end-product expression (RAGE) [ 17 ]. Higher concentrations of S100A9 have been reported in the BALF of patients with IPF than in that from patients with other ILDs, including sarcoidosis, non-specific interstitial pneumonia (NSIP), and pulmonary fibrosis associated with connective tissue diseases that have a potential biomarker [ 18 , 19 ]. However, previous studies have provided only limited information since they had a small number of subjects. Therefore, we measured the concentrations of S100A9 in BALF to evaluate the association between S100A9 and the development of IPF. We also investigated the clinical impact of IPF, particularly the long-term survival rate in a relatively large number of subjects and those with ILDs. Materials And Methods Study subjects Lung tissues and BALF from study subjects were obtained from the biobank of Soonchunhyang University Hospital, Bucheon, Korea (Schbc-biobank-18101601-14-01). The study protocol was approved by the Ethics Committee of Soonchunhyang University Hospital (Schbc-medicine-2018-10). Informed written consent for study participation was obtained from the subjects, and a sample donation was obtained from each subject. All subjects were examined by physicians and underwent a chest X-ray, high-resolution chest computed tomography (HRCT), and pulmonary function tests. There was no evidence of any underlying collagen vascular diseases in IPF patients according to their laboratory results and clinical symptoms. The diagnostic criteria for IPF, hypersensitivity pneumonitis (HP), NSIP, and sarcoidosis were established based on an international consensus statement [ 20 – 23 ]. IPF was diagnosed by the presence of usual interstitial pneumonia (UIP) patterns in the pathological specimens (surgical IPF) and/or by HRCT in patients who did not undergo surgical lung biopsy (clinical IPF). Two pathologists examined each slide independently after being informed of the subjects’ sex, age, and HCRT results. Pathological recognition of the NSIP pattern included two major aspects: (1) exclusion of other patterns of interstitial lung diseases, and (2) categorization of the histological features according to the ATS/ERS 2002 classification [ 23 , 24 ] and the modified histological definition of the NSIP pattern [ 25 ]. HP was diagnosed by the presence of clinical symptoms compatible with non-necrotizing granulomatous bronchiolocentric pneumonitis [ 20 ]. The diagnosis of sarcoidosis was based on histological evidence of non-caseating granuloma and compatible clinical images [ 22 ]. HP and sarcoidosis were diagnosed after excluding other diseases with similar histological profiles. Biopsy tissues were subjected to acid-fast bacillus and Gömöri methenamine silver staining to verify the absence of microorganisms and fungi. The serial diffusing capacity of lungs for carbon monoxide (DLCO) and forced vital capacity (FVC) were measured, and the annual rate of decline was estimated as follows: (last FVC [or DLCO] − baseline FVC [or DLCO])/baseline FVC [or DLCO]/follow-up years. Normal controls (NC) exhibited no respiratory symptoms as determined by a screening questionnaire and had a predicted forced expiratory volume at 1 second (FEV1) and FVC > 80% and normal chest radiograms. Bronchoalveolar lavage fluids procedure The bronchial alveolar lavage fluid (BALF) procedure was performed in lung segments that were not under immunosuppressive therapy, were in the right middle lobe of the NCs, and exhibited the greatest disease involvement when HRCT was done, as described previously [ 26 ]. A cytocentrifuge was used to prepare the cells, which were then mounted on slides and stained with Diff-Quik stain. A hemocytometer was used to differentially count the cells to a total count of 500 cells. The supernatants were isolated using centrifugation (500 × g , 5 min) and stored at − 80 °C. Enzyme-linked immunosorbent assay (ELISA) of S100A9 in BALF The S100A9 level in the supernatants was measured using an ELISA (MyBioSource, San Diego, CA, USA) according to the manufacturer’s recommendations. The lower limit of detection was 0.1 ng/mL, and values below this limit were set to 0. The inter- and intra-assay coefficients of variation were below 15%. Immunofluorescence stain of S100A9 in bronchial alveolar lavage fluid cells and lung tissues Tissue sections were deparaffinized and rehydrolyzed, and BALF cell slides were fixed with 0.4% cold paraformaldehyde for 30 minutes at room temperature. The sections were then incubated overnight at 4 °C with macrophage markers, including monoclonal anti-human S100A9 monoclonal mouse antibody (1:200 dilution; Novus Biological, Littleton, CA, USA), polyclonal anti-human α-SMA antibody (1:200 dilution; Abcam, Cambridge, MA, USA), and monoclonal goat anti-CD163 antibody (1:200 dilution, Hycult Biotech, Uden, PB, Netherlands). The sections were also incubated with monoclonal rabbit anti-neutrophil elastase antibody (1:100 dilution; Abcam, Cambridge, MA, UK) as a neutrophil marker. Tissue sections were deparaffinized and rehydrolyzed, and BALF cell slides were fixed with 0.4% cold paraformaldehyde for 30 minutes at room temperature. The sections were incubated for 1 hour in an Fc receptor blocking agent (FC blocker, Innovex Biosciences, Richmond, CA, USA) containing 5% bovine serum albumin (BSA) to block non-specific binding. The sections were then incubated overnight at 4 °C with macrophage markers, including monoclonal anti-human S100A9 monoclonal mouse antibody (1:200 dilution; Novus Biological, Littleton, CA, USA), polyclonal anti-human α-SMA antibody (1:200 dilution; Abcam, Cambridge, MA, USA), and monoclonal goat anti-CD163 antibody (1:200 dilution, Hycult Biotech, Uden, PB, Netherlands). The sections were also incubated with monoclonal rabbit anti-neutrophil elastase antibody (1:100 dilution; Abcam, Cambridge, MA, UK) as a neutrophil marker. Additional details are provided in the on-line supplement. After washing three times with Tris Buffered Saline (TBS), the slides were incubated for 1 hour at room temperature with the following fluorescent secondary antibodies: anti-rabbit IgG H&L (FITC) (1:1,000 dilution; Abcam, Cambridge, MA, UK), anti-mouse IgG H&L (PE) (1:1,000 dilution; Abcam, Cambridge, MA, UK), and anti-goat IgG H&L (PE) (1:1,000 dilution; Abcam, Cambridge, MA, UK). After washing in TBS, the slides were incubated for 3 minutes at room temperature with 4′,6-diamidino-2-phenylindole (DAPI) (Sigma-Aldrich, St. Louis, USA) and observed under a confocal laser scanning microscope (LSM 510 META, Zeiss, Jena, Germany). Statistical analysis The Kruskal–Wallis test and the post-hoc Mann–Whitney U test were used to compare the S100A9 levels between groups. Correlations between the S100A9 levels and other parameters were analyzed using Spearman’s correlation coefficient. The data are presented as medians in the 25% and 75% quartiles for variables with a skewed distribution, or as a mean ± standard error of the mean for variables with a normal distribution. Receiver operating characteristic (ROC) analysis was performed, and the area under the ROC curve (AUC) and cutoff values were determined using MedCalc statistical software. Optimal cutoff levels of S100A9 and the neutrophil percentage were calculated using Cutoff Finder [ 27 ]. Survival rates were estimated using the Kaplan–Meier method and compared using a log-rank test. The data were analyzed using SPSS software v. 20.0. Values of p < 0.05 were considered statistically significant. Results Study group patient demographic characteristics BALFs were obtained from patients with IPF (n = 87) and those with ILDs including NSIP (n = 22), HP (n = 19), and sarcoidosis (n = 10). BALFs were also obtained from NC patients (n = 33). The clinical characteristics of all patients are summarized in Table 1 . The BALFs of patients with IPF and ILDs had significantly higher numbers of macrophages, neutrophils, lymphocytes, and eosinophils compared to NC patients. They also had lower FVC and FEV1 values than those of NCs (p < 0.05). S100A9 levels in BALFs of patients with IPF or other ILDs and normal controls The levels of S100A9 were significantly higher in BALF from patients with IPF than in that from NC patients (IPF, 0.4 [0.18–0.9] ng/mL vs. 0 [0–0.5] ng/mL, p < 0.001; HP, 0.19 [0.07–0.33] ng/mL, p = 0.043; sarcoidosis, 0.06 [0–0.11] ng/mL, p < 0.001). However, the S100A9 levels were not different from those with NSIP (0.28 [0.07–0.52] ng/mL, p = 0.1933) (Fig. 1 A). The S100A9 levels significantly correlated with neutrophil counts in the BALF of patients with IPF (n = 87, r = 0.356, p = 0.0007) (Fig. 1 B). The ROC curve showed a clear distinction between the IPF patients and the NCs (AUC = 0.833, Fig. 1 C). A cutoff level of 0.093 ng/mL S100A9, determined from the ROC curve, showed a specificity of 78.79% and a sensitivity of 81.61% for differentiating IPF patients from NCs. A cutoff level of 0.0279 ng/mL S100A9 exhibited a specificity of 72.73% and a sensitivity of 76.47% for distinguishing patients with IPF from those with other ILDs (AUC = 0.735, Fig. 1 D). Survival rates and clinical features in relation to S100A9 levels and percentage of neutrophils in BALF from IPF patients Eighty-four patients with IPF were followed for 1 to 10 years. Cutoff values for the S100A9 level and the neutrophil percentage were chosen, and the subjects were divided into two groups. With a cutoff value of 0.5536 ng/mL, the survival rate was significantly lower in the group with a S100A9 level above 0.5536 ng/mL (n = 35) than in the group that had a S100A9 level at or below 0.5536 ng/mL (n = 49; hazard ratio (HR), 3.62, 95% confidence interval (CI), 1.13–11.63; p = 0.021, Fig. 2 A). With a cutoff value of 49.09% neutrophils, the survival rate was significantly lower in the group with a neutrophil percentage above 49.09% (n = 17) compared with the group with a neutrophil percentage at or below 49.09% (n = 67; HR, 3.11; 95% CI, 1.5–11.26; p = 0.003, Fig. 2 B). A combined analysis of the neutrophil percentage and the S100A9 levels in BALF was performed with respect to the survival rate. Patients with an S100A9 level above 0.5536 ng/mL or a neutrophil percentage above 49.09% (n = 43) had a significantly lower survival rate than those with S100A9 levels at or below 0.5536 ng/mL and a neutrophil percentage at or below 49.09% (n = 41; HR, 9.28; 95% CI, 2.08–41.26; p = 0.0004, Fig. 2 C). Patients that had S100A9 levels above 0.5536 ng/mL (n = 35) had a significantly higher total cell count and neutrophil count in BALF than those that had S100A9 levels at or below 0.5536 ng/mL (n = 49; p = 0.0004 and p < 0.0002, respectively; Supplemental Table 1). Patients with or a neutrophil percentage above 49.09% (n = 17) tended to have a higher neutrophil count in BALF than those with a neutrophil percentage at or below 49.09% (n = 67; p = 0.079, Supplemental Table 2). In the combination analysis (Table 2 ), males were predominant and the BALF total cell counts were higher in the group that had S100A9 levels above 0.5535 ng/mL or a neutrophil percentage above 49.09% (n = 43) than in those with S100A9 levels at or below 0.5535 ng/mL and a neutrophil percentage at or below 49.09% (n = 41) (p = 0.02). Otherwise, there were no differences in age, BMI, smoking status, GAP stage, or lung function. S100A9 levels in lung tissues and BALF cells of patients with idiopathic pulmonary fibrosis measured by immunofluorescence staining To confirm S100A9 expression in the lungs of patients with IPF, S100A9/α-SMA double immunofluorescence staining was performed on lung tissues of three IPF patients and three controls. In the control lung tissues, perivascular and peribronchial areas were stained by both α-SMA and S100A9. In the IPF lung tissues, α-SMA was robustly expressed by interstitial fibroblasts, most of which also expressed S100A9 (Fig. 3 ). To confirm S100A9 expression in the BALF cells of IPF patients, S100A9 and CD163 double immunofluorescence staining was performed. In the cells of these patients, CD163 was robustly expressed by macrophages, most of which also expressed S100A9 (Fig. 3 ). Discussion In this study, we demonstrated that S100A9 levels were significantly higher in BALF from patients with IPF than in BALF from NC subjects, or those with other ILDs. Additionally, S100A9 level of 0.093 ng/ml and 0.0279 ng/mL exhibited high sensitivity and specificity for diagnosing IPF and for differential diagnosis of other ILDs, respectively. Over the past decade, higher concentrations of S100A9 in BALF from IPF patients have been reported compared to patients with other ILDs [ 18 , 19 , 28 , 29 ]. However, these reports have only come from a relatively small number of patients. The concentrations of S100A9 in BALF were inversely correlated with impairments in lung function, as indicated by reduced forced vital capacity and diffusing capacity of carbon monoxide [ 19 ]. Certain concentrations of S100A9 also showed sufficient specificity and sensitivity to distinguish IPF from NSIP and CVD-IP [ 28 ]. Recently, Bennett et al. reported that higher concentrations of S100A9 were related to a more advanced IPF condition, lower lung function values, a shorter distance walked in the 6-minte walk test, and BALF neutrophilia in 30 patients with IPF [ 30 ]. It is important to re-evaluate the clinical implications of these parameters in a larger number of IPF patients. The present study demonstrated that the level of S100A9 in BALF is a surrogate biomarker for survival chances. A cutoff value of 0.5536 ng/mL divided IPF patients into short- and long-term survival groups with a hazard ratio of 3.62. S100A9 is a small calcium-binding protein released by stressed cells that are undergoing necrosis [ 15 ]. S100A9 acts as an endogenous danger signal that accelerates and exacerbates the neutrophilic response in non-infectious inflammation via enhanced chemotaxis of neutrophils and macrophages and modulation of their functions [ 31 , 32 ]. Because of the predominance of neutrophilic inflammation in the lungs of IPF patients [ 6 , 7 ], S100A9 had been presumed to be responsible for the neutrophilic inflammation of IPF. This hypothesis was well demonstrated in the present study by a good correlation between the two parameters. Additionally, a cutoff value of 49.09% for neutrophils in BALF divided patients into short- and long-term survival groups with a hazard ratio of 3.11. Interestingly, when a combined analysis of neutrophil percentage and S100A9 levels was performed, patients with S100A9 levels above 0.5536 ng/mL and a neutrophil percentage above 49.09% had a significantly lower survival rate than those with S100A9 levels at or below 0.5536 and neutrophil percentage at or below 49.09%, with a hazard ratio of 9.28, three times higher than the hazard ratio of the BALF S100A9 level or the neutrophil percentage individually. This indicates that both high levels of S100A9 or high percentages of neutrophils may be related to early mortality in IPF. Thee S100A9 and neutrophils in BALF are known to be involved in the pathogenesis of inflammatory conditions such as asthma [ 33 , 34 ] and COPD [ 35 ], and there is also ample evidence of S100A9 having fibrotic effects. The process of fibrosis has been shown to be mediated by combinatorial signaling pathways that involve components of the TGF-β/CTGF pathway, and also signaling events induced by epidermal growth factor (EGF) and Insulin like growth factor 2 (IGF-2) activated receptors [ 36 ]. S100A9 also stimulates the proliferation of fibroblasts, albeit at higher concentrations than the former factors [ 3 , 5 ]. In addition, S100A9 induces cellular communication network factor 2 (CCN2) mRNA and protein, the latter of which stimulates fibroblast growth and myofibroblast differentiation [ 36 ] via Toll-like receptor 4 (TLR4) and RAGE [ 37 ]. Type 1 alveolar epithelial (AT1) cells [ 38 ] and type 2 alveolar epithelial (AT2) cells [ 39 ] express high levels of RAGE in lung [ 40 ]. S100A9 enhances the basal migratory motility of fibrocytes [ 41 ] and promotes lung fibroblast activation, resulting in the expression of collagen type III and α-smooth muscle actin via the RAGE pathway [ 17 ], and RAGE levels are increased in IPF [ 42 ]. In addition, TLR4 is strongly expressed in parenchymal fibroblasts and infiltrating cells located at fibrotic loci [ 43 ]. Thus, patients with high levels of S100A9 may have a more rapid fibrotic process that leads to a lower survival rate. One limitation of this study is that it did not measure other mediators of IPF besides neutrophils. In this study, some patients with low levels of S100A9 and a high neutrophil percentage also showed early mortality. This indicates that mediators other than S100A9 produced from neutrophils may contribute to early mortality in IPF. Neutrophil elastase degrades various ECM components [ 13 ] and leads to fibroblast proliferation and myofibroblast differentiation in a SMAD-dependent but TGF-β-independent fashion [ 14 ]. An additional mediator is the neutrophil extracellular trap, a major product of neutrophils that promotes fibrosis via TGF-β1 production and subsequent myofibroblast activation [ 44 ]. Thus, these mediators should be evaluated and analyzed for their role in IPF mortality in the future. Conclusion To understand the role of S100A9 in neutrophilic inflammation related to IPF, S100A9 concentrations were measured in BALF. The levels of S100A9 were significantly higher in IPF patients than in NC subjects and patients with other ILDs. Furthermore, the levels of S100A9 had good discriminating power for the differential diagnosis of IPF. The survival rates were significantly lower in IPF patients that had higher S100A9 levels and neutrophil percentages than those with lower S100A9 levels and neutrophil percentages. These results suggest that S100A9 participates in the development and progression of IPF, and that the IPF levels in BALF could be used as a surrogate marker for diagnosing IPF and predicting prognosis. Abbreviations IPF: Idiopathic pulmonary fibrosis, ECM: extracellular matrix, BAL: bronchoalveolar lavage, NC: normal controls, NSIP: non-specific interstitial pneumonia, HP: hypersensitivity pneumonitis, ROC: receiver operating characteristic Declarations Ethics approval and consent to participate It was writing at the materials and methods sections; as follows: The study protocol was approved by institutional review board (IRB) in the Soonchunhyang University hospital ethics committee (medicine 2018-10). Consent for publication All authors have read and approved the submission of manuscript. Competing interests The authors declare that they have no competing interests. Availability of data and materials Available Funding This study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Education ( 2017R1A2B4012693 ) and a research grant from Soonchunhyang University to JS Park. JU Lee was supported by the Basic Science Research Program of NRF (2018R1A6A3A01011004). Authors’ contributions JU Lee and CS Park conceived and designed the experiments, JU Lee, RH Kim, JS Park and ES Go performed IF stain, IHC stain and ELISA, CS Park and JS Park provided clinical samples, JS Park, HS Chang and JU Lee performed statistical analysis, Lee JU, HS Chang and CS Park wrote the manuscript. Acknowledgements The samples were generously provided by a Biobank in Soonchunhyang University, Bucheon Hospital. References Selman M, King TE, Pardo A: Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy . Annals of internal medicine 2001, 134 (2):136-151. Kim DS, Collard HR, King TE, Jr.: Classification and natural history of the idiopathic interstitial pneumonias . Proceedings of the American Thoracic Society 2006, 3 (4):285-292. Chambers RC, Mercer PF: Mechanisms of alveolar epithelial injury, repair, and fibrosis . Ann Am Thorac Soc 2015, 12 Suppl 1 (Suppl 1):S16-S20. Cheresh P, Kim SJ, Tulasiram S, Kamp DW: Oxidative stress and pulmonary fibrosis . Biochimica et biophysica acta 2013, 1832 (7):1028-1040. Wynn TA: Integrating mechanisms of pulmonary fibrosis . The Journal of experimental medicine 2011, 208 (7):1339-1350. Kinder BW, Brown KK, Schwarz MI, Ix JH, Kervitsky A, King TE, Jr.: Baseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis . Chest 2008, 133 (1):226-232. Watters LC, Schwarz MI, Cherniack RM, Waldron JA, Dunn TL, Stanford RE, King TE: Idiopathic pulmonary fibrosis. Pretreatment bronchoalveolar lavage cellular constituents and their relationships with lung histopathology and clinical response to therapy . The American review of respiratory disease 1987, 135 (3):696-704. Desai O, Winkler J, Minasyan M, Herzog EL: The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis . Front Med (Lausanne) 2018, 5 :43-43. Tabuena RP, Nagai S, Tsutsumi T, Handa T, Minoru T, Mikuniya T, Shigematsu M, Hamada K, Izumi T, Mishima M: Cell profiles of bronchoalveolar lavage fluid as prognosticators of idiopathic pulmonary fibrosis/usual interstitial pneumonia among Japanese Patients . Respiration; international review of thoracic diseases 2005, 72 (5):490-498. Ziegenhagen MW, Zabel P, Zissel G, Schlaak M, Muller-Quernheim J: Serum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity . American journal of respiratory and critical care medicine 1998, 157 (3 Pt 1):762-768. Inage M, Nakamura H, Kato S, Saito H, Abe S, Hino T, Tomoike H: Levels of cytokeratin 19 fragments in bronchoalveolar lavage fluid correlate to the intensity of neutrophil and eosinophil-alveolitis in patients with idiopathic pulmonary fibrosis . Respiratory medicine 2000, 94 (2):155-160. Giannandrea M, Parks WC: Diverse functions of matrix metalloproteinases during fibrosis . Disease models & mechanisms 2014, 7 (2):193-203. Chua F, Dunsmore SE, Clingen PH, Mutsaers SE, Shapiro SD, Segal AW, Roes J, Laurent GJ: Mice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis . The American journal of pathology 2007, 170 (1):65-74. Gregory AD, Kliment CR, Metz HE, Kim KH, Kargl J, Agostini BA, Crum LT, Oczypok EA, Oury TA, Houghton AM: Neutrophil elastase promotes myofibroblast differentiation in lung fibrosis . Journal of leukocyte biology 2015, 98 (2):143-152. Foell D, Wittkowski H, Vogl T, Roth J: S100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules . Journal of leukocyte biology 2007, 81 (1):28-37. Shibata F, Miyama K, Shinoda F, Mizumoto J, Takano K, Nakagawa H: Fibroblast growth-stimulating activity of S100A9 (MRP-14) . European journal of biochemistry 2004, 271 (11):2137-2143. Xu X, Chen H, Zhu X, Ma Y, Liu Q, Xue Y, Chu H, Wu W, Wang J, Zou H: S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-kappaB-dependent pathways . Clinical and experimental immunology 2013, 173 (3):523-535. Bargagli E, Olivieri C, Prasse A, Bianchi N, Magi B, Cianti R, Bini L, Rottoli P: Calgranulin B (S100A9) levels in bronchoalveolar lavage fluid of patients with interstitial lung diseases . Inflammation 2008, 31 (5):351-354. Bargagli E, Olivieri C, Cintorino M, Refini RM, Bianchi N, Prasse A, Rottoli P: Calgranulin B (S100A9/MRP14): a key molecule in idiopathic pulmonary fibrosis? Inflammation 2011, 34 (2):85-91. Selman M, Pardo A, King Jr TE: Hypersensitivity pneumonitis: insights in diagnosis and pathobiology . American journal of respiratory and critical care medicine 2012, 186 (4):314-324. Parrish S, Turner J: Diagnosis of sarcoidosis . Disease-a-Month 2009, 55 (11):693-703. Baughman RP, Culver DA, Judson MA: A concise review of pulmonary sarcoidosis . American journal of respiratory and critical care medicine 2011, 183 (5):573-581. Travis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M, Wells AU: An official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias . American journal of respiratory and critical care medicine 2013, 188 (6):733-748. Society AT: This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001 . Am J Respir Crit Care Med 2002, 165 :277-304. Travis WD, Hunninghake G, King Jr TE, Lynch DA, Colby TV, Galvin JR, Brown KK, Chung MP, Cordier J-F, Du Bois RM: Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project . American journal of respiratory and critical care medicine 2008, 177 (12):1338-1347. Park S-W, Ahn M-H, Jang HK, Jang AS, Kim D-J, Koh E-S, Park J-S, Uh S-T, Kim YH, Park JS: Interleukin-13 and its receptors in idiopathic interstitial pneumonia: clinical implications for lung function . Journal of Korean medical science 2009, 24 (4):614-620. Budczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, Denkert C: Cutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization . PloS one 2012, 7 (12):e51862. Hara A, Sakamoto N, Ishimatsu Y, Kakugawa T, Nakashima S, Hara S, Adachi M, Fujita H, Mukae H, Kohno S: S100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis . Respiratory medicine 2012, 106 (4):571-580. Korthagen NM, Nagtegaal MM, van Moorsel CH, Kazemier KM, van den Bosch JM, Grutters JC: MRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases . Clinical and experimental immunology 2010, 161 (2):342-347. Bennett D, Salvini M, Fui A, Cillis G, Cameli P, Mazzei MA, Fossi A, Refini RM, Rottoli P: Calgranulin B and KL-6 in Bronchoalveolar Lavage of Patients with IPF and NSIP . Inflammation 2019, 42 (2):463-470. Ryckman C, McColl SR, Vandal K, de Medicis R, Lussier A, Poubelle PE, Tessier PA: Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis . Arthritis and rheumatism 2003, 48 (8):2310-2320. Cesaro A, Anceriz N, Plante A, Page N, Tardif MR, Tessier PA: An inflammation loop orchestrated by S100A9 and calprotectin is critical for development of arthritis . PloS one 2012, 7 (9):e45478. Lee TH, Jang AS, Park JS, Kim TH, Choi YS, Shin HR, Park SW, Uh ST, Choi JS, Kim YH et al : Elevation of S100 calcium binding protein A9 in sputum of neutrophilic inflammation in severe uncontrolled asthma . Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 2013, 111 (4):268-275.e261. Lee TH, Chang HS, Bae DJ, Song HJ, Kim MS, Park JS, Jun JA, Lee SY, Uh ST, Kim SH et al : Role of S100A9 in the development of neutrophilic inflammation in asthmatics and in a murine model . Clinical immunology (Orlando, Fla) 2017, 183 :158-166. Pouwels SD, Nawijn MC, Bathoorn E, Riezebos-Brilman A, van Oosterhout AJ, Kerstjens HA, Heijink IH: Increased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients . The European respiratory journal 2015, 45 (5):1482-1485. Grotendorst GR, Rahmanie H, Duncan MR: Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation . FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2004, 18 (3):469-479. Nikitorowicz-Buniak J, Shiwen X, Denton CP, Abraham D, Stratton R: Abnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhanced secretion of CCN2 and S100A9 . The Journal of investigative dermatology 2014, 134 (11):2693-2702. Dahlin K, Mager EM, Allen L, Tigue Z, Goodglick L, Wadehra M, Dobbs L: Identification of genes differentially expressed in rat alveolar type I cells . American journal of respiratory cell and molecular biology 2004, 31 (3):309-316. Katsuoka F, Kawakami Y, Arai T, Imuta H, Fujiwara M, Kanma H, Yamashita K: Type II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene . Biochemical and biophysical research communications 1997, 238 (2):512-516. Englert JM, Hanford LE, Kaminski N, Tobolewski JM, Tan RJ, Fattman CL, Ramsgaard L, Richards TJ, Loutaev I, Nawroth PP et al : A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis . The American journal of pathology 2008, 172 (3):583-591. Wang CH, Punde TH, Huang CD, Chou PC, Huang TT, Wu WH, Liu CH, Chung KF, Kuo HP: Fibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation . The Journal of allergy and clinical immunology 2015, 135 (5):1154-1162.e1151-1155. Kyung SY, Byun KH, Yoon JY, Kim YJ, Lee SP, Park JW, Lee BH, Park JS, Jang AS, Park CS et al : Advanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP . International journal of clinical and experimental pathology 2014, 7 (1):221-228. Bhattacharyya S, Kelley K, Melichian DS, Tamaki Z, Fang F, Su Y, Feng G, Pope RM, Budinger GR, Mutlu GM et al : Toll-like receptor 4 signaling augments transforming growth factor-beta responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma . The American journal of pathology 2013, 182 (1):192-205. Chrysanthopoulou A, Mitroulis I, Apostolidou E, Arelaki S, Mikroulis D, Konstantinidis T, Sivridis E, Koffa M, Giatromanolaki A, Boumpas DT et al : Neutrophil extracellular traps promote differentiation and function of fibroblasts . The Journal of pathology 2014, 233 (3):294-307. Tables Table 1. Clinical characteristics of study participants who underwent bronchoalveolar lavage Parameters NC IPF ILDs NSIP HP Sarcoidosis Number of subjects 33 87 22 19 10 Age (year) 55 (35–72) 63.8 (32–86)* 60.1 (39–70) 51.3 (28–70) 43.3 (28–69) Sex (male/female) 20/13 54/33 9/13 10/9 6/4 Smoking (CS/ES/NS) 2/1/30 38/29/20 2/5/12 3/2/13 3/2/5 FVC (% pred.) 106.1 (87.0–119) 75.0 (63.7–83.0)* 78.0 (66.0–91.8)* 64.5 (57.0–82.5)* 77.0 (65.0–86.0)* FEV1 (% pred.) 102.1 (88.2–117) 89.0 (77.5–100.5)* 85.0 (73.8–101.3)* 74.5 (64.3–92.0)* 85.0 (64.0–101.0)* DLCO (% pred.) NA 64.0 (38.5–72.5)* 76.0 (59.0–92.0)* 67.0 (55.0–90.0)* 75.5 (57.8–84.5)* dFVC (%/year) NA −7.0 (−16.5–0.0) NA NA NA dDLco (%/year) NA -13(-30-0) -5(-20.5-0) NA NA Follow-up (years) NA 4.1 (2.1–6.3) ND ND ND BALF total cells (10 4 /mL) 3.42±0.96 5.61±3.71* 6.09±2.74* 6.12±3.79* 4.31±2.92* Macrophages (10 4 /mL) 3.25±0.93 3.43±2.24* 3.16±1.89* 3.19±2* 3.71±2.76* Neutrophils (10 4 /mL) 0.08±0.07 1.66±2.3* 2.44±2.23* 2.7±2.89* 0.37±0.4* Eosinophils (10 4 /mL) 0.02±0.03 0.29±1.1* 0.17±0.27* 0.17±0.21* 0.01±0.01* Lymphocytes (10 4 /mL) 0.07±0.06 0.23±0.25* 0.32±0.29* 0.41±0.43* 0.22±0.18* IPF, idiopathic pulmonary fibrosis, NSIP, non-specific interstitial fibrosis; HP, hypersensitivity pneumonitis; CS/ES/NS: current smoker/ex-smoker/never smoker; ND, not determined, NA, not applicate; dFVC (%)/year, annual decline rate of forced vital capacity (FVC); dDLco (%/year),annual decline rate of diffusing capacity of the lungs for carbon monoxide (DLco). Patient characteristics and pulmonary function test results are shown as medians (inter-quartile range). Groups among the normal controls and the IPF, NSIP, HP, and sarcoidosis patients were calculated with a Kruskal–Wallis analysis of variance (ANOVA) with the Mann–Whitney U as the post-hoc test. BALF cell numbers are shown as mean ± standard error of the mean (SEM) and were calculated with a one-way ANOVA and Tukey's honestly significant difference test as the post-hoc test among the five groups. Significance: compared with control, *P < 0.05; compared with IPF, †P < 0.05; compared with NSIP and HP, #P 0.5536 ng/mL or Neu % > 49.09% S100A9 ≤ 0.5536 ng/mL and Neu % ≤ 49.09% P value Number of subjects 43 41 - Age (years) 65 (56.5–73) 63 (59–68) 0.3423 BMI 23.34 (22.16–24.84) 21.97 (19.77–24.03) 0.0417 Sex (male/female) 22/21 31/10 0.0202 Smoking (CS/ES/NS) 21/12/10 15/17/9 0.3929 Gap score 2 (2–5) 4 (2.5–4.25) 0.6914 FVC (% pred.) 75.86 ± 14.84 77.07 ±17.5 0.5788 FEV1 (% pred.) 89.93 ± 16.44 91.32 ± 19.19 0.7169 DLCO (% pred.) 67.02 ± 23.18 70.25 ± 16.99 0.2102 dFVC (%/year) –7.74 ± 18.26 –12.33 ± 13.23 0.3590 dDLco (%/year) –15.1 ± 18.35 –20.85 ± 16.05 0.0586 Follow-up duration (years) 4.06 (2.57-5.94) 4.25 (2.17–7.02) 0.5373 Survival/death 28/15 39/2 0.5603 BAL total cell count (10 4 /mL) 6.9 ± 4.59 4.36 ± 1.96 0.0016 Macrophages (10 4 /mL) 3.58 ± 2.88 3.31 ± 1.41 0.2808 Neutrophils (10 4 /mL) 2.62 ± 2.91 0.71 ± 0.71 3.82E-08 Eosinophils (10 4 /mL) 0.44 ± 1.53 0.14 ± 0.25 0.2369 Lymphocytes (10 4 /mL) 0.27 ± 0.28 0.21 ± 0.22 0.5357 CS/ES/NS, current smoker/ex-smoker/never smoker; dFVC (%)/year, annual decline rate of forced vital capacity (FVC); dDLco (%/year), annual rate of diffusing capacity of the lungs for carbon monoxide (DLco). Differences in patient characteristics and pulmonary function test results are shown as medians (inter-quartile range). Bronchoalveolar lavage (BAL) cell numbers are shown as mean ± standard error of the mean (SEM). Supplemental Information Note Supplemental Figure . S100A9 protein concentrations in BAL fluids from IPF patients according to the GAP stage, smoking, and sex. Comparisons of S100A9 protein levels according to (A) the GAP stage (B) smoking status, and (C) sex. Supplementary Files SupplementalTables.docx SupplementalFigure.tif Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-20772","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":463247,"identity":"e08a4142-5a86-4c86-8419-55211960f6fa","order_by":1,"name":"Jong-Uk Lee","email":"","orcid":"","institution":"Soonchunhyang University Hospital Bucheon","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jong-Uk","middleName":"","lastName":"Lee","suffix":""},{"id":463248,"identity":"4bd799eb-b086-40f1-928d-0e511f1510d3","order_by":2,"name":"Jong-Sook Park","email":"","orcid":"","institution":"Soonchunhyang University Hospital Bucheon","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jong-Sook","middleName":"","lastName":"Park","suffix":""},{"id":463249,"identity":"03a0f66e-7664-4a9d-8b39-9c4947733233","order_by":3,"name":"Myung-Shin Kim","email":"","orcid":"","institution":"Soonchunhyang University Hospital Gumi","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Myung-Shin","middleName":"","lastName":"Kim","suffix":""},{"id":463250,"identity":"dfd369b6-4653-48f8-877d-c1aa7c05ca07","order_by":4,"name":"Jai-Seong Park","email":"","orcid":"","institution":"Soonchunhyang University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jai-Seong","middleName":"","lastName":"Park","suffix":""},{"id":463251,"identity":"cfefdab3-0e48-47ac-ba33-838b7d0a42a6","order_by":5,"name":"Eun-Suk Go","email":"","orcid":"","institution":"Soonchunhyang University College of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Eun-Suk","middleName":"","lastName":"Go","suffix":""},{"id":463252,"identity":"59c4f300-956b-4825-bebc-ec1056ba7df5","order_by":6,"name":"Hun Soo Chang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYBACAwYGNhAtx8DAAxMgUosx6VoSG4jWYs5/+NmDnztq0+e3nz3A8KOGwdi8gYAWyxlp5oa9Z47nbjiTl8DYc4zBTOYAIYfd4GGT4G07lrtBgseAgbeBwUaCoF/On2GT/Nt2LF1+Bo8B41+itBzIYZPmbatJYLjBY8AMtMWMsJYbaWbSsm0HDDecyTE4LHNMwpgIhx1+Jvm2rU5evv2M4cM3NTaGMwhpgYLDYPIAAwNBO+CgjmiVo2AUjIJRMAIBAA/2OkGVnq9pAAAAAElFTkSuQmCC","orcid":"","institution":"Soonchunhyang University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Hun","middleName":"Soo","lastName":"Chang","suffix":""},{"id":463253,"identity":"00746d53-5011-4736-810d-9e2d66fdf433","order_by":7,"name":"Choon-Sik Park","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuklEQVRIiWNgGAWjYFCCBDBpwA9lkKBFsgGqhYdoLQYHiNWi2578+HNBzT1j4+PJz6RuMNyRsyekxezMMzPpGceKzcCMHIZnxgRtMbuRw8bMw5ZgY3YjAaTlcGIPEVqYP/P8S7AxnpH+DaSlnhgtDNK8bQlmBhI5YFsSCDsM5IWZfQnGEmfeFFvnGBw27DlASMtxUIh9SzDsb0/feDun4rA8ewMha4CAGcE0IEI5mpZRMApGwSgYBVgAANEtPebvmop2AAAAAElFTkSuQmCC","orcid":"","institution":"Soonchunhyang University Hospital Bucheon","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Choon-Sik","middleName":"","lastName":"Park","suffix":""}],"badges":[],"createdAt":"2020-04-01 14:19:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-20772/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-20772/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":832212,"identity":"862c9bfb-4ad1-4595-abe9-d28a6336da3d","added_by":"auto","created_at":"2020-04-03 14:54:50","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":154446,"visible":true,"origin":"","legend":"S100A9 concentrations, correlation with neutrophil percentage in BALF, and receiver operating characteristic (ROC) analysis. (A) S100A9 was detected in 12 of 33 normal controls, 76 of 87 IPF patients, 17 of 22 NSIP patients, 15 of 19 HP patients, and six of 10 sarcoidosis patients. The data are presented as medians (inter quartile range). * P \u003c 0.05; ** P \u003c 0.01. (B) Correlation between S100A9 levels and neutrophil percentages in BALF (n = 87, r = 0.356, p = 0.007). (C) ROC curves of S100A9 concentrations in the IPF and NC groups. A cutoff value of 0.093 ng/mL had an area under the ROC curve (AUC) of 0.833, a specificity of 78.79%, and a sensitivity of 81.61% for differentiating IPF patients from normal controls. (D) A cutoff level of 0.0279 ng/mL S100A9 exhibited a specificity of 72.73% and a sensitivity of 76.47% for distinguishing between IPF patients and those with other interstitial lung diseases (AUC = 0.735).","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-20772/v1/1.png"},{"id":832214,"identity":"62fd848a-df17-4ddf-8a1d-1b50eaa94a88","added_by":"auto","created_at":"2020-04-03 14:54:51","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":198799,"visible":true,"origin":"","legend":"Survival rates in relation to S100A9 levels and neutrophil percentages in BALF from idiopathic pulmonary fibrosis (IPF) patients. A Kaplan–Meier plot was used to analyze 84 subjects with IPF who were followed for one to ten years. (A) Comparison of survival rates of the group with S100A9 levels above 0.5536 ng/ml (n = 49, solid line) and that with S100A9 levels at or below 0.5536 ng/ml (n = 35, dotted line) (HR = 3.62; 95% CI, 1.13–11.63; p = 0.021). (B) Comparison of survival rates of the group with a neutrophil percentage above 49.09% (n = 67, solid line) and that with a neutrophil percentage at or below 49.09% (n = 17, dotted line) (HR = 3.11; 95% CI, 1.5–11.26; p = 0.003). (C) Comparison of survival rates in patients with S100A9 levels above 0.5536 ng/mL (n = 41) or a neutrophil percentage above 49.09% (n = 43, solid line), and those with S100A9 levels at or below 0.5536 ng/mL and a neutrophil percentage at or below 49.09% (n = 41, dotted line) (HR = 9.28; 95% CI, 2.08–41.26; p = 0.0004). Neu %, neutrophil percentage; HR, hazard ratio.","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-20772/v1/2.png"},{"id":832215,"identity":"dec2aa82-33e7-494d-a57f-364d5e152c56","added_by":"auto","created_at":"2020-04-03 14:54:51","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1200537,"visible":true,"origin":"","legend":"","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-20772/v1/3.png"},{"id":13496852,"identity":"f3e9d548-d377-44b5-b49f-8cf52b3e77be","added_by":"auto","created_at":"2021-09-16 22:51:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2407182,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-20772/v1/0df742ae-7c4b-44a6-8f63-0c2cf338201f.pdf"},{"id":832213,"identity":"6bb910e4-1471-41d7-846f-6dec8b127ae5","added_by":"auto","created_at":"2020-04-03 14:54:51","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":19743,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTables.docx","url":"https://assets-eu.researchsquare.com/files/rs-20772/v1/Supplemental Tables.docx"},{"id":832211,"identity":"407b5218-7892-4638-bb94-b6b56685c9f0","added_by":"auto","created_at":"2020-04-03 14:54:50","extension":"tif","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":78018,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalFigure.tif","url":"https://assets-eu.researchsquare.com/files/rs-20772/v1/Supplemental Figure.tif"}],"financialInterests":"","formattedTitle":"Upregulation of S100 Calcium-Binding Protein A9 levels in the lungs of patients with idiopathic pulmonary fibrosis","fulltext":[{"header":"Introduction","content":" \u003cp\u003eIdiopathic interstitial pneumonia (IIP) is a group of lung diseases whose etiology is unknown. IIP is characterized by an accumulation of inflammatory cells in the pulmonary parenchyma and interstitium that leads to fibrosis. Idiopathic pulmonary fibrosis (IPF), the most common form of IIP, results in gradual deterioration with a diverse clinical course [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The poor prognosis of IPF is due to alveolar epithelial injury and abnormal repair mechanisms that ultimately develop into irreversible pulmonary fibrosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Abnormalities in multiple biological pathways lead to processes related to the pathogenesis of IPF, and affect inflammation and wound repair. The processes and factors include the clotting cascade, oxidant\u0026ndash;antioxidant pathways, apoptosis, inflammatory cytokines, angiogenesis, vascular remodeling, growth factors, surfactants, and matrix regulatory factors [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Among the inflammatory patterns, neutrophilic inflammation is predominant in bronchoalveolar lavage fluid (BALF) of IPF patients [\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and is related to early mortality in these patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Levels of the neutrophil chemoattractant CXCL8 are higher in the BALF and serum of patients with IPF [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. In addition, levels of the alveolar epithelial marker cytokeratin 19 are correlated with neutrophil infiltration, suggesting a relationship between epithelial injury and neutrophilic inflammation [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNeutrophilic inflammation was recently revealed as being related to fibrosis. In neutrophilic inflammation, neutrophil granules release neutrophil elastase (NE) and matrix-degrading proteins such as matrix metalloproteinases (MMPs), which are the main tissue destructive agents and are heavily involved in matrix degradation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. NE increases in the lungs of IPF patients [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and regulates the degradation of the extracellular matrix (ECM) into collagens I, II, III, IV, fibronectin, laminin, and elastin. It also induces fibroblast proliferation and myofibroblast differentiation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eS100A9 is one of the main mediators of neutrophils and macrophages and is now considered a damage-associated molecular pattern protein (DAMP) because it exists intracellularly and is released upon activation or damage under conditions of cellular stress [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. S100A9 has the potential to cause fibroblast proliferation [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], and to upregulate collagen type III α-smooth muscle actin and the receptor for advanced glycation end-product expression (RAGE) [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Higher concentrations of S100A9 have been reported in the BALF of patients with IPF than in that from patients with other ILDs, including sarcoidosis, non-specific interstitial pneumonia (NSIP), and pulmonary fibrosis associated with connective tissue diseases that have a potential biomarker [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. However, previous studies have provided only limited information since they had a small number of subjects. Therefore, we measured the concentrations of S100A9 in BALF to evaluate the association between S100A9 and the development of IPF. We also investigated the clinical impact of IPF, particularly the long-term survival rate in a relatively large number of subjects and those with ILDs.\u003c/p\u003e "},{"header":"Materials And Methods","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy subjects\u003c/h2\u003e \u003cp\u003eLung tissues and BALF from study subjects were obtained from the biobank of Soonchunhyang University Hospital, Bucheon, Korea (Schbc-biobank-18101601-14-01). The study protocol was approved by the Ethics Committee of Soonchunhyang University Hospital (Schbc-medicine-2018-10). Informed written consent for study participation was obtained from the subjects, and a sample donation was obtained from each subject. All subjects were examined by physicians and underwent a chest X-ray, high-resolution chest computed tomography (HRCT), and pulmonary function tests. There was no evidence of any underlying collagen vascular diseases in IPF patients according to their laboratory results and clinical symptoms. The diagnostic criteria for IPF, hypersensitivity pneumonitis (HP), NSIP, and sarcoidosis were established based on an international consensus statement [\u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. IPF was diagnosed by the presence of usual interstitial pneumonia (UIP) patterns in the pathological specimens (surgical IPF) and/or by HRCT in patients who did not undergo surgical lung biopsy (clinical IPF). Two pathologists examined each slide independently after being informed of the subjects\u0026rsquo; sex, age, and HCRT results. Pathological recognition of the NSIP pattern included two major aspects: (1) exclusion of other patterns of interstitial lung diseases, and (2) categorization of the histological features according to the ATS/ERS 2002 classification [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] and the modified histological definition of the NSIP pattern [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. HP was diagnosed by the presence of clinical symptoms compatible with non-necrotizing granulomatous bronchiolocentric pneumonitis [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The diagnosis of sarcoidosis was based on histological evidence of non-caseating granuloma and compatible clinical images [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. HP and sarcoidosis were diagnosed after excluding other diseases with similar histological profiles. Biopsy tissues were subjected to acid-fast bacillus and G\u0026ouml;m\u0026ouml;ri methenamine silver staining to verify the absence of microorganisms and fungi. The serial diffusing capacity of lungs for carbon monoxide (DLCO) and forced vital capacity (FVC) were measured, and the annual rate of decline was estimated as follows: (last FVC [or DLCO]\u0026thinsp;\u0026minus;\u0026thinsp;baseline FVC [or DLCO])/baseline FVC [or DLCO]/follow-up years. Normal controls (NC) exhibited no respiratory symptoms as determined by a screening questionnaire and had a predicted forced expiratory volume at 1 second (FEV1) and FVC\u0026thinsp;\u0026gt;\u0026thinsp;80% and normal chest radiograms.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eBronchoalveolar lavage fluids procedure\u003c/h2\u003e \u003cp\u003eThe bronchial alveolar lavage fluid (BALF) procedure was performed in lung segments that were not under immunosuppressive therapy, were in the right middle lobe of the NCs, and exhibited the greatest disease involvement when HRCT was done, as described previously [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. A cytocentrifuge was used to prepare the cells, which were then mounted on slides and stained with Diff-Quik stain. A hemocytometer was used to differentially count the cells to a total count of 500 cells. The supernatants were isolated using centrifugation (500\u0026thinsp;\u0026times;\u0026thinsp;\u003cspan type=\"Italic\" class=\"Italic\" name=\"Emphasis\"\u003eg\u003c/span\u003e, 5\u0026nbsp;min) and stored at \u0026minus;\u0026thinsp;80\u0026nbsp;\u0026deg;C.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEnzyme-linked immunosorbent assay (ELISA) of S100A9 in BALF\u003c/h2\u003e \u003cp\u003eThe S100A9 level in the supernatants was measured using an ELISA (MyBioSource, San Diego, CA, USA) according to the manufacturer\u0026rsquo;s recommendations. The lower limit of detection was 0.1\u0026nbsp;ng/mL, and values below this limit were set to 0. The inter- and intra-assay coefficients of variation were below 15%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eImmunofluorescence stain of S100A9 in bronchial alveolar lavage fluid cells and lung tissues\u003c/h2\u003e \u003cp\u003eTissue sections were deparaffinized and rehydrolyzed, and BALF cell slides were fixed with 0.4% cold paraformaldehyde for 30 minutes at room temperature. The sections were then incubated overnight at 4\u0026nbsp;\u0026deg;C with macrophage markers, including monoclonal anti-human S100A9 monoclonal mouse antibody (1:200 dilution; Novus Biological, Littleton, CA, USA), polyclonal anti-human α-SMA antibody (1:200 dilution; Abcam, Cambridge, MA, USA), and monoclonal goat anti-CD163 antibody (1:200 dilution, Hycult Biotech, Uden, PB, Netherlands). The sections were also incubated with monoclonal rabbit anti-neutrophil elastase antibody (1:100 dilution; Abcam, Cambridge, MA, UK) as a neutrophil marker. Tissue sections were deparaffinized and rehydrolyzed, and BALF cell slides were fixed with 0.4% cold paraformaldehyde for 30 minutes at room temperature. The sections were incubated for 1 hour in an Fc receptor blocking agent (FC blocker, Innovex Biosciences, Richmond, CA, USA) containing 5% bovine serum albumin (BSA) to block non-specific binding. The sections were then incubated overnight at 4\u0026nbsp;\u0026deg;C with macrophage markers, including monoclonal anti-human S100A9 monoclonal mouse antibody (1:200 dilution; Novus Biological, Littleton, CA, USA), polyclonal anti-human α-SMA antibody (1:200 dilution; Abcam, Cambridge, MA, USA), and monoclonal goat anti-CD163 antibody (1:200 dilution, Hycult Biotech, Uden, PB, Netherlands). The sections were also incubated with monoclonal rabbit anti-neutrophil elastase antibody (1:100 dilution; Abcam, Cambridge, MA, UK) as a neutrophil marker. Additional details are provided in the on-line supplement. After washing three times with Tris Buffered Saline (TBS), the slides were incubated for 1 hour at room temperature with the following fluorescent secondary antibodies: anti-rabbit IgG H\u0026amp;L (FITC) (1:1,000 dilution; Abcam, Cambridge, MA, UK), anti-mouse IgG H\u0026amp;L (PE) (1:1,000 dilution; Abcam, Cambridge, MA, UK), and anti-goat IgG H\u0026amp;L (PE) (1:1,000 dilution; Abcam, Cambridge, MA, UK). After washing in TBS, the slides were incubated for 3 minutes at room temperature with 4\u0026prime;,6-diamidino-2-phenylindole (DAPI) (Sigma-Aldrich, St. Louis, USA) and observed under a confocal laser scanning microscope (LSM 510 META, Zeiss, Jena, Germany).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe Kruskal\u0026ndash;Wallis test and the post-hoc Mann\u0026ndash;Whitney U test were used to compare the S100A9 levels between groups. Correlations between the S100A9 levels and other parameters were analyzed using Spearman\u0026rsquo;s correlation coefficient. The data are presented as medians in the 25% and 75% quartiles for variables with a skewed distribution, or as a mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard error of the mean for variables with a normal distribution. Receiver operating characteristic (ROC) analysis was performed, and the area under the ROC curve (AUC) and cutoff values were determined using MedCalc statistical software. Optimal cutoff levels of S100A9 and the neutrophil percentage were calculated using Cutoff Finder [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Survival rates were estimated using the Kaplan\u0026ndash;Meier method and compared using a log-rank test. The data were analyzed using SPSS software v. 20.0. Values of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n\u003cp\u003e\u003cstrong\u003eStudy group patient demographic characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBALFs were obtained from patients with IPF (n\u0026thinsp;=\u0026thinsp;87) and those with ILDs including NSIP (n\u0026thinsp;=\u0026thinsp;22), HP (n\u0026thinsp;=\u0026thinsp;19), and sarcoidosis (n\u0026thinsp;=\u0026thinsp;10). BALFs were also obtained from NC patients (n\u0026thinsp;=\u0026thinsp;33). The clinical characteristics of all patients are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The BALFs of patients with IPF and ILDs had significantly higher numbers of macrophages, neutrophils, lymphocytes, and eosinophils compared to NC patients. They also had lower FVC and FEV1 values than those of NCs (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eS100A9 levels in BALFs of patients with IPF or other ILDs and normal controls\u003c/strong\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n\u003cp\u003eThe levels of S100A9 were significantly higher in BALF from patients with IPF than in that from NC patients (IPF, 0.4 [0.18\u0026ndash;0.9] ng/mL vs. 0 [0\u0026ndash;0.5] ng/mL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; HP, 0.19 [0.07\u0026ndash;0.33] ng/mL, p\u0026thinsp;=\u0026thinsp;0.043; sarcoidosis, 0.06 [0\u0026ndash;0.11] ng/mL, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). However, the S100A9 levels were not different from those with NSIP (0.28 [0.07\u0026ndash;0.52] ng/mL, p\u0026thinsp;=\u0026thinsp;0.1933) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eA). The S100A9 levels significantly correlated with neutrophil counts in the BALF of patients with IPF (n\u0026thinsp;=\u0026thinsp;87, r\u0026thinsp;=\u0026thinsp;0.356, p\u0026thinsp;=\u0026thinsp;0.0007) (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eB). The ROC curve showed a clear distinction between the IPF patients and the NCs (AUC\u0026thinsp;=\u0026thinsp;0.833, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eC). A cutoff level of 0.093\u0026nbsp;ng/mL S100A9, determined from the ROC curve, showed a specificity of 78.79% and a sensitivity of 81.61% for differentiating IPF patients from NCs. A cutoff level of 0.0279\u0026nbsp;ng/mL S100A9 exhibited a specificity of 72.73% and a sensitivity of 76.47% for distinguishing patients with IPF from those with other ILDs (AUC\u0026thinsp;=\u0026thinsp;0.735, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003eD).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan class=\"Bold\"\u003eSurvival rates and clinical features in relation to S100A9 levels and percentage of neutrophils in BALF from IPF patients\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEighty-four patients with IPF were followed for 1 to 10\u0026nbsp;years. Cutoff values for the S100A9 level and the neutrophil percentage were chosen, and the subjects were divided into two groups. With a cutoff value of 0.5536\u0026nbsp;ng/mL, the survival rate was significantly lower in the group with a S100A9 level above 0.5536\u0026nbsp;ng/mL (n\u0026thinsp;=\u0026thinsp;35) than in the group that had a S100A9 level at or below 0.5536\u0026nbsp;ng/mL (n\u0026thinsp;=\u0026thinsp;49; hazard ratio (HR), 3.62, 95% confidence interval (CI), 1.13\u0026ndash;11.63; p\u0026thinsp;=\u0026thinsp;0.021, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eA). With a cutoff value of 49.09% neutrophils, the survival rate was significantly lower in the group with a neutrophil percentage above 49.09% (n\u0026thinsp;=\u0026thinsp;17) compared with the group with a neutrophil percentage at or below 49.09% (n\u0026thinsp;=\u0026thinsp;67; HR, 3.11; 95% CI, 1.5\u0026ndash;11.26; p\u0026thinsp;=\u0026thinsp;0.003, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eB). A combined analysis of the neutrophil percentage and the S100A9 levels in BALF was performed with respect to the survival rate. Patients with an S100A9 level above 0.5536\u0026nbsp;ng/mL or a neutrophil percentage above 49.09% (n\u0026thinsp;=\u0026thinsp;43) had a significantly lower survival rate than those with S100A9 levels at or below 0.5536\u0026nbsp;ng/mL and a neutrophil percentage at or below 49.09% (n\u0026thinsp;=\u0026thinsp;41; HR, 9.28; 95% CI, 2.08\u0026ndash;41.26; p\u0026thinsp;=\u0026thinsp;0.0004, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eC). Patients that had S100A9 levels above 0.5536\u0026nbsp;ng/mL (n\u0026thinsp;=\u0026thinsp;35) had a significantly higher total cell count and neutrophil count in BALF than those that had S100A9 levels at or below 0.5536\u0026nbsp;ng/mL (n\u0026thinsp;=\u0026thinsp;49; p\u0026thinsp;=\u0026thinsp;0.0004 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.0002, respectively; Supplemental Table\u0026nbsp;1). Patients with or a neutrophil percentage above 49.09% (n\u0026thinsp;=\u0026thinsp;17) tended to have a higher neutrophil count in BALF than those with a neutrophil percentage at or below 49.09% (n\u0026thinsp;=\u0026thinsp;67; p\u0026thinsp;=\u0026thinsp;0.079, Supplemental Table\u0026nbsp;2). In the combination analysis (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e), males were predominant and the BALF total cell counts were higher in the group that had S100A9 levels above 0.5535\u0026nbsp;ng/mL or a neutrophil percentage above 49.09% (n\u0026thinsp;=\u0026thinsp;43) than in those with S100A9 levels at or below 0.5535\u0026nbsp;ng/mL and a neutrophil percentage at or below 49.09% (n\u0026thinsp;=\u0026thinsp;41) (p\u0026thinsp;=\u0026thinsp;0.02). Otherwise, there were no differences in age, BMI, smoking status, GAP stage, or lung function.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cspan class=\"Bold\"\u003eS100A9 levels in lung tissues and BALF cells of patients with idiopathic pulmonary fibrosis measured by immunofluorescence staining\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo confirm S100A9 expression in the lungs of patients with IPF, S100A9/\u0026alpha;-SMA double immunofluorescence staining was performed on lung tissues of three IPF patients and three controls. In the control lung tissues, perivascular and peribronchial areas were stained by both \u0026alpha;-SMA and S100A9. In the IPF lung tissues, \u0026alpha;-SMA was robustly expressed by interstitial fibroblasts, most of which also expressed S100A9 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). To confirm S100A9 expression in the BALF cells of IPF patients, S100A9 and CD163 double immunofluorescence staining was performed. In the cells of these patients, CD163 was robustly expressed by macrophages, most of which also expressed S100A9 (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eIn this study, we demonstrated that S100A9 levels were significantly higher in BALF from patients with IPF than in BALF from NC subjects, or those with other ILDs. Additionally, S100A9 level of 0.093\u0026nbsp;ng/ml and 0.0279\u0026nbsp;ng/mL exhibited high sensitivity and specificity for diagnosing IPF and for differential diagnosis of other ILDs, respectively. Over the past decade, higher concentrations of S100A9 in BALF from IPF patients have been reported compared to patients with other ILDs [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. However, these reports have only come from a relatively small number of patients. The concentrations of S100A9 in BALF were inversely correlated with impairments in lung function, as indicated by reduced forced vital capacity and diffusing capacity of carbon monoxide [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Certain concentrations of S100A9 also showed sufficient specificity and sensitivity to distinguish IPF from NSIP and CVD-IP [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Recently, Bennett et al. reported that higher concentrations of S100A9 were related to a more advanced IPF condition, lower lung function values, a shorter distance walked in the 6-minte walk test, and BALF neutrophilia in 30 patients with IPF [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. It is important to re-evaluate the clinical implications of these parameters in a larger number of IPF patients. The present study demonstrated that the level of S100A9 in BALF is a surrogate biomarker for survival chances. A cutoff value of 0.5536\u0026nbsp;ng/mL divided IPF patients into short- and long-term survival groups with a hazard ratio of 3.62.\u003c/p\u003e \u003cp\u003eS100A9 is a small calcium-binding protein released by stressed cells that are undergoing necrosis [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. S100A9 acts as an endogenous danger signal that accelerates and exacerbates the neutrophilic response in non-infectious inflammation via enhanced chemotaxis of neutrophils and macrophages and modulation of their functions [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Because of the predominance of neutrophilic inflammation in the lungs of IPF patients [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], S100A9 had been presumed to be responsible for the neutrophilic inflammation of IPF. This hypothesis was well demonstrated in the present study by a good correlation between the two parameters. Additionally, a cutoff value of 49.09% for neutrophils in BALF divided patients into short- and long-term survival groups with a hazard ratio of 3.11. Interestingly, when a combined analysis of neutrophil percentage and S100A9 levels was performed, patients with S100A9 levels above 0.5536\u0026nbsp;ng/mL and a neutrophil percentage above 49.09% had a significantly lower survival rate than those with S100A9 levels at or below 0.5536 and neutrophil percentage at or below 49.09%, with a hazard ratio of 9.28, three times higher than the hazard ratio of the BALF S100A9 level or the neutrophil percentage individually. This indicates that both high levels of S100A9 or high percentages of neutrophils may be related to early mortality in IPF.\u003c/p\u003e \u003cp\u003eThee S100A9 and neutrophils in BALF are known to be involved in the pathogenesis of inflammatory conditions such as asthma [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] and COPD [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], and there is also ample evidence of S100A9 having fibrotic effects. The process of fibrosis has been shown to be mediated by combinatorial signaling pathways that involve components of the TGF-β/CTGF pathway, and also signaling events induced by epidermal growth factor (EGF) and Insulin like growth factor 2 (IGF-2) activated receptors [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. S100A9 also stimulates the proliferation of fibroblasts, albeit at higher concentrations than the former factors [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, S100A9 induces cellular communication network factor 2 (CCN2) mRNA and protein, the latter of which stimulates fibroblast growth and myofibroblast differentiation [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e] via Toll-like receptor 4 (TLR4) and RAGE [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Type 1 alveolar epithelial (AT1) cells [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e] and type 2 alveolar epithelial (AT2) cells [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] express high levels of RAGE in lung [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. S100A9 enhances the basal migratory motility of fibrocytes [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] and promotes lung fibroblast activation, resulting in the expression of collagen type III and α-smooth muscle actin via the RAGE pathway [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and RAGE levels are increased in IPF [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. In addition, TLR4 is strongly expressed in parenchymal fibroblasts and infiltrating cells located at fibrotic loci [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Thus, patients with high levels of S100A9 may have a more rapid fibrotic process that leads to a lower survival rate.\u003c/p\u003e \u003cp\u003eOne limitation of this study is that it did not measure other mediators of IPF besides neutrophils. In this study, some patients with low levels of S100A9 and a high neutrophil percentage also showed early mortality. This indicates that mediators other than S100A9 produced from neutrophils may contribute to early mortality in IPF. Neutrophil elastase degrades various ECM components [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and leads to fibroblast proliferation and myofibroblast differentiation in a SMAD-dependent but TGF-β-independent fashion [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. An additional mediator is the neutrophil extracellular trap, a major product of neutrophils that promotes fibrosis via TGF-β1 production and subsequent myofibroblast activation [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Thus, these mediators should be evaluated and analyzed for their role in IPF mortality in the future.\u003c/p\u003e "},{"header":"Conclusion","content":"\u003cp\u003eTo understand the role of S100A9 in neutrophilic inflammation related to IPF, S100A9 concentrations were measured in BALF. The levels of S100A9 were significantly higher in IPF patients than in NC subjects and patients with other ILDs. Furthermore, the levels of S100A9 had good discriminating power for the differential diagnosis of IPF. The survival rates were significantly lower in IPF patients that had higher S100A9 levels and neutrophil percentages than those with lower S100A9 levels and neutrophil percentages.\u0026nbsp;These results suggest that S100A9 participates in the development and progression of IPF, and that the IPF levels in BALF could be used as a surrogate marker for diagnosing IPF and predicting prognosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eIPF: Idiopathic pulmonary fibrosis, ECM: extracellular matrix, BAL: bronchoalveolar lavage, NC: normal controls, NSIP: non-specific interstitial pneumonia, HP: hypersensitivity pneumonitis, ROC: receiver operating characteristic\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt was writing at the materials and methods sections; as follows: The study protocol was approved by institutional review board (IRB) in the Soonchunhyang University hospital ethics committee (medicine 2018-10).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors have read and approved the submission of manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvailable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Education (\u003cstrong\u003e\u003cem\u003e2017R1A2B4012693\u003c/em\u003e\u003c/strong\u003e) and a research grant from Soonchunhyang\u0026nbsp;University to JS Park.\u0026nbsp; JU Lee was supported by the Basic Science Research Program of NRF (2018R1A6A3A01011004).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJU Lee and CS Park conceived and designed the experiments, JU Lee, RH Kim, JS Park and ES Go performed IF stain, IHC stain and ELISA, CS Park and JS Park provided clinical samples, JS Park, HS Chang and JU Lee performed statistical analysis, Lee JU, HS Chang and CS Park wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe samples were generously provided by a\u0026nbsp;Biobank in Soonchunhyang University, Bucheon Hospital.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSelman M, King TE, Pardo A: \u003cstrong\u003eIdiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy\u003c/strong\u003e. \u003cem\u003eAnnals of internal medicine \u003c/em\u003e2001, \u003cstrong\u003e134\u003c/strong\u003e(2):136-151.\u003c/li\u003e\n\u003cli\u003eKim DS, Collard HR, King TE, Jr.: \u003cstrong\u003eClassification and natural history of the idiopathic interstitial pneumonias\u003c/strong\u003e. \u003cem\u003eProceedings of the American Thoracic Society \u003c/em\u003e2006, \u003cstrong\u003e3\u003c/strong\u003e(4):285-292.\u003c/li\u003e\n\u003cli\u003eChambers RC, Mercer PF: \u003cstrong\u003eMechanisms of alveolar epithelial injury, repair, and fibrosis\u003c/strong\u003e. \u003cem\u003eAnn Am Thorac Soc \u003c/em\u003e2015, \u003cstrong\u003e12 Suppl 1\u003c/strong\u003e(Suppl 1):S16-S20.\u003c/li\u003e\n\u003cli\u003eCheresh P, Kim SJ, Tulasiram S, Kamp DW: \u003cstrong\u003eOxidative stress and pulmonary fibrosis\u003c/strong\u003e. \u003cem\u003eBiochimica et biophysica acta \u003c/em\u003e2013, \u003cstrong\u003e1832\u003c/strong\u003e(7):1028-1040.\u003c/li\u003e\n\u003cli\u003eWynn TA: \u003cstrong\u003eIntegrating mechanisms of pulmonary fibrosis\u003c/strong\u003e. \u003cem\u003eThe Journal of experimental medicine \u003c/em\u003e2011, \u003cstrong\u003e208\u003c/strong\u003e(7):1339-1350.\u003c/li\u003e\n\u003cli\u003eKinder BW, Brown KK, Schwarz MI, Ix JH, Kervitsky A, King TE, Jr.: \u003cstrong\u003eBaseline BAL neutrophilia predicts early mortality in idiopathic pulmonary fibrosis\u003c/strong\u003e. \u003cem\u003eChest \u003c/em\u003e2008, \u003cstrong\u003e133\u003c/strong\u003e(1):226-232.\u003c/li\u003e\n\u003cli\u003eWatters LC, Schwarz MI, Cherniack RM, Waldron JA, Dunn TL, Stanford RE, King TE: \u003cstrong\u003eIdiopathic pulmonary fibrosis. Pretreatment bronchoalveolar lavage cellular constituents and their relationships with lung histopathology and clinical response to therapy\u003c/strong\u003e. \u003cem\u003eThe American review of respiratory disease \u003c/em\u003e1987, \u003cstrong\u003e135\u003c/strong\u003e(3):696-704.\u003c/li\u003e\n\u003cli\u003eDesai O, Winkler J, Minasyan M, Herzog EL: \u003cstrong\u003eThe Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis\u003c/strong\u003e. \u003cem\u003eFront Med (Lausanne) \u003c/em\u003e2018, \u003cstrong\u003e5\u003c/strong\u003e:43-43.\u003c/li\u003e\n\u003cli\u003eTabuena RP, Nagai S, Tsutsumi T, Handa T, Minoru T, Mikuniya T, Shigematsu M, Hamada K, Izumi T, Mishima M: \u003cstrong\u003eCell profiles of bronchoalveolar lavage fluid as prognosticators of idiopathic pulmonary fibrosis/usual interstitial pneumonia among Japanese Patients\u003c/strong\u003e. \u003cem\u003eRespiration; international review of thoracic diseases \u003c/em\u003e2005, \u003cstrong\u003e72\u003c/strong\u003e(5):490-498.\u003c/li\u003e\n\u003cli\u003eZiegenhagen MW, Zabel P, Zissel G, Schlaak M, Muller-Quernheim J: \u003cstrong\u003eSerum level of interleukin 8 is elevated in idiopathic pulmonary fibrosis and indicates disease activity\u003c/strong\u003e. \u003cem\u003eAmerican journal of respiratory and critical care medicine \u003c/em\u003e1998, \u003cstrong\u003e157\u003c/strong\u003e(3 Pt 1):762-768.\u003c/li\u003e\n\u003cli\u003eInage M, Nakamura H, Kato S, Saito H, Abe S, Hino T, Tomoike H: \u003cstrong\u003eLevels of cytokeratin 19 fragments in bronchoalveolar lavage fluid correlate to the intensity of neutrophil and eosinophil-alveolitis in patients with idiopathic pulmonary fibrosis\u003c/strong\u003e. \u003cem\u003eRespiratory medicine \u003c/em\u003e2000, \u003cstrong\u003e94\u003c/strong\u003e(2):155-160.\u003c/li\u003e\n\u003cli\u003eGiannandrea M, Parks WC: \u003cstrong\u003eDiverse functions of matrix metalloproteinases during fibrosis\u003c/strong\u003e. \u003cem\u003eDisease models \u0026amp; mechanisms \u003c/em\u003e2014, \u003cstrong\u003e7\u003c/strong\u003e(2):193-203.\u003c/li\u003e\n\u003cli\u003eChua F, Dunsmore SE, Clingen PH, Mutsaers SE, Shapiro SD, Segal AW, Roes J, Laurent GJ: \u003cstrong\u003eMice lacking neutrophil elastase are resistant to bleomycin-induced pulmonary fibrosis\u003c/strong\u003e. \u003cem\u003eThe American journal of pathology \u003c/em\u003e2007, \u003cstrong\u003e170\u003c/strong\u003e(1):65-74.\u003c/li\u003e\n\u003cli\u003eGregory AD, Kliment CR, Metz HE, Kim KH, Kargl J, Agostini BA, Crum LT, Oczypok EA, Oury TA, Houghton AM: \u003cstrong\u003eNeutrophil elastase promotes myofibroblast differentiation in lung fibrosis\u003c/strong\u003e. \u003cem\u003eJournal of leukocyte biology \u003c/em\u003e2015, \u003cstrong\u003e98\u003c/strong\u003e(2):143-152.\u003c/li\u003e\n\u003cli\u003eFoell D, Wittkowski H, Vogl T, Roth J: \u003cstrong\u003eS100 proteins expressed in phagocytes: a novel group of damage-associated molecular pattern molecules\u003c/strong\u003e. \u003cem\u003eJournal of leukocyte biology \u003c/em\u003e2007, \u003cstrong\u003e81\u003c/strong\u003e(1):28-37.\u003c/li\u003e\n\u003cli\u003eShibata F, Miyama K, Shinoda F, Mizumoto J, Takano K, Nakagawa H: \u003cstrong\u003eFibroblast growth-stimulating activity of S100A9 (MRP-14)\u003c/strong\u003e. \u003cem\u003eEuropean journal of biochemistry \u003c/em\u003e2004, \u003cstrong\u003e271\u003c/strong\u003e(11):2137-2143.\u003c/li\u003e\n\u003cli\u003eXu X, Chen H, Zhu X, Ma Y, Liu Q, Xue Y, Chu H, Wu W, Wang J, Zou H: \u003cstrong\u003eS100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-kappaB-dependent pathways\u003c/strong\u003e. \u003cem\u003eClinical and experimental immunology \u003c/em\u003e2013, \u003cstrong\u003e173\u003c/strong\u003e(3):523-535.\u003c/li\u003e\n\u003cli\u003eBargagli E, Olivieri C, Prasse A, Bianchi N, Magi B, Cianti R, Bini L, Rottoli P: \u003cstrong\u003eCalgranulin B (S100A9) levels in bronchoalveolar lavage fluid of patients with interstitial lung diseases\u003c/strong\u003e. \u003cem\u003eInflammation \u003c/em\u003e2008, \u003cstrong\u003e31\u003c/strong\u003e(5):351-354.\u003c/li\u003e\n\u003cli\u003eBargagli E, Olivieri C, Cintorino M, Refini RM, Bianchi N, Prasse A, Rottoli P: \u003cstrong\u003eCalgranulin B (S100A9/MRP14): a key molecule in idiopathic pulmonary fibrosis?\u003c/strong\u003e \u003cem\u003eInflammation \u003c/em\u003e2011, \u003cstrong\u003e34\u003c/strong\u003e(2):85-91.\u003c/li\u003e\n\u003cli\u003eSelman M, Pardo A, King Jr TE: \u003cstrong\u003eHypersensitivity pneumonitis: insights in diagnosis and pathobiology\u003c/strong\u003e. \u003cem\u003eAmerican journal of respiratory and critical care medicine \u003c/em\u003e2012, \u003cstrong\u003e186\u003c/strong\u003e(4):314-324.\u003c/li\u003e\n\u003cli\u003eParrish S, Turner J: \u003cstrong\u003eDiagnosis of sarcoidosis\u003c/strong\u003e. \u003cem\u003eDisease-a-Month \u003c/em\u003e2009, \u003cstrong\u003e55\u003c/strong\u003e(11):693-703.\u003c/li\u003e\n\u003cli\u003eBaughman RP, Culver DA, Judson MA: \u003cstrong\u003eA concise review of pulmonary sarcoidosis\u003c/strong\u003e. \u003cem\u003eAmerican journal of respiratory and critical care medicine \u003c/em\u003e2011, \u003cstrong\u003e183\u003c/strong\u003e(5):573-581.\u003c/li\u003e\n\u003cli\u003eTravis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA, Nicholson AG, Ryerson CJ, Ryu JH, Selman M, Wells AU: \u003cstrong\u003eAn official American Thoracic Society/European Respiratory Society statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias\u003c/strong\u003e. \u003cem\u003eAmerican journal of respiratory and critical care medicine \u003c/em\u003e2013, \u003cstrong\u003e188\u003c/strong\u003e(6):733-748.\u003c/li\u003e\n\u003cli\u003eSociety AT: \u003cstrong\u003eThis joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001\u003c/strong\u003e. \u003cem\u003eAm J Respir Crit Care Med \u003c/em\u003e2002, \u003cstrong\u003e165\u003c/strong\u003e:277-304.\u003c/li\u003e\n\u003cli\u003eTravis WD, Hunninghake G, King Jr TE, Lynch DA, Colby TV, Galvin JR, Brown KK, Chung MP, Cordier J-F, Du Bois RM: \u003cstrong\u003eIdiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project\u003c/strong\u003e. \u003cem\u003eAmerican journal of respiratory and critical care medicine \u003c/em\u003e2008, \u003cstrong\u003e177\u003c/strong\u003e(12):1338-1347.\u003c/li\u003e\n\u003cli\u003ePark S-W, Ahn M-H, Jang HK, Jang AS, Kim D-J, Koh E-S, Park J-S, Uh S-T, Kim YH, Park JS: \u003cstrong\u003eInterleukin-13 and its receptors in idiopathic interstitial pneumonia: clinical implications for lung function\u003c/strong\u003e. \u003cem\u003eJournal of Korean medical science \u003c/em\u003e2009, \u003cstrong\u003e24\u003c/strong\u003e(4):614-620.\u003c/li\u003e\n\u003cli\u003eBudczies J, Klauschen F, Sinn BV, Gyorffy B, Schmitt WD, Darb-Esfahani S, Denkert C: \u003cstrong\u003eCutoff Finder: a comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization\u003c/strong\u003e. \u003cem\u003ePloS one \u003c/em\u003e2012, \u003cstrong\u003e7\u003c/strong\u003e(12):e51862.\u003c/li\u003e\n\u003cli\u003eHara A, Sakamoto N, Ishimatsu Y, Kakugawa T, Nakashima S, Hara S, Adachi M, Fujita H, Mukae H, Kohno S: \u003cstrong\u003eS100A9 in BALF is a candidate biomarker of idiopathic pulmonary fibrosis\u003c/strong\u003e. \u003cem\u003eRespiratory medicine \u003c/em\u003e2012, \u003cstrong\u003e106\u003c/strong\u003e(4):571-580.\u003c/li\u003e\n\u003cli\u003eKorthagen NM, Nagtegaal MM, van Moorsel CH, Kazemier KM, van den Bosch JM, Grutters JC: \u003cstrong\u003eMRP14 is elevated in the bronchoalveolar lavage fluid of fibrosing interstitial lung diseases\u003c/strong\u003e. \u003cem\u003eClinical and experimental immunology \u003c/em\u003e2010, \u003cstrong\u003e161\u003c/strong\u003e(2):342-347.\u003c/li\u003e\n\u003cli\u003eBennett D, Salvini M, Fui A, Cillis G, Cameli P, Mazzei MA, Fossi A, Refini RM, Rottoli P: \u003cstrong\u003eCalgranulin B and KL-6 in Bronchoalveolar Lavage of Patients with IPF and NSIP\u003c/strong\u003e. \u003cem\u003eInflammation \u003c/em\u003e2019, \u003cstrong\u003e42\u003c/strong\u003e(2):463-470.\u003c/li\u003e\n\u003cli\u003eRyckman C, McColl SR, Vandal K, de Medicis R, Lussier A, Poubelle PE, Tessier PA: \u003cstrong\u003eRole of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air-pouch model of acute gouty arthritis\u003c/strong\u003e. \u003cem\u003eArthritis and rheumatism \u003c/em\u003e2003, \u003cstrong\u003e48\u003c/strong\u003e(8):2310-2320.\u003c/li\u003e\n\u003cli\u003eCesaro A, Anceriz N, Plante A, Page N, Tardif MR, Tessier PA: \u003cstrong\u003eAn inflammation loop orchestrated by S100A9 and calprotectin is critical for development of arthritis\u003c/strong\u003e. \u003cem\u003ePloS one \u003c/em\u003e2012, \u003cstrong\u003e7\u003c/strong\u003e(9):e45478.\u003c/li\u003e\n\u003cli\u003eLee TH, Jang AS, Park JS, Kim TH, Choi YS, Shin HR, Park SW, Uh ST, Choi JS, Kim YH\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eElevation of S100 calcium binding protein A9 in sputum of neutrophilic inflammation in severe uncontrolled asthma\u003c/strong\u003e. \u003cem\u003eAnnals of allergy, asthma \u0026amp; immunology : official publication of the American College of Allergy, Asthma, \u0026amp; Immunology \u003c/em\u003e2013, \u003cstrong\u003e111\u003c/strong\u003e(4):268-275.e261.\u003c/li\u003e\n\u003cli\u003eLee TH, Chang HS, Bae DJ, Song HJ, Kim MS, Park JS, Jun JA, Lee SY, Uh ST, Kim SH\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eRole of S100A9 in the development of neutrophilic inflammation in asthmatics and in a murine model\u003c/strong\u003e. \u003cem\u003eClinical immunology (Orlando, Fla) \u003c/em\u003e2017, \u003cstrong\u003e183\u003c/strong\u003e:158-166.\u003c/li\u003e\n\u003cli\u003ePouwels SD, Nawijn MC, Bathoorn E, Riezebos-Brilman A, van Oosterhout AJ, Kerstjens HA, Heijink IH: \u003cstrong\u003eIncreased serum levels of LL37, HMGB1 and S100A9 during exacerbation in COPD patients\u003c/strong\u003e. \u003cem\u003eThe European respiratory journal \u003c/em\u003e2015, \u003cstrong\u003e45\u003c/strong\u003e(5):1482-1485.\u003c/li\u003e\n\u003cli\u003eGrotendorst GR, Rahmanie H, Duncan MR: \u003cstrong\u003eCombinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation\u003c/strong\u003e. \u003cem\u003eFASEB journal : official publication of the Federation of American Societies for Experimental Biology \u003c/em\u003e2004, \u003cstrong\u003e18\u003c/strong\u003e(3):469-479.\u003c/li\u003e\n\u003cli\u003eNikitorowicz-Buniak J, Shiwen X, Denton CP, Abraham D, Stratton R: \u003cstrong\u003eAbnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhanced secretion of CCN2 and S100A9\u003c/strong\u003e. \u003cem\u003eThe Journal of investigative dermatology \u003c/em\u003e2014, \u003cstrong\u003e134\u003c/strong\u003e(11):2693-2702.\u003c/li\u003e\n\u003cli\u003eDahlin K, Mager EM, Allen L, Tigue Z, Goodglick L, Wadehra M, Dobbs L: \u003cstrong\u003eIdentification of genes differentially expressed in rat alveolar type I cells\u003c/strong\u003e. \u003cem\u003eAmerican journal of respiratory cell and molecular biology \u003c/em\u003e2004, \u003cstrong\u003e31\u003c/strong\u003e(3):309-316.\u003c/li\u003e\n\u003cli\u003eKatsuoka F, Kawakami Y, Arai T, Imuta H, Fujiwara M, Kanma H, Yamashita K: \u003cstrong\u003eType II alveolar epithelial cells in lung express receptor for advanced glycation end products (RAGE) gene\u003c/strong\u003e. \u003cem\u003eBiochemical and biophysical research communications \u003c/em\u003e1997, \u003cstrong\u003e238\u003c/strong\u003e(2):512-516.\u003c/li\u003e\n\u003cli\u003eEnglert JM, Hanford LE, Kaminski N, Tobolewski JM, Tan RJ, Fattman CL, Ramsgaard L, Richards TJ, Loutaev I, Nawroth PP\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eA role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis\u003c/strong\u003e. \u003cem\u003eThe American journal of pathology \u003c/em\u003e2008, \u003cstrong\u003e172\u003c/strong\u003e(3):583-591.\u003c/li\u003e\n\u003cli\u003eWang CH, Punde TH, Huang CD, Chou PC, Huang TT, Wu WH, Liu CH, Chung KF, Kuo HP: \u003cstrong\u003eFibrocyte trafficking in patients with chronic obstructive asthma and during an acute asthma exacerbation\u003c/strong\u003e. \u003cem\u003eThe Journal of allergy and clinical immunology \u003c/em\u003e2015, \u003cstrong\u003e135\u003c/strong\u003e(5):1154-1162.e1151-1155.\u003c/li\u003e\n\u003cli\u003eKyung SY, Byun KH, Yoon JY, Kim YJ, Lee SP, Park JW, Lee BH, Park JS, Jang AS, Park CS\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eAdvanced glycation end-products and receptor for advanced glycation end-products expression in patients with idiopathic pulmonary fibrosis and NSIP\u003c/strong\u003e. \u003cem\u003eInternational journal of clinical and experimental pathology \u003c/em\u003e2014, \u003cstrong\u003e7\u003c/strong\u003e(1):221-228.\u003c/li\u003e\n\u003cli\u003eBhattacharyya S, Kelley K, Melichian DS, Tamaki Z, Fang F, Su Y, Feng G, Pope RM, Budinger GR, Mutlu GM\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eToll-like receptor 4 signaling augments transforming growth factor-beta responses: a novel mechanism for maintaining and amplifying fibrosis in scleroderma\u003c/strong\u003e. \u003cem\u003eThe American journal of pathology \u003c/em\u003e2013, \u003cstrong\u003e182\u003c/strong\u003e(1):192-205.\u003c/li\u003e\n\u003cli\u003eChrysanthopoulou A, Mitroulis I, Apostolidou E, Arelaki S, Mikroulis D, Konstantinidis T, Sivridis E, Koffa M, Giatromanolaki A, Boumpas DT\u003cem\u003e et al\u003c/em\u003e: \u003cstrong\u003eNeutrophil extracellular traps promote differentiation and function of fibroblasts\u003c/strong\u003e. \u003cem\u003eThe Journal of pathology \u003c/em\u003e2014, \u003cstrong\u003e233\u003c/strong\u003e(3):294-307.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp style='margin: 0in 0in 8pt;line-height: 20px;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"line-height: 20px; font-family: Verdana, Geneva, sans-serif; font-size: 10px; color: rgb(0, 0, 0);\"\u003eTable 1. Clinical characteristics of study participants who underwent bronchoalveolar lavage\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"width: 784px;border-collapse: collapse;\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 158.09375px;border-top-width: 1pt;border-style: solid none;border-top-color: black;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.75pt 0.75pt 0in;height: 15.55pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style=\"margin-right: 0in;margin-left: 0in;font-size:16px;font-family: Gulim, sans-serif;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eParameters\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 135.234375px;border-top-width: 1pt;border-style: solid none;border-top-color: black;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.1pt 0.1pt 0in;height: 15.55pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style=\"margin-right: 0in;margin-left: -5.9pt;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNC\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 143.671875px;border-top-width: 1pt;border-style: solid none;border-top-color: black;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.05pt 0.05pt 0in;height: 15.55pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style=\"margin-right: 0in;margin-left: 0in;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eIPF\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;border-top-width: 1pt;border-style: solid none;border-top-color: black;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.75pt 0.75pt 0in;height: 15.55pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;border-top-width: 1pt;border-style: solid none;border-top-color: black;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.75pt 0.75pt 0in;height: 15.55pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eILDs\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;border-top-width: 1pt;border-style: solid none;border-top-color: black;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.75pt 0.75pt 0in;height: 15.55pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 112.78125px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.75pt 0.75pt 0in;height: 15.55pt;\" width=\"33.333333333333336%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNSIP\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.75pt 0.75pt 0in;height: 15.55pt;\" width=\"30.952380952380953%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eHP\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: black;padding: 0.75pt 0.75pt 0in;height: 15.55pt;\" width=\"35.714285714285715%\"\u003e\n \u003cp style=\"margin: 0in 0in 0.0001pt;font-size:16px;font-family: Gulim, sans-serif;text-align: center;line-height: 24px;vertical-align: middle;\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eSarcoidosis\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;border: none;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNumber of subjects\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;border: none;padding: 0.05pt 0.05pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e33\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;border: none;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e87\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;border: none;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e22\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;border: none;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e19\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;border: none;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e10\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eAge (year)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e55 (35\u0026ndash;72)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e63.8 (32\u0026ndash;86)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e60.1 (39\u0026ndash;70)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e51.3 (28\u0026ndash;70)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e43.3 (28\u0026ndash;69)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eSex (male/female)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e20/13\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e54/33\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e9/13\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e10/9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e6/4\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eSmoking (CS/ES/NS)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e2/1/30\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e38/29/20\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e2/5/12\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3/2/13\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3/2/5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eFVC (% pred.)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e106.1 (87.0\u0026ndash;119)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e75.0 (63.7\u0026ndash;83.0)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e78.0 (66.0\u0026ndash;91.8)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e64.5 (57.0\u0026ndash;82.5)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e77.0 (65.0\u0026ndash;86.0)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eFEV1 (% pred.)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e102.1 (88.2\u0026ndash;117)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e89.0 (77.5\u0026ndash;100.5)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e85.0 (73.8\u0026ndash;101.3)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e74.5 (64.3\u0026ndash;92.0)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e85.0 (64.0\u0026ndash;101.0)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eDLCO (% pred.)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e64.0 (38.5\u0026ndash;72.5)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e76.0 (59.0\u0026ndash;92.0)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e67.0 (55.0\u0026ndash;90.0)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e75.5 (57.8\u0026ndash;84.5)*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003edFVC (%/year)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 9.85pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e\u0026minus;7.0 (\u0026minus;16.5\u0026ndash;0.0)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003edDLco\u0026nbsp;(%/year)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 9.85pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e-13(-30-0)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e-5(-20.5-0)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: justify;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eFollow-up (years)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 135.359375px;padding: 0.05pt 0.05pt 0in;height: 9.85pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eNA\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e4.1 (2.1\u0026ndash;6.3)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eND\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eND\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 9.85pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eND\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;line-height: 20px;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eBALF total cells (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133.484375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3.42\u0026plusmn;0.96\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e5.61\u0026plusmn;3.71*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e6.09\u0026plusmn;2.74*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e6.12\u0026plusmn;3.79*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e4.31\u0026plusmn;2.92*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;line-height: 20px;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eMacrophages (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133.484375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3.25\u0026plusmn;0.93\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3.43\u0026plusmn;2.24*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3.16\u0026plusmn;1.89*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3.19\u0026plusmn;2*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e3.71\u0026plusmn;2.76*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;line-height: 20px;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eNeutrophils (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133.484375px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.08\u0026plusmn;0.07\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;vertical-align: bottom;\" valign=\"bottom\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e1.66\u0026plusmn;2.3*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;vertical-align: bottom;\" valign=\"bottom\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e2.44\u0026plusmn;2.23*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;vertical-align: bottom;\" valign=\"bottom\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e2.7\u0026plusmn;2.89*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 10.7pt;vertical-align: bottom;\" valign=\"bottom\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.37\u0026plusmn;0.4*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;line-height: 20px;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eEosinophils (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133.484375px;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.02\u0026plusmn;0.03\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.29\u0026plusmn;1.1*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.17\u0026plusmn;0.27*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.17\u0026plusmn;0.21*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.01\u0026plusmn;0.01*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 158.09375px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"20.61855670103093%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;line-height: 20px;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003eLymphocytes (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 133.484375px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"17.52577319587629%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.07\u0026plusmn;0.06\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 141.796875px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"18.556701030927837%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.23\u0026plusmn;0.25*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.78125px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"14.43298969072165%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.32\u0026plusmn;0.29*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 106.203125px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"13.402061855670103%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.41\u0026plusmn;0.43*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 119.6875px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;padding: 0.75pt 0.75pt 0in;height: 8.3pt;\" width=\"15.463917525773196%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: center;line-height: 20px;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 16px;\"\u003e0.22\u0026plusmn;0.18*\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin: 0in 0in 0.0001pt;text-align: justify;line-height: 20px;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 20px;\"\u003eIPF, idiopathic pulmonary fibrosis, NSIP, non-specific interstitial fibrosis; HP, hypersensitivity pneumonitis; CS/ES/NS: current smoker/ex-smoker/never smoker; ND, not determined, NA, not applicate;\u0026nbsp;dFVC (%)/year, annual decline rate of\u0026nbsp;forced vital capacity (FVC); dDLco (%/year),annual decline rate of\u0026nbsp;\u003c/span\u003e\u003cspan style=\"background-color: white;\"\u003ediffusing capacity of the lungs for carbon monoxide\u0026nbsp;\u003c/span\u003e\u003cspan style=\"line-height: 20px;\"\u003e(DLco).\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin: 0in 0in 0.0001pt;text-align: justify;line-height: 20px;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 20px;\"\u003ePatient characteristics and pulmonary function test results are shown as medians (inter-quartile range). Groups among the normal controls and the IPF, NSIP, HP, and sarcoidosis patients were calculated with a Kruskal\u0026ndash;Wallis analysis of variance (ANOVA) with the Mann\u0026ndash;Whitney U as the post-hoc test. BALF cell numbers are shown as mean \u0026plusmn;\u0026nbsp;standard error of the mean (SEM)\u0026nbsp;and were calculated with a one-way ANOVA and\u0026nbsp;Tukey\u0026#39;s\u0026nbsp;honestly significant difference test as the post-hoc test\u0026nbsp;among the five groups.\u0026nbsp;Significance: compared with control, *P \u0026lt; 0.05; compared with IPF, \u0026dagger;P \u0026lt; 0.05; compared with NSIP and HP, #P \u0026lt; 0.05.\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin: 0in 0in 0.0001pt;text-align: justify;line-height: 20px;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin: 0in 0in 0.0001pt;line-height: 20px;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin: 0in 0in 0.0001pt;line-height: 20px;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u003cspan style=\"line-height: 20px;\"\u003eTable 2. Clinical characteristics of patients with IPF classified according to the levels of S100A9 and percentage of neutrophils in BALF\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellpadding=\"0\" cellspacing=\"0\" style=\"border-collapse: collapse;\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eParameter\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eS100A9 \u0026gt; 0.5536\u0026nbsp;ng/mL\u0026nbsp;or Neu % \u0026gt; 49.09%\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eS100A9 \u0026le; 0.5536\u0026nbsp;ng/mL\u0026nbsp;and\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eNeu % \u0026le; 49.09%\u0026nbsp;\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;border-top-width: 1pt;border-style: solid none;border-top-color: windowtext;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eP value\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eNumber of subjects\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e43\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e41\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e-\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eAge (years)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e65 (56.5\u0026ndash;73)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e63 (59\u0026ndash;68)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.3423\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eBMI\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e23.34 (22.16\u0026ndash;24.84)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e21.97 (19.77\u0026ndash;24.03)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.0417\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eSex (male/female)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e22/21\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e31/10\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.0202\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eSmoking (CS/ES/NS)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e21/12/10\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e15/17/9\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.3929\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eGap score\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e2 (2\u0026ndash;5)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e4 (2.5\u0026ndash;4.25)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.6914\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eFVC (% pred.)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e75.86 \u0026plusmn; 14.84\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e77.07 \u0026plusmn;17.5\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.5788\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eFEV1 (% pred.)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e89.93 \u0026plusmn; 16.44\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e91.32 \u0026plusmn; 19.19\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.7169\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eDLCO (% pred.)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e67.02 \u0026plusmn; 23.18\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e70.25 \u0026plusmn; 16.99\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.2102\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003edFVC (%/year)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u0026ndash;7.74 \u0026plusmn; 18.26\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u0026ndash;12.33 \u0026plusmn; 13.23\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.3590\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003edDLco (%/year)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u0026ndash;15.1 \u0026plusmn; 18.35\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e\u0026ndash;20.85 \u0026plusmn; 16.05\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.0586\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eFollow-up duration (years)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e4.06 (2.57-5.94)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e4.25 (2.17\u0026ndash;7.02)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.5373\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eSurvival/death\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e28/15\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e39/2\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.5603\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eBAL total cell count (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e6.9 \u0026plusmn; 4.59\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e4.36 \u0026plusmn; 1.96\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.0016\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eMacrophages (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e3.58 \u0026plusmn; 2.88\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e3.31 \u0026plusmn; 1.41\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.2808\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eNeutrophils (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e2.62 \u0026plusmn; 2.91\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.71 \u0026plusmn; 0.71\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e3.82E-08\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eEosinophils (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.44 \u0026plusmn; 1.53\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.14 \u0026plusmn; 0.25\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;background-color: white;padding: 0in 4.95pt;height: 15pt;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.2369\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 176.890625px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;text-align: left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003eLymphocytes (10\u003csup\u003e4\u003c/sup\u003e/mL)\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 237.09375px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"26.804123711340207%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.27 \u0026plusmn; 0.28\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 210.21875px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"29.896907216494846%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.21 \u0026plusmn; 0.22\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 107.0625px;border-style: none none solid;border-bottom-width: 1pt;border-bottom-color: windowtext;background-color: white;padding: 0in 4.95pt;height: 15pt;background-position: initial initial;background-repeat: initial initial;\" width=\"16.49484536082474%\"\u003e\n \u003cp style='margin: 0in 0in 0.0001pt;text-align: center;line-height: normal;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cspan style=\"font-family: \n Verdana, Geneva, sans-serif;\"\u003e\u003cspan style=\"font-size: \n 10px;\"\u003e0.5357\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin: 0in 0in 8pt;text-align: justify;line-height: 14.266666412353516px;font-size:13px;font-family: \"Malgun Gothic\", sans-serif;'\u003e\u003cspan style=\"line-height: 14.266666412353516px; font-family: Verdana, Geneva, sans-serif; font-size: 10px; color: rgb(0, 0, 0);\"\u003eCS/ES/NS, current smoker/ex-smoker/never smoker; dFVC (%)/year, annual decline rate of forced vital capacity (FVC); dDLco (%/year), annual rate of diffusing capacity of the lungs for carbon monoxide (DLco). Differences in patient characteristics and pulmonary function test results are shown as medians (inter-quartile range). Bronchoalveolar lavage (BAL) cell numbers are shown as mean \u0026plusmn; standard error of the mean (SEM). \u003c/span\u003e\u003c/p\u003e"},{"header":"Supplemental Information Note","content":"\u003cp\u003e\u003cstrong\u003eSupplemental Figure\u003c/strong\u003e\u003cstrong\u003e. S100A9 protein concentrations in BAL fluids from IPF patients according to the GAP stage, smoking, and sex.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eComparisons of S100A9 protein levels according to (A) the GAP stage (B) smoking status, and (C) sex.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"IPF, S100A9, BAL fluid, Diagnosis, Prognosis","lastPublishedDoi":"10.21203/rs.3.rs-20772/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-20772/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Neutrophilic inflammation is a predominant characteristic of idiopathic pulmonary fibrosis (IPF). S100 Calcium-Binding Protein A9 (S100A9) is a neutrophil-derived protein and is involved in the development of neutrophil-related chronic inflammatory disorders. However, the role of S100A9 in IPF has not been evaluated.\u003c/p\u003e\u003cp\u003eMethods : S100A9 concentrations were measured by ELISA in the BAL fluid obtained from NCs (n = 33) and patients with IPF (n = 87), NSIP (n = 22), HP (n = 19), or sarcoidosis (n = 10).\u003c/p\u003e\u003cp\u003eResults: The S100A9 levels in BALF were significantly higher in patients with IPF than in those with NC (0.4 [0.18–0.9] vs. 0 [0–0.5] ng/mL, p \u0026lt; 0.001), HP (0.19 [0.07–0.33] ng/mL, p = 0.043), or sarcoidosis (0.06 [0–0.11] ng/mL, p \u0026lt; 0.001) patients. A S100A9 level of 0.093 ng/mL had discriminating powers of 78.79% for specificity and 81.61% for sensitivity between IPF patients and NCs. S100A9 levels were also correlated with neutrophil numbers (r = 0.356, p = 0.0007) and S100A9 was expressed on neutrophils and macrophages in the BALF of IPF patients. Patients with\u0026nbsp;S100A9 levels above 0.5535 ng/mL or a neutrophil percentage above 49.09% (n = 43) had significantly lower survival rates than those with S100A9 levels at or below 0.5535 ng/mL and a neutrophil percentage at or below 49.09% (n = 41)\u0026nbsp;(HR, 9.28; p = 0.0004).\u003c/p\u003e\u003cp\u003eConclusion: S100A9 may participate in the development and progression of IPF. The levels of S100A9 in BALF may be a surrogate marker for diagnosing IPF and predicting its prognosis.\u003c/p\u003e","manuscriptTitle":"Upregulation of S100 Calcium-Binding Protein A9 levels in the lungs of patients with idiopathic pulmonary fibrosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-04-03 14:54:48","doi":"10.21203/rs.3.rs-20772/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"41292fc3-6f71-4516-add4-56dea7135bb8","owner":[],"postedDate":"April 3rd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":78825,"name":"Pulmonology"}],"tags":[],"updatedAt":"2020-04-17T15:31:43+00:00","versionOfRecord":[],"versionCreatedAt":"2020-04-03 14:54:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-20772","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-20772","identity":"rs-20772","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}