Serum cytokines in the mediation roles on the relationship between nutritional support and bronchopulmonary dysplasia in premature infants

Serum cytokines in the mediation roles on the relationship between nutritional support and bronchopulmonary dysplasia in premature infants | 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 Serum cytokines in the mediation roles on the relationship between nutritional support and bronchopulmonary dysplasia in premature infants jingjing jiang, zhenjie zhang, weilin wan, zhenghong li, yunwei li This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3237649/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 Objectives To verify whether nutritional support is associated with Bronchopulmonary Dysplasia (BPD) by mediating serum cytokines. Methods We recorded in a retrospective cohort study the intake of enteral nutrition (EN) and parenteral nutrition (PN) in the first week, serum cytokines on Day 2–7 and Day 14–28 by examining the nutritional and clinical history of 34 newborns born at gestational age ≤ 32 weeks admitted to the neonatal intensive care unit from January 2018 to October 2019. Results Non-BPD group (24 infants) had a significantly higher gestational age and higher birth weight than the BPD group (14 infants). Among the infants with non-BPD, total proteins, total energy and EN carbohydrates, EN proteins, EN lipids, and EN energy in the first week intake and IL-4, IL-6, IL-8 on Day 14–28 and FiO 2 on Day 28 were significantly lower, and IL-10 on Day 2–7 and IL-13 on Day 14–28 was significantly higher. Pearson correlation analysis showed a negative correlation between total protein, total energy and EN proteins, EN carbohydrates, EN lipids, and EN energy in the first week with IL-4, IL-6, and IL-8 on Day 14–28. In mediation analyses, total protein, EN proteins, EN carbohydrates, EN lipid, EN energy, total energy in the first week were related to FiO2 on day 28 partly mediated by IL-6 and IL-8 on Day 14–28. Conclusions Our results showed that inefficient nutrition, especially EN nutrition intake in the first week of life were associated with BPD by mediating proinflammatory cytokines on Day 14–28. Serum cytokines nutritional status BPD fraction of inspired oxygen Figures Figure 1 Introduction BPD is a common chronic lung disease in preterm infants that is based on pulmonary hypoplasia characterized by pulmonary inflammation, pulmonary microvascular development disorder, alveolar decrease and pulmonary interstitial fibrosis [ 1 ]. In premature infants born at < 32 gestational weeks, whose alveoli formation begins and is incomplete, several factors, such as hyperopia, tissue apoptosis, and pre- and postnatal exposure to infection, contribute to the arrest of lung development[ 2 ]. Nutritional support and inflammatory reactions in the lung are also important factors in the pathogenesis of BPD. Many studies have shown that early sufficient nutrition can reduce the incidence of BPD in premature infants[ 3 , 4 ]. As the imbalance of proinflammatory cytokines and anti-inflammatory cytokines induces pulmonary inflammation, profibrotic cytokines further cause pulmonary fibrosis in the late stage of BPD. Moreover, many studies[ 5 , 6 ] have shown that the factors underlying the onset of BPD in premature infants were lung immaturity and cytokine changes. Our previous study[ 7 ] also indicated that IL-6 and IL-8 were significantly increased and were high-risk factors for BPD, and the IL-6 level was associated with BPD disease severity. However, the pathways and mechanisms of the mediation of serum cytokines are unclear. The aim of this study was to explore the relationship between nutritional support, serum cytokines and BPD in preterm infants and assess the mediating role of cytokines in the nutritional support associated with BPD. Methods We conducted a retrospective cohort study, which was approved by the Ethics Institutional Review Board of Peking Union Medical College Hospital. 2.1 Study Population Inclusion criteria (1) preterm infants born at gestational age ≤ 32 weeks, (2) preterm infants born from January 2018 to October 2019, (3) preterm infants admitted to the NICU at Peking Union Medical College Hospital within 1 hour after birth. The exclusion criteria were as follows (1) infants with severe congenital malformations, (2) infants with inherited metabolic diseases, and (3) infants who died, discharged, or were transported to other hospitals before they were 28 days old. (4) Incomplete medical records. The infants enrolled were assigned to BPD group according to the diagnosis of BPD, and other infants were assigned to non-BPD group. For the present study, BPD was defined as the need for supplemental oxygen > 21% on Day 28 of life according to the workshop definition by the National Institutes of Child Health, the Human Development/National Heart, Lung, and Blood Institute and the Office of Rare Diseases[ 8 ]. 2.2 Data collection Basic perinatal information was collected retrospectively from medical records, including sex, gestation age, and birth weight. Nutrition support data were collected, including supplements of energy (total energy, EN energy and parenteral nutrition (PN) energy), protein (total protein, EN protein and PN protein), carbohydrates (total carbohydrates, EN carbohydrates and PN carbohydrates) and lipids (total lipids, EN lipids and PN lipids) and total liquid, protein energy ratio in the first week, and FiO2 on Day 28 of both groups were recorded. The cytokine data were based on previous data collected by our research team [ 7 ], and all the serum cytokine data, including interferon-gamma (IFN-γ), necroptosis factor-alpha (TNF-α), interleukin-10 (IL-10), IL-12p70, IL-13, IL-1β, IL-4, IL-6, and IL-8 were collected and regrouped to Day 2–7 and Day 14–28. Our PN support strategy followed the standard protocol and ESPGHAN/ESPEN/ESPR/CSPEN recommendations[ 9 ]. The energy coefficients of protein, calories-carbohydrates and lipids were 4.0 kcal/g, 4.0 kcal/g and 9.0 kcal/g, respectively. The energy, carbohydrate, protein and fat content of formula milk for premature infants are calculated according to the ingredient list provided by the milk powder brand, and every 100 ml of human milk contains protein 1.6 g, calories-carbohydrates 7.3 g, and lipids 3.5 g on average[ 10 ]. 2.3 Statistics Statistical analysis was performed using SPSS 26.0. Normality testing was undertaken to determine if quantitative data were normally distributed. Comparisons of perinatal factors, serum cytokine concentrations and nutritional support were conducted between the two groups. The quantitative data with a normal distribution are described as the mean ± standard error of the mean (X ± S). The data between two groups were compared using the t test. The quantitative data that did not meet the normal distribution were described by M (P25-P75), and the comparison between groups was tested by the Mann‒Whitney U test. The qualitative data were described by frequency, and Fisher’s exact test was performed. The Pearson correlation test was used to examine the pairwise correlation between nutritional support and serum cytokines. Mediation analyses were conducted to examine the mediation of serum cytokines on the relationship between nutritional support and FiO2 on Day 28. Since the mediation analysis requires a continuous variable as the outcome variable, we used the FiO2 on Day 28 as the outcome variable for this analysis, and linear regression analysis can be used directly to construct a model. The mediation effects of IL-4, IL-6, and IL-8 on days 14–28 on the relationship between nutritional support and FiO2 on day 28 were analyzed using mediation analysis SPSS procedures developed by Andrew Hayes (Figue1)[ 11 ]. Mediation variables (M), independent variables (X), and dependent variables (Y) were standardized to make them comparable. The mediation analysis procedure is based on the mediation theory proposed by Baron and Kenny[ 12 ]. Results 3.1 Baseline Data From January 2018 to October 2019, 38 preterm infants were enrolled in this study, including 14 infants in BPD group and 24 infants in non-BPD group. Perinatal and neonatal characteristics is shown in Table 1 . Non-BPD group had a significantly higher gestational age (29.63 ± 1.17 weeks vs. 27.00 ± 1.41 weeks, P < 0.001) and higher birth weight (1405.00 ± 348.69 g vs. 928.57 ± 213.71 g, P < 0.001) than BPD group. Table 1 Perinatal and neonatal characteristics. Non-BPD(n = 24) BPD(n = 14) P-value INFANT CHARACTERISTICS Male gender (%) 16(50%) 9(64.3%) 0.370 Singleton(%) 28(87.5%) 10(71.4%) 0.183 Birth weight (grams) 1489 ± 357 1021 ± 261 0.000 Gestational age (weeks) 29.9 ± 1.3 27.5 ± 1.3 0.000 SGA(%) 1(3.1%) 0(0%) 1.000 Apgar < 7 at 5 minutes 6(25) 6(42.85) 0.833 NRDS(%) 23(71.9%) 14(100%) 0.048 Mechanical Ventilation (days) 10(7–15) 36(27–53) 0.000 LOS(%) 15(46.9%) 7(50%) 0.844 Nebulized inhaled hormone (%) 4(12.5%) 8(57.1%) 0.003 Anemia(%) 23(71.9%) 14(100%) 0.030 FiO 2 on day 28(%) 33.07 ± 7.92 21.00 ± 0.00 < 0.001 MATERNAL CHARACTERISTICS MATERNAL age 33.5 ± 4.1 30.7 ± 3.5 0.065 Caesarean Section (%) 29(90.6%) 10(71.4%) 0.173 Antenatal steroids (%) 17(53.1%) 10(71.4%) 0.246 Premature rupture of membranes (%) 17(53.1) 5(35.7%) 0.023 intrauterine infection n(%) 7(21.9%) 2(14.3%) 0.700 Values are reported as n (%) or median (range). NRDS, neonatal respiratory distress syndrome, SGA, small for gestational age, BPD, Bronchopulmonary dysplasia; LOS, Late-onset neonatal sepsis 3.2. Comparison between BPD group and non-BPD group 3.2.1 Nutritional support The results of the nutritional support comparison between two groups are shown in Table 2 . The total proteins, total energy and EN carbohydrates, EN proteins, EN lipids, and EN energy in the first week of non-BPD group were higher than those in BPD group significantly (P < 0.05). Table 2 Comparison of nutritional support in the first week of life between two groups. Non-BPD( n = 24) BPD( n = 14) t P-value Total liquid (ml/kg/w) 865.27 ± 96.76 918.84 ± 106.89 1.590 0.120 Total proteins (g/kg/w) 18.54 ± 2.10 16.98 ± 1.74 2.340 0.025 EN proteins (g/kg/w) 4.12 ± 2.34 1.71 ± 1.37 4.013 < 0.001 PN proteins (g/kg/w) 14.42 ± 2.84 15.27 ± 2.00 0.984 0.332 Total carbohydrates (g/kg/w) 54.46 ± 15.98 45.69 ± 15.75 1.640 0.110 EN carbohydrates (g/kg/w) 16.95 ± 11.72 8.46 ± 6.10 2.509 0.017 PN carbohydrates (g/kg) 37.50 ± 11.96 37.22 ± 15.83 0.062 0.951 Total lipids (g/kg/w) 19.17 ± 5.70 20.53 ± 16.73 0.294 0.773 EN lipids (g/kg/w) 9.38 ± 5.74 4.75 ± 3.54 2.722 0.010 PN lipids (g/kg/w) 9.79 ± 1.98 15.78 ± 15.11 1.476 0.163 Total energy (kcal/kg/w) 466.16 ± 76.53 415.64 ± 66.65 2.054 0.047 EN energy (kcal/kg/w) 140.43 ± 83.44 71.81 ± 54.88 3.053 0.004 PN energy (kcal/kg/w) 325.73 ± 43.65 343.83 ± 43.85 1.231 0.226 Protein energy ratio (g/100 kcal) 4.15 ± 0.69 4.15 ± 0.57 0.008 0.993 PN = parenteral nutrient, EN = Enteral nutrient 3.2.2 Serum cytokines The total of 8 cytokine data in 38 infants in this research were subsets of data that have been previously published by our team [ 7 ] and were regrouped to Day 2–7 and Day 14–28, and all prior data were reanalyzed to provide a consistent comparison (Table 3 ). Compared to non-BPD group, IL-10 on Day 2–7 and IL-13 on Day 14–28 were significantly decreased in BPD group (P < 0.05), while IL-4, IL-6, and IL-8 on Day 14–28 were significantly increased in BPD group (P < 0.05). Table 3 Comparison of neonatal serum cytokine concentrations between premature infants with BPD and Non-BPD group Age (days) Non-BPD( n = 24) BPD( n = 14) Z P-value IFN-γ (pg/mL) 2–7 8.85(6.75,18.00) 8.95(6.80,15.00) -0.288 0.777 14–28 12.55(7.20,18.00) 8.95(6.90,12.53) -0.924 0.361 IL-10 (pg/mL) 2–7 3.00(2.18,5.30) 2.45(2.03,2.73) -2.276 0.023 14–28 2.90(2.10,5.30) 2.30(2.10,2.95) -1.475 0.144 IL-12p70 (pg/mL) 2–7 1.10(0.90,1.28) 1.25(1.00,1.40) -1.636 0.106 14–28 0.90(0.53,1.10) 0.80(0.38,1.03) -0.7 0.501 IL-13 (pg/mL) 2–7 7.75(5.70,9.33) 6.65(5.00,9.05) -0.682 0.501 14–28 9.10(8.03,10.40) 8.00(7.73,8.43) -2.536 0.010 IL-4 (pg/mL) 2–7 0.30(0.20,0.58) 0.40(0.20,0.50) -0.368 0.731 14–28 0.30(0.20,0.50) 0.90(0.38,1.20) -3.099 0.002 IL-6 (pg/mL) 2–7 5.60(5.05,6.85) 6.20(5.83,7.00) -1.364 0.173 14–28 5.90(5.13,7.15) 8.15(7.90,9.45) -3.213 0.001 IL-8 (pg/mL) 2–7 159.00(154.00,176.00) 175.50(148.25,181.50) -0.485 0.643 14–28 277.00(248.25,318.75) 472.00(429.75,513.75) -3.829 < 0.001 TNF-α (pg/mL) 2–7 0.50(0.23,0.60) 0.70(0.48,0.90) -1.805 0.076 14–28 0.65(0.40,1.15) 0.95(0.75,1.25) -1.837 0.067 PN = parenteral nutrient, EN = Enteral nutrient 3.2.3 FiO2 on Day 28 FiO2 on Day 28 was higher in BPD group than in non-BPD group (33.07 ± 7.92 vs 21.00 ± 0.00, P < 0.001). Correlation analysis between nutritional support and serum cytokines Correlation analyses for the indicators with significant differences in comparison between BPD group and non-BPD group were carried out. The correlation between serum cytokines and nutritional support is shown in Table 4 , total protein, total energy and EN proteins, EN carbohydrates, EN lipids, and EN energy in the first week were negatively correlated with IL-4, IL-6, and IL-8 on Day 14–28, and total protein was positively correlated with IL-10 on Day 2–7; these differences were statistically significant (r < 0, P < 0.05). Table 4 Correlation between serum cytokines and nutritional support in the first week IL-10 on Day 2–7 IL-13 on Day 14–28 IL-4 on Day 14–28 IL-6 on Day 14–28 IL-8 on Day 14–28 r P r P r P r P r P Total protein 0.322 0.050 -0.173 0.298 -0.426 0.008 -0.411 0.010 -0.456 0.004 EN proteins 0.023 0.890 0.006 0.971 -0.460 0.004 -0.528 0.001 -0.474 0.003 EN carbohydrates -0.124 0.458 -0.117 0.483 -0.345 0.034 -0.445 0.005 -0.391 0.015 EN lipids -0.109 0.516 0.073 0.665 -0.363 0.025 -0.472 0.003 -0.409 0.011 EN energy 0.105 0.532 0.123 0.461 -0.375 0.021 -0.398 0.013 -0.435 0.006 Total energy 0.183 0.271 0.000 0.998 -0.374 0.021 -0.374 0.021 -0.453 0.004 PN = parenteral nutrient, EN = Enteral nutrient Mediation of serum cytokines on the relation between nutritional support and FiO2 on Day 28. Since IL-10 was positively correlated with total protein in the first week but did not show a significant correlation with FiO2 on Day 28, and IL-13 was negatively correlated with FiO2 on Day 28 but did not show a significant correlation with nutrition status, both of them were excluded from further analysis. According to the mediation effect theory raised by Kenny and Baron, we conducted a mediation analysis to test the mediation effect of IL-4, IL-6, and IL-8 between nutritional support factors, including EN proteins, total protein, EN carbohydrates, EN energy in the first week, and FiO2 on Day 28. Based on bootstrap sampling, the 95% confidence interval was calculated, and the results indicated that the intermediary effect was significant when 0 was not included in the confidence interval. The results are shown in Table 5 and Table 6 . IL-4 was a mediator of the relationship between EN lipid, EN carbohydrates, EN energy, total energy in the first week and FiO2 on Day 28. At the same time, a similar mediation effect of IL-6 and IL-8 was examined in regard to the relationship between total protein, EN proteins, EN carbohydrates, EN lipid, EN energy, total energy in the first week and FiO2 on Day 28. Table 5 Association between nutritional support, or serum cytokines on Day 14–28 and FiO 2 on Day 28 X M Y Coefficient c path a path b path EN proteins IL-4 FiO 2 β(SE),P -0.404(0.152),0.012 -0.460(0.148),0.004 0.280(0.168),0.104 IL-6 β(SE),P -0.404(0.152),0.012 -0.528(0.142),0.001 0.343(0.173),0.055 IL-8 β(SE),P -0.404(0.152),0.012 -0.474(0.147),0.003 0.491(0.155),0.003 Total protein IL-4 FiO 2 β(SE),P -0.386(0.154),0.017 -0.426(0.151),0.008 0.295(0.165),0.082 IL-6 β(SE),P -0.386(0.154),0.017 -0.411(0.152),0.010 0.363(0.160),0.029 IL-8 β(SE),P -0.386(0.154),0.017 -0.456(0.148),0.004 0.500(0.153),0.003 EN lipids IL-4 FiO 2 β(SE),P -0.317(0.158),0.052 -0.363(0.155),0.025 0.335(0.162),0.047 IL-6 β(SE),P -0.317(0.158),0.052 -0.472(0.147),0.003 0.400(0.169),0.023 IL-8 β(SE),P -0.317(0.158),0.052 -0.409(0.152),0.011 0.531(0.151),0.001 EN carbohydrates IL-4 FiO 2 β(SE),P -0.333(0.157),0.041 -0.345(0.156),0.034 0.331(0.160),0.047 IL-6 β(SE),P -0.333(0.157),0.041 -0.445(0.149),0.005 0.389(0.165),0.024 IL-8 β(SE),P -0.333(0.157),0.041 -0.391(0.153),0.015 0.521(0.149),0.001 EN energy IL-4 FiO 2 β(SE),P -0.331(0.157),0.043 -0.375(0.155),0.021 0.328(0.163),0.051 IL-6 β(SE),P -0.331(0.157),0.043 -0.398(0.153),0.013 0.391(0.161),0.020 IL-8 β(SE),P -0.331(0.157),0.043 -0.435(0.150),0.006 0.528(0.153),0.001 Total energy IL-4 FiO 2 β(SE),P -0.287(0.160),0.080 -0.374(0.155),0.021 0.347(0.164),0.042 IL-6 β(SE),P -0.287(0.160),0.080 -0.374(0.155),0.021 0.411(0.160),0.015 IL-8 β(SE),P -0.287(0.160),0.080 -0.453(0.149),0.004 0.556(0.155),0.001 FiO 2 = fraction of inspired oxygen on Day 28, PN = parenteral nutrient, EN = Enteral nutrient c total association between the independent variables (X = nutritional support) and the outcome variable (Y = FiO 2 on Day 28), the association between X and the potential mediator (M = serum cytokines on Days 14–28), b association between M and Y was examined, adjusted for the X. Level of serum cytokines, nutritional support, FiO 2 on Day 28 were natural log transformed for mediation analysis. Table 6 Mediation of serum cytokines on Day 14–28 on the relationship between nutritional supports and FiO 2 on Day 28 X M Y Direct association Indirect association β(95% CI) P β(95% CI) P EN proteins IL-4 FiO 2 -0.275(-0.615-0.065) 0.110 -0.129(-0.335 ~ 0.011) > 0.05 IL-6 -0.223(-0.573-0.128) 0.206 -0.181(-0.601~-0.025) < 0.05 IL-8 -0.171(-0.485 ~ 0.143) 0.277 -0.233(-0.573~-0.068) 0.05 IL-6 -0.237(-0.561 ~ 0.087) 0.147 -0.149(-0.413~-0.042) < 0.05 IL-8 -0.158(-0.470 ~ 0.153) 0.310 -0.228(-0.542~-0.074) < 0.05 EN lipids IL-4 FiO 2 -0.195(-0.525 ~ 0.134) 0.237 -0.122(-0.367~-0.013) < 0.05 IL-6 -0.129(-0.471 ~ 0.214) 0.452 -0.189(-0.456~-0.039) < 0.05 IL-8 -0.100(-0.406 ~ 0.207) 0.513 -0.217(-0.527~-0.077) < 0.05 EN Carbohydrates IL-4 FiO 2 -0.219(-0.545 ~ 0.107) 0.181 -0.114(-0.305~-0.011) < 0.05 IL-6 -0.160(-0.496 ~ 0.176) 0.340 -0.173(-0.434~-0.049) < 0.05 IL-8 -0.129(-0.432 ~ 0.174) 0.393 -0.204(-0.447~-0.073) < 0.05 EN energy IL-4 FiO 2 -0.208(-0.538 ~ 0.123) 0.211 -0.123(-0.296~-0.016) < 0.05 IL-6 -0.175(-0.502 ~ 0.151) 0.283 -0.155(-0.415~-0.035) < 0.05 IL-8 -0.101(-0.412 ~ 0.210) 0.513 -0.230(-0.513~-0.079) < 0.05 Total energy IL-4 FiO 2 -0.157(-0.491 ~ 0.177) 0.346 -0.130(-0.371~-0.009) < 0.05 IL-6 -0.133(-0.459 ~ 0.192) 0.411 -0.154(-0.410~-0.035) < 0.05 IL-8 -0.036(-0.351 ~ 0.280) 0.820 -0.252(-0.546~-0.095) < 0.05 FiO 2 = fraction of inspired oxygen on Day 28, PN = parenteral nutrient, EN = Enteral nutrient Discussion BPD is a lung disease that causes dependence on oxygen supplementation for an extended period of time, which is a common respiratory disease with a high mortality rate that affects premature infants. Survivors often leave behind repeated lower respiratory tract infections and growth retardation, which makes it a critical factor affecting the quality of life of premature infants. The risk factors for BPD suggested by previous studies include low gestational age, small birth weight, oxygen, respiratory support, nutrition and infection[ 13 ]. Recently, studies have also shown a close association between various cytokines and the occurrence and development of BPD in preterm infants. In premature infants born at < 32 gestational weeks, alveoli formation begins and is incomplete, Tissue apoptosis and the accumulation and activation of inflammatory cells in the lungs due to various inflammatory cytokines are possible contributors to BPD[ 14 ].Results provided by the scarce studies carried out in infants support the evidence from previous animal experiments. IL-1β, IL-6, TNF-α, and IL-10 cytokine levels were altered in the amniotic fluid[ 15 ], core blood[ 16 ] and serum[ 6 ]were observed in BPD infants. In addition, studies showed pro-inflammatory cytokine (such as IL-6) activity in cord blood positively correlates with gestational age, whereas anti-inflammatory cytokine (such as IL-10 ) does not [ 17 ]. On the basis of previous studies[ 7 ], compared to non-BPD infants, some particular cytokine levels were upregulated in the first 28 days of life in BPD infants. In the study presented here, we further explored the correlation between the cytokine profile and FiO 2 on day 28. Our results confirm the fact that during the first week of life, infants with BPD had significantly lower IL-10 levels. However, this inflammation is transient and no longer present on days 14–28. Instead, IL-4, IL-6, and IL-8 were increased in the BPD group on days 14–28. Which means Persistent lung inflammation, with an imbalance of pro-inflammatory versus anti-inflammatory mediators, plays a central role in the pathogenesis of BPD along with an arrest of lung growth.IL-6 and IL-8 are pro-inflammatory cytokines. IL-6 is secreted by macrophages, T cells and endothelial cells to stimulate the immune response, leading to the synthesis of a variety of inflammatory mediators, including neutrophils, and secreting a variety of inflammatory mediators to promote inflammation, thus causing airway remodeling. which is an independent risk factor for BPD in premature infants[ 18 ]. The biological function of IL-8 is to mediate neutrophil migration, development and aggravation of inflammatory responses. It has been hypothesized that elevated cord blood IL-8 is associated with death or moderate/severe BPD[ 16 ]. IL-10 is a potent anti-inflammatory cytokine, and an increasing number of studies have shown that IL-10 could be a protective factor against the development of BPD by reducing acute lung injury caused by mechanical stretching [ 19 ]. In addition, inhibiting the activation of nuclear transcription factor-κB (NF-κB) is secondary to hyperoxia injury [ 20 ]. In our research, the non-BPD group had higher IL-10 on days 2–7, and the difference between the two groups disappeared on days 14–28. This result may suggest that the protective effect of IL-10 decreased over time. At the same time, the results of our study showed lower IL-13 on days 14–28 and higher IL-4 in the BPD group than in the non-BPD control group, which suggested that the increased expression of IL-4 may be involved in abnormal lung development and maturation in neonates with BPD and that IL-13 may play a protective role in the development of BPD. Even though IL-13 is associated with the development of bronchial hyperreactivity[ 21 ], but it also inhibits inflammatory cytokine production in macrophages andepithelial cells such as TNF-α, IL-6, IL-8 and IL-1β [ 22 , 23 ] and upregulates the anti-inflammatory cytokine[ 24 ]. At the same time, the action of IL-4 was two-sided effects of lung inflammation, it may inhibits to some aspects of lung inflammation, furthermore, it may induces collagen production and proliferation of subsets of lung fibroblasts[ 25 ]. It has been clearly demonstrated that nutrition status influences immune cell function in previous research and that immune cell function determines the cellular metabolic state, and the role of cytokines as mediators of weight loss and anorexia or chronic liver disease has been previously proven in studies concerning malignancies, showing an apparent relationship between the levels of IL-6, IL-1 and TNF and neoplastic cachexia [ 26 , 27 ]. Is it possible that nutritional status promotes the development of BPD by affecting cytokines? How do it contribute to bpd? Given the above, we attempted to assess the mediation effect of serum cytokines in the development of BPD from nutrition to explore the mechanism of BPD. For very low birth weight (VLBW) and extremely low birth weight (ELBW) infants whose alveolar maturity mostly or completely occurs after birth, nutrition supply in the early postnatal period plays a crucial role in respiratory development[ 28 , 29 ]. Regarding the association of nutritional support with the development of BPD described by our research, the BPD group had a significantly lower total energy and total protein intake than the non-BPD group within the first week after birth. Malnutrition interferes with pulmonary defenses against volutrauma and infection, all of which are harmful to lung repair, development and maturation. Early sufficient protein supply in premature infants can lower protein breakdown, promote improved protein balance, and increase protein synthesis[ 3 , 30 ]. In a retrospective cohort study of BPD infants, it was found that an energy intake in the range of 120–150 kcal/kg/day and a minimum protein intake of at least 3.5 g/kg/day are needed in BPD infants[ 31 ]. Moreover, our results show that infants who survived without BPD had a significantly higher intake of enteral feed (including each ingredient and energy) and a lower parenteral intake than infants who developed BPD. In a prospective study, the same association identified that enteral nutrition can reduce the incidence of growth retardation in premature infants with BPD[ 32 ]. The start of enteral nutrition was delayed by the presence of hemodynamic or respiratory instability, which means that such infants may suffer from inflammation of the storm caused by infection, the lungs of shunt caused by PDA, or mechanical stretch caused by mechanical ventilation. Our results showed dynamic changes in cytokines at different time points. Some cytokines (e.g.IL-4, IL-6, IL-8 and IL-13) showed no significant changes in the early stages but exhibited significant changes in the late stages in premature infants who received insufficient nutrition in the first week of life and subsequently developed BPD. From a comprehensive perspective of the results of the correlation study between cytokines and nutritional support, we supposed that early nutritional support influenced the development of BPD though IL-4, IL-6, IL-8 and IL-13. Then the role of inflammatory mediating effect in nutrition and BPD was further explored in our study. The results show that there is an intermediary relationship between total protein, enteral nutrition (including carbohydrates, energy and proteins) and FiO2 on day 28, which supports the idea that early protein and enteral nutrition deficiency can improve oxygen dependence on day 28 after birth and promote BPD by increasing proinflammatory mediators on days 14–28. As shown in Table 1 , the occurrence and development of BPD was involving various factors, such as birth weight and gestational age, and these characteristics make difference of complications, such as infections, PDA, mechanical Ventilation time and NRDS etc. (which can in turn affect the inflammatory status) in two group. These clinical complications of premature birth were complex processes involving multiple factors, and multi-stage interactions, in addition, some maternal factors could also affect the inflammatory state of the newborn (e.g. intrauterine infection), nutritional support was only accounts for a part of it. At that same time, nutrition support also affects the occurrence of BPD through various ways, our findings illustrate that serum cytokines mediated a partial association between nutrition support and BPD, which implies that for premature infants, BPD may result from cytokine changes caused by other factors (such as hyperoxia injury and gut microbiota), apart from the mediating role of the change in serum cytokines in nutritional support, which is worthy of further investigation. Our results provide evidence for BPD control measures in early nutrition and provide hints for exploring the potential mechanisms of these risk factors. Based on these facts, the efforts of clinicians have been focused on effective nutritional treatment strategies. We must note that the sample in our study was very small, and this observation needs to be verified in a larger cohort. We are aware of the limitations of our study, as it is a single-center retrospective cohort, and the present study is a cross-sectional study, which could only provide association and by nature could not provide causality. Future longitudinal studies may further verify the serum cytokine mediation effect of nutrition and BPD. Certainly, the design of retrospective data collection and analysis does allow us to generate a hypothesis by identifying significant associations between several variables and the outcomes and it should be well tested by a prospective, randomized clinical trial in future researches. What’s more, cytokine was partly intermediate between nutritional factors and BPD, and we are looking forward more researches to explore other intermediary factors. However, we believe that our data can help support future meta-analysis studies on this hypothesis. Strong evidence indicates that energy and protein intake in the first weeks of life is important in the lung development of premature infants. Conclusions Our results show that poor nutrition intake is associated with the upregulation of proinflammatory Cytokines also increased the incidence of BPD. Inefficient EN nutrition, total energy and protein intake in the first week of life is associated with FiO2 on Day 28 by mediating serum cytokines. Declarations Ethical approval and consent to participate The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration. The collection of cytokine data in this study was approved by the Human Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. The ethical review number was ZS-1552. All of the procedures were performed in accordance with the Declaration of Helsinki and relevant policies in China. All parent or legal guardian for this study participation gave their informed consent for publication Consent for publication Not Applicable Data availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. Conflict of interest The authors have declared they have no conflicting interests. Funding This work was supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Science Author contributions Jing-Jing Jiang performed the research, analyzed the data and wrote the paper, Zhen-jie Zhang was responsible for the data curation and investigation, Yun-wei Li was responsible for data curation, Weilin Wan was responsible for methodology, and project administration. Zheng-hong Li as Corresponding Author designed the research study, review and editing. References Mourani, P.M. and S.H. Abman, Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Curr Opin Pediatr, 2013. 25(3): p. 329-37. Jensen, E.A. and B. Schmidt, Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol, 2014. 100(3): p. 145-57. Uberos, J., et al., Early energy restriction in premature infants and bronchopulmonary dysplasia: a cohort study. Br J Nutr, 2020. 123(9): p. 1024-1031. Poindexter, B.B. and C.R. Martin, Impact of Nutrition on Bronchopulmonary Dysplasia. Clin Perinatol, 2015. 42(4): p. 797-806. Speer, C.P., Inflammation and bronchopulmonary dysplasia. Semin Neonatol, 2003. 8(1): p. 29-38. Kaneko, M., et al., Serum cytokine concentrations, chorioamnionitis and the onset of bronchopulmonary dysplasia in premature infants. J Neonatal Perinatal Med, 2017. 10(2): p. 147-155. Zhang, Z., et al., Cytokines and Exhaled Nitric Oxide Are Risk Factors in Preterm Infants for Bronchopulmonary Dysplasia. Biomed Res Int, 2021. 2021: p. 6648208. Jobe, A.H. and E. Bancalari, Bronchopulmonary dysplasia. Am J Respir Crit Care Med, 2001. 163(7): p. 1723-9. Mihatsch, W., et al., ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Guideline development process for the updated guidelines. Clin Nutr, 2018. 37(6 Pt B): p. 2306-2308. Ziegler, E.E., Human milk and human milk fortifiers. World Rev Nutr Diet, 2014. 110: p. 215-27. Preacher, K.J. and A.F. Hayes, SPSS and SAS procedures for estimating indirect effects in simple mediation models. Behav Res Methods Instrum Comput, 2004. 36(4): p. 717-31. Baron, R.M. and D.A. Kenny, The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol, 1986. 51(6): p. 1173-82. Thebaud, B., et al., Bronchopulmonary dysplasia. Nat Rev Dis Primers, 2019. 5(1): p. 78. Choo-Wing, R., et al., Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol, 2007. 293(1): p. L142-50. Yoon, B.H., et al., Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol, 1997. 177(4): p. 825-30. Rocha, G., et al., Cord blood levels of IL-6, IL-8 and IL-10 may be early predictors of bronchopulmonary dysplasia in preterm newborns small for gestational age. Dis Markers, 2012. 33(1): p. 51-60. Dembinski, J., et al., Modulation of pro- and anti-inflammatory cytokine production in very preterm infants. Cytokine, 2003. 21(4): p. 200-6. Tian, X.Y., et al., Biological markers in cord blood for prediction of bronchopulmonary dysplasia in premature infants. Clin Exp Obstet Gynecol, 2014. 41(3): p. 313-8. Hawwa, R.L., et al., IL-10 inhibits inflammatory cytokines released by fetal mouse lung fibroblasts exposed to mechanical stretch. Pediatr Pulmonol, 2011. 46(7): p. 640-9. Li, H.D., et al., Exogenous interleukin-10 attenuates hyperoxia-induced acute lung injury in mice. Exp Physiol, 2015. 100(3): p. 331-40. Wong, W.S. and D.S. Koh, Advances in immunopharmacology of asthma. Biochem Pharmacol, 2000. 59(11): p. 1323-35. Egholm, C., et al., The Regulatory Effects of Interleukin-4 Receptor Signaling on Neutrophils in Type 2 Immune Responses. Front Immunol, 2019. 10: p. 2507. Heeb, L.E.M., C. Egholm, and O. Boyman, Evolution and function of interleukin-4 receptor signaling in adaptive immunity and neutrophils. Genes Immun, 2020. 21(3): p. 143-149. de Waal Malefyt, R., et al., Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10. J Immunol, 1993. 151(11): p. 6370-81. Torsuev, N.A. and N.I. Gusakov, [Contribution of I.I. Mechnikov to the development of syphilology (on the 60th anniversary of his death)]. Vestn Dermatol Venerol, 1976(8): p. 88-9. Santetti, D., et al., Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease. World J Gastroenterol, 2015. 21(29): p. 8927-34. Patel, H.J. and B.M. Patel, TNF-alpha and cancer cachexia: Molecular insights and clinical implications. Life Sci, 2017. 170: p. 56-63. Al-Jebawi, Y., et al., Low caloric intake and high fluid intake during the first week of life are associated with the severity of bronchopulmonary dysplasia in extremely low birth weight infants. J Neonatal Perinatal Med, 2020. 13(2): p. 207-214. Milanesi, B.G., et al., Assessment of early nutritional intake in preterm infants with bronchopulmonary dysplasia: a cohort study. Eur J Pediatr, 2021. 180(5): p. 1423-1430. Thiess, T., et al., Correlation of Early Nutritional Supply and Development of Bronchopulmonary Dysplasia in Preterm Infants <1,000 g. Front Pediatr, 2021. 9: p. 741365. Gianni, M.L., et al., The role of nutrition in promoting growth in pre-term infants with bronchopulmonary dysplasia: a prospective non-randomised interventional cohort study. BMC Pediatr, 2014. 14: p. 235. Uberos, J., et al., Nutrition in extremely low birth weight infants: impact on bronchopulmonary dysplasia. Minerva Pediatr, 2016. 68(6): p. 419-426. Additional Declarations No competing interests reported. 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. We do this by developing innovative software and high quality services for the global research community. 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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-3237649","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":236558758,"identity":"1705dea3-c86d-408c-a471-650c67287644","order_by":0,"name":"jingjing jiang","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"jingjing","middleName":"","lastName":"jiang","suffix":""},{"id":236558759,"identity":"185b0630-c306-42f3-8b13-e246a07ebf64","order_by":1,"name":"zhenjie zhang","email":"","orcid":"","institution":"Peking Union Medical 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li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+0lEQVRIiWNgGAWjYHACxgM8BRIMBkAWM0MFkGQHCjUQ0HOAxwCm5QwDAw8zcVoYIFoY24jQYnC898GBNwYW9ubsvYdfF86zSdzPzHzw4QwGOzldHPoMzhw3ODjHQILZsudcmvXMbWmJPcxsyYYbGJKNzQ5g12J2I43hMNAvbAY3csyMebcdBmrhMZN8wHAgcRsBLTwG998AtcwhQYuEwQ0e48e8DVAtG/BosT9zjAHkFwODMzlmzDzH0ox7DgP9MsMAt18k29sYH7ypqLM3OH7G+DNPjY1se3vzwYc9FXZyuLQgAzYJBNuAsHIQYP5AnLpRMApGwSgYaQAAicJZ2amtWe4AAAAASUVORK5CYII=","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"zhenghong","middleName":"","lastName":"li","suffix":""},{"id":236558762,"identity":"1800cbca-e0e6-458e-8e20-49126a5e0f78","order_by":4,"name":"yunwei li","email":"","orcid":"","institution":"Peking Union Medical College Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"yunwei","middleName":"","lastName":"li","suffix":""}],"badges":[],"createdAt":"2023-08-05 15:14:15","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3237649/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3237649/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":44143699,"identity":"c87b7a4e-6a32-458c-b01c-c77d64ce744e","added_by":"auto","created_at":"2023-10-05 15:10:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":21326,"visible":true,"origin":"","legend":"\u003cp\u003eModel of mediation analysis.\u003c/p\u003e\n\u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e=\u003ca href=\"file:///C:/Users/Drweidoudou/AppData/Local/youdao/dict/Application/8.9.9.0/resultui/html/index.html#/javascript:;\"\u003efraction\u003c/a\u003e\u0026nbsp;\u003ca href=\"file:///C:/Users/Drweidoudou/AppData/Local/youdao/dict/Application/8.9.9.0/resultui/html/index.html#/javascript:;\"\u003eof\u003c/a\u003e\u0026nbsp;\u003ca href=\"file:///C:/Users/Drweidoudou/AppData/Local/youdao/dict/Application/8.9.9.0/resultui/html/index.html#/javascript:;\"\u003einspired\u003c/a\u003e\u0026nbsp;\u003ca href=\"file:///C:/Users/Drweidoudou/AppData/Local/youdao/dict/Application/8.9.9.0/resultui/html/index.html#/javascript:;\"\u003eoxygen\u003c/a\u003e on Day 28\u003c/p\u003e\n\u003cp\u003eDirect association was association between X and Y after controlling for M.；Indirect association (Mediation effect) =a×b (Bootstrap test was conducted)\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eX is the independent variable (Model of mediation analysis), M is the potential mediator (Serum cytokines\u003cstrong\u003e)\u003c/strong\u003e, and Y is the dependent variable (FiO\u003csub\u003e2 \u003c/sub\u003eon Day 28).\u003c/p\u003e\n\u003cp\u003eAssociation a: association between X and M.\u003c/p\u003e\n\u003cp\u003eAssociation b: association between M and Y after controlling for X.\u003c/p\u003e\n\u003cp\u003eAssociation c′: association between X and Y after controlling for M.\u003c/p\u003e\n\u003cp\u003eAssociation c: association between independent variable (X) and dependent variable (Y).\u0026nbsp;\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-3237649/v1/473757077988b5156b06ba00.png"},{"id":55298899,"identity":"0932d20e-2231-4493-ac80-3cc4e9ab31da","added_by":"auto","created_at":"2024-04-25 11:31:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":858279,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3237649/v1/6db60d36-fb07-438d-aaca-fdefca8c2e93.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Serum cytokines in the mediation roles on the relationship between nutritional support and bronchopulmonary dysplasia in premature infants ","fulltext":[{"header":"Introduction","content":"\u003cp\u003eBPD is a common chronic lung disease in preterm infants that is based on pulmonary hypoplasia characterized by pulmonary inflammation, pulmonary microvascular development disorder, alveolar decrease and pulmonary interstitial fibrosis [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In premature infants born at \u0026lt;\u0026thinsp;32 gestational weeks, whose alveoli formation begins and is incomplete, several factors, such as hyperopia, tissue apoptosis, and pre- and postnatal exposure to infection, contribute to the arrest of lung development[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Nutritional support and inflammatory reactions in the lung are also important factors in the pathogenesis of BPD. Many studies have shown that early sufficient nutrition can reduce the incidence of BPD in premature infants[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As the imbalance of proinflammatory cytokines and anti-inflammatory cytokines induces pulmonary inflammation, profibrotic cytokines further cause pulmonary fibrosis in the late stage of BPD. Moreover, many studies[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] have shown that the factors underlying the onset of BPD in premature infants were lung immaturity and cytokine changes. Our previous study[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] also indicated that IL-6 and IL-8 were significantly increased and were high-risk factors for BPD, and the IL-6 level was associated with BPD disease severity. However, the pathways and mechanisms of the mediation of serum cytokines are unclear. The aim of this study was to explore the relationship between nutritional support, serum cytokines and BPD in preterm infants and assess the mediating role of cytokines in the nutritional support associated with BPD.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e We conducted a retrospective cohort study, which was approved by the Ethics Institutional Review Board of Peking Union Medical College Hospital.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study Population\u003c/h2\u003e \u003cp\u003e \u003cstrong\u003eInclusion criteria\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e(1) preterm infants born at gestational age ≤ 32 weeks, (2) preterm infants born from January 2018 to October 2019, (3) preterm infants admitted to the NICU at Peking Union Medical College Hospital within 1 hour after birth.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eThe exclusion criteria were as follows\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e(1) infants with severe congenital malformations, (2) infants with inherited metabolic diseases, and (3) infants who died, discharged, or were transported to other hospitals before they were 28 days old. (4) Incomplete medical records.\u003c/p\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e The infants enrolled were assigned to BPD group according to the diagnosis of BPD, and other infants were assigned to non-BPD group. For the present study, BPD was defined as the need for supplemental oxygen \u0026gt; 21% on Day 28 of life according to the workshop definition by the National Institutes of Child Health, the Human Development/National Heart, Lung, and Blood Institute and the Office of Rare Diseases[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data collection\u003c/h2\u003e \u003cp\u003eBasic perinatal information was collected retrospectively from medical records, including sex, gestation age, and birth weight. Nutrition support data were collected, including supplements of energy (total energy, EN energy and parenteral nutrition (PN) energy), protein (total protein, EN protein and PN protein), carbohydrates (total carbohydrates, EN carbohydrates and PN carbohydrates) and lipids (total lipids, EN lipids and PN lipids) and total liquid, protein energy ratio in the first week, and FiO2 on Day 28 of both groups were recorded.\u003c/p\u003e \u003cp\u003eThe cytokine data were based on previous data collected by our research team [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], and all the serum cytokine data, including interferon-gamma (IFN-γ), necroptosis factor-alpha (TNF-α), interleukin-10 (IL-10), IL-12p70, IL-13, IL-1β, IL-4, IL-6, and IL-8 were collected and regrouped to Day 2–7 and Day 14–28.\u003c/p\u003e \u003cp\u003eOur PN support strategy followed the standard protocol and ESPGHAN/ESPEN/ESPR/CSPEN recommendations[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The energy coefficients of protein, calories-carbohydrates and lipids were 4.0 kcal/g, 4.0 kcal/g and 9.0 kcal/g, respectively. The energy, carbohydrate, protein and fat content of formula milk for premature infants are calculated according to the ingredient list provided by the milk powder brand, and every 100 ml of human milk contains protein 1.6 g, calories-carbohydrates 7.3 g, and lipids 3.5 g on average[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistics\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SPSS 26.0. Normality testing was undertaken to determine if quantitative data were normally distributed. Comparisons of perinatal factors, serum cytokine concentrations and nutritional support were conducted between the two groups. The quantitative data with a normal distribution are described as the mean ± standard error of the mean (X ± S). The data between two groups were compared using the \u003cem\u003et\u003c/em\u003e test. The quantitative data that did not meet the normal distribution were described by M (P25-P75), and the comparison between groups was tested by the Mann‒Whitney U test. The qualitative data were described by frequency, and Fisher’s exact test was performed. The Pearson correlation test was used to examine the pairwise correlation between nutritional support and serum cytokines.\u003c/p\u003e \u003cp\u003eMediation analyses were conducted to examine the mediation of serum cytokines on the relationship between nutritional support and FiO2 on Day 28. Since the mediation analysis requires a continuous variable as the outcome variable, we used the FiO2 on Day 28 as the outcome variable for this analysis, and linear regression analysis can be used directly to construct a model. The mediation effects of IL-4, IL-6, and IL-8 on days 14–28 on the relationship between nutritional support and FiO2 on day 28 were analyzed using mediation analysis SPSS procedures developed by Andrew Hayes (Figue1)[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Mediation variables (M), independent variables (X), and dependent variables (Y) were standardized to make them comparable. The mediation analysis procedure is based on the mediation theory proposed by Baron and Kenny[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":"\u003ch2\u003e3.1 Baseline Data\u003c/h2\u003e\u003cp\u003eFrom January 2018 to October 2019, 38 preterm infants were enrolled in this study, including 14 infants in BPD group and 24 infants in non-BPD group. Perinatal and neonatal characteristics is shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Non-BPD group had a significantly higher gestational age (29.63 ± 1.17 weeks vs. 27.00 ± 1.41 weeks, P \u0026lt; 0.001) and higher birth weight (1405.00 ± 348.69 g vs. 928.57 ± 213.71 g, P \u0026lt; 0.001) than BPD group.\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePerinatal and neonatal characteristics.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-BPD(n = 24)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBPD(n = 14)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eINFANT CHARACTERISTICS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale gender (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16(50%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9(64.3%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.370\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSingleton(%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(87.5%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(71.4%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.183\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (grams)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1489 ± 357\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1021 ± 261\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age (weeks)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29.9 ± 1.3\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.5 ± 1.3\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSGA(%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(3.1%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0(0%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eApgar \u0026lt; 7 at 5 minutes\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(25)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(42.85)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.833\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNRDS(%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(71.9%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(100%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.048\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical Ventilation (days)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(7–15)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36(27–53)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLOS(%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(46.9%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7(50%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.844\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNebulized inhaled hormone (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4(12.5%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(57.1%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia(%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(71.9%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14(100%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.030\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e on day 28(%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.07 ± 7.92\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.00 ± 0.00\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMATERNAL CHARACTERISTICS\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMATERNAL age\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.5 ± 4.1\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.7 ± 3.5\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.065\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCaesarean Section (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29(90.6%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(71.4%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntenatal steroids (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(53.1%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10(71.4%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.246\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePremature rupture of membranes (%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(53.1)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5(35.7%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eintrauterine infection n(%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(21.9%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2(14.3%)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.700\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eValues are reported as n (%) or median (range).\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eNRDS, neonatal respiratory distress syndrome, SGA, small for gestational age, BPD, Bronchopulmonary dysplasia; LOS, Late-onset neonatal sepsis\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003ch2\u003e3.2. Comparison between BPD group and non-BPD group\u003c/h2\u003e\u003ch2\u003e3.2.1 Nutritional support\u003c/h2\u003e\u003cp\u003eThe results of the nutritional support comparison between two groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The total proteins, total energy and EN carbohydrates, EN proteins, EN lipids, and EN energy in the first week of non-BPD group were higher than those in BPD group significantly (P \u0026lt; 0.05).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"±\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"±\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of nutritional support in the first week of life between two groups.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-BPD(\u003cem\u003en\u003c/em\u003e = 24)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBPD(\u003cem\u003en\u003c/em\u003e = 14)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003et\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal liquid (ml/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e865.27 ± 96.76\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e918.84 ± 106.89\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.590\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal proteins (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e18.54 ± 2.10\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e16.98 ± 1.74\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.340\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN proteins (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e4.12 ± 2.34\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e1.71 ± 1.37\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.013\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePN proteins (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e14.42 ± 2.84\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e15.27 ± 2.00\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.984\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.332\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal carbohydrates (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e54.46 ± 15.98\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e45.69 ± 15.75\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.640\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN carbohydrates (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e16.95 ± 11.72\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e8.46 ± 6.10\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.509\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePN carbohydrates (g/kg)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e37.50 ± 11.96\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e37.22 ± 15.83\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.062\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.951\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal lipids (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e19.17 ± 5.70\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e20.53 ± 16.73\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.773\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN lipids (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e9.38 ± 5.74\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e4.75 ± 3.54\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.722\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePN lipids (g/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e9.79 ± 1.98\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e15.78 ± 15.11\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.476\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.163\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal energy (kcal/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e466.16 ± 76.53\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e415.64 ± 66.65\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.054\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN energy (kcal/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e140.43 ± 83.44\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e71.81 ± 54.88\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.053\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePN energy (kcal/kg/w)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e325.73 ± 43.65\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e343.83 ± 43.85\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.231\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein energy ratio (g/100 kcal)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c2\"\u003e \u003cp\u003e4.15 ± 0.69\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"±\" colname=\"c3\"\u003e \u003cp\u003e4.15 ± 0.57\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.993\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003ePN = parenteral nutrient, EN = Enteral nutrient\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003ch2\u003e3.2.2 Serum cytokines\u003c/h2\u003e\u003cp\u003eThe total of 8 cytokine data in 38 infants in this research were subsets of data that have been previously published by our team [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and were regrouped to Day 2–7 and Day 14–28, and all prior data were reanalyzed to provide a consistent comparison (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Compared to non-BPD group, IL-10 on Day 2–7 and IL-13 on Day 14–28 were significantly decreased in BPD group (P \u0026lt; 0.05), while IL-4, IL-6, and IL-8 on Day 14–28 were significantly increased in BPD group (P \u0026lt; 0.05).\u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of neonatal serum cytokine concentrations between premature infants with BPD and Non-BPD group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (days)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNon-BPD(\u003cem\u003en\u003c/em\u003e = 24)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eBPD(\u003cem\u003en\u003c/em\u003e = 14)\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eZ\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eP-value\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIFN-γ\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8.85(6.75,18.00)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.95(6.80,15.00)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.288\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.777\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.55(7.20,18.00)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.95(6.90,12.53)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.924\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.361\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIL-10\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.00(2.18,5.30)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.45(2.03,2.73)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.276\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.90(2.10,5.30)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.30(2.10,2.95)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.475\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.144\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIL-12p70\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.10(0.90,1.28)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.25(1.00,1.40)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.636\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.106\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.90(0.53,1.10)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.80(0.38,1.03)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.501\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIL-13\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.75(5.70,9.33)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.65(5.00,9.05)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.682\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.501\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.10(8.03,10.40)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.00(7.73,8.43)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.536\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.30(0.20,0.58)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.40(0.20,0.50)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.368\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.731\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.30(0.20,0.50)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.90(0.38,1.20)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-3.099\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.60(5.05,6.85)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6.20(5.83,7.00)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.364\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.173\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.90(5.13,7.15)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.15(7.90,9.45)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-3.213\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e159.00(154.00,176.00)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e175.50(148.25,181.50)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.485\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.643\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e277.00(248.25,318.75)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e472.00(429.75,513.75)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-3.829\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTNF-α\u003c/p\u003e \u003cp\u003e(pg/mL)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2–7\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.50(0.23,0.60)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.70(0.48,0.90)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.805\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.076\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14–28\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.65(0.40,1.15)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.95(0.75,1.25)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.837\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.067\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003ePN = parenteral nutrient, EN = Enteral nutrient\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003cp\u003e\u003c/p\u003e\u003ch2\u003e3.2.3 FiO2 on Day 28\u003c/h2\u003e\u003cp\u003eFiO2 on Day 28 was higher in BPD group than in non-BPD group (33.07 ± 7.92 vs 21.00 ± 0.00, \u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001).\u003c/p\u003e\n\u003ch3\u003eCorrelation analysis between nutritional support and serum cytokines\u003c/h3\u003e\n\u003cp\u003eCorrelation analyses for the indicators with significant differences in comparison between BPD group and non-BPD group were carried out. The correlation between serum cytokines and nutritional support is shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, total protein, total energy and EN proteins, EN carbohydrates, EN lipids, and EN energy in the first week were negatively correlated with IL-4, IL-6, and IL-8 on Day 14\u0026ndash;28, and total protein was positively correlated with IL-10 on Day 2\u0026ndash;7; these differences were statistically significant (r\u0026thinsp;\u0026lt;\u0026thinsp;0, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCorrelation between serum cytokines and nutritional support in the first week\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"11\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eIL-10 on Day 2\u0026ndash;7\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eIL-13 on Day 14\u0026ndash;28\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eIL-4 on Day 14\u0026ndash;28\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c9\" namest=\"c8\"\u003e \u003cp\u003eIL-6 on Day 14\u0026ndash;28\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eIL-8 on Day 14\u0026ndash;28\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cem\u003er\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal protein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.322\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.050\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.298\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.426\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e-0.456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN proteins\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.890\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.971\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.528\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e-0.474\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN carbohydrates\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.458\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-0.117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.483\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.445\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e-0.391\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.015\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN lipids\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-0.109\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.516\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.472\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e-0.409\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN energy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.532\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.398\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e-0.435\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.006\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal energy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e-0.374\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e \u003cp\u003e-0.453\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"11\"\u003ePN\u0026thinsp;=\u0026thinsp;parenteral nutrient, EN\u0026thinsp;=\u0026thinsp;Enteral nutrient\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eMediation of serum cytokines on the relation between nutritional support and FiO2 on Day\u003c/h3\u003e\n\u003ch3\u003e28.\u003c/h3\u003e\n\u003cp\u003eSince IL-10 was positively correlated with total protein in the first week but did not show a significant correlation with FiO2 on Day 28, and IL-13 was negatively correlated with FiO2 on Day 28 but did not show a significant correlation with nutrition status, both of them were excluded from further analysis. According to the mediation effect theory raised by Kenny and Baron, we conducted a mediation analysis to test the mediation effect of IL-4, IL-6, and IL-8 between nutritional support factors, including EN proteins, total protein, EN carbohydrates, EN energy in the first week, and FiO2 on Day 28. Based on bootstrap sampling, the 95% confidence interval was calculated, and the results indicated that the intermediary effect was significant when 0 was not included in the confidence interval. The results are shown in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. IL-4 was a mediator of the relationship between EN lipid, EN carbohydrates, EN energy, total energy in the first week and FiO2 on Day 28. At the same time, a similar mediation effect of IL-6 and IL-8 was examined in regard to the relationship between total protein, EN proteins, EN carbohydrates, EN lipid, EN energy, total energy in the first week and FiO2 on Day 28.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociation between nutritional support, or serum cytokines on Day 14–28 and FiO\u003csub\u003e2\u003c/sub\u003e on Day 28\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCoefficient\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ec path\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ea path\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eb path\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN proteins\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.404(0.152),0.012\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.460(0.148),0.004\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.280(0.168),0.104\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.404(0.152),0.012\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.528(0.142),0.001\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.343(0.173),0.055\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.404(0.152),0.012\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.474(0.147),0.003\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.491(0.155),0.003\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal protein\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.386(0.154),0.017\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.426(0.151),0.008\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.295(0.165),0.082\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.386(0.154),0.017\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.411(0.152),0.010\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.363(0.160),0.029\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.386(0.154),0.017\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.456(0.148),0.004\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.500(0.153),0.003\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN lipids\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.317(0.158),0.052\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.363(0.155),0.025\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.335(0.162),0.047\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.317(0.158),0.052\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.472(0.147),0.003\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.400(0.169),0.023\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.317(0.158),0.052\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.409(0.152),0.011\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.531(0.151),0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eEN carbohydrates\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.333(0.157),0.041\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.345(0.156),0.034\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.331(0.160),0.047\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eβ(SE),P\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.333(0.157),0.041\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.445(0.149),0.005\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.389(0.165),0.024\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.333(0.157),0.041\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.391(0.153),0.015\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.521(0.149),0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eEN energy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.331(0.157),0.043\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.375(0.155),0.021\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.328(0.163),0.051\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.331(0.157),0.043\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.398(0.153),0.013\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.391(0.161),0.020\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.331(0.157),0.043\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.435(0.150),0.006\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.528(0.153),0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal energy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.287(0.160),0.080\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.374(0.155),0.021\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.347(0.164),0.042\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.287(0.160),0.080\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.374(0.155),0.021\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.411(0.160),0.015\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(SE),P\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.287(0.160),0.080\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e-0.453(0.149),0.004\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.556(0.155),0.001\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eFiO\u003csub\u003e2\u003c/sub\u003e \u003cb\u003e=\u003c/b\u003e fraction of inspired oxygen on Day 28, PN = parenteral nutrient, EN = Enteral nutrient\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003ec total association between the independent variables (X = nutritional support) and the outcome variable (Y = FiO\u003csub\u003e2\u003c/sub\u003e on Day 28), the association between X and the potential mediator (M = serum cytokines on Days 14–28), b association between M and Y was examined, adjusted for the X. Level of serum cytokines, nutritional support, FiO\u003csub\u003e2\u003c/sub\u003e on Day 28 were natural log transformed for mediation analysis.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\u003cdiv class=\"gridtable\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"−\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"−\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMediation of serum cytokines on Day 14–28 on the relationship between nutritional supports and FiO\u003csub\u003e2\u003c/sub\u003e on Day 28\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e\u003ccolgroup cols=\"7\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eX\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eM\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eDirect association\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eIndirect association\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eβ(95% CI)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cem\u003eβ(95% CI)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eEN proteins\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.275(-0.615-0.065)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.110\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.129(-0.335 ~ 0.011)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.223(-0.573-0.128)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.206\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.181(-0.601~-0.025)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.171(-0.485 ~ 0.143)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.277\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.233(-0.573~-0.068)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eTotal protein\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.260(-0.595 ~ 0.074)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.123\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.126(-0.341 ~ 0.028)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026gt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.237(-0.561 ~ 0.087)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.147\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.149(-0.413~-0.042)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.158(-0.470 ~ 0.153)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.310\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.228(-0.542~-0.074)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eEN lipids\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.195(-0.525 ~ 0.134)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.237\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.122(-0.367~-0.013)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.129(-0.471 ~ 0.214)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.452\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.189(-0.456~-0.039)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.100(-0.406 ~ 0.207)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.513\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.217(-0.527~-0.077)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eEN Carbohydrates\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.219(-0.545 ~ 0.107)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.181\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.114(-0.305~-0.011)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.160(-0.496 ~ 0.176)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.340\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.173(-0.434~-0.049)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.129(-0.432 ~ 0.174)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.393\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.204(-0.447~-0.073)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEN energy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.208(-0.538 ~ 0.123)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.211\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.123(-0.296~-0.016)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.175(-0.502 ~ 0.151)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.283\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.155(-0.415~-0.035)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.101(-0.412 ~ 0.210)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.513\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.230(-0.513~-0.079)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eTotal energy\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-4\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eFiO\u003csub\u003e2\u003c/sub\u003e\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.157(-0.491 ~ 0.177)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.346\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.130(-0.371~-0.009)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-6\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.133(-0.459 ~ 0.192)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.411\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.154(-0.410~-0.035)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIL-8\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c4\"\u003e \u003cp\u003e-0.036(-0.351 ~ 0.280)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.820\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\"−\" colname=\"c6\"\u003e \u003cp\u003e-0.252(-0.546~-0.095)\u003c/p\u003e \u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt; 0.05\u003c/p\u003e \u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eFiO\u003csub\u003e2\u003c/sub\u003e \u003cb\u003e=\u003c/b\u003e fraction of inspired oxygen on Day 28, PN = parenteral nutrient, EN = Enteral nutrient\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e \u003cp\u003e\u003c/p\u003e "},{"header":"Discussion","content":"\u003cp\u003eBPD is a lung disease that causes dependence on oxygen supplementation for an extended period\u003c/p\u003e\u003cp\u003eof time, which is a common respiratory disease with a high mortality rate that affects premature infants. Survivors often leave behind repeated lower respiratory tract infections and growth retardation, which makes it a critical factor affecting the quality of life of premature infants. The risk factors for BPD suggested by previous studies include low gestational age, small birth weight, oxygen, respiratory support, nutrition and infection[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recently, studies have also shown a close association between various cytokines and the occurrence and development of BPD in preterm infants.\u003c/p\u003e\u003cp\u003eIn premature infants born at \u0026lt; 32 gestational weeks, alveoli formation begins and is incomplete, Tissue apoptosis and the accumulation and activation of inflammatory cells in the lungs due to various inflammatory cytokines are possible contributors to BPD[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].Results provided by the scarce studies carried out in infants support the evidence from previous animal experiments. IL-1β, IL-6, TNF-α, and IL-10 cytokine levels were altered in the amniotic fluid[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], core blood[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and serum[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]were observed in BPD infants. In addition, studies showed pro-inflammatory cytokine (such as IL-6) activity in cord blood positively correlates with gestational age, whereas anti-inflammatory cytokine (such as IL-10 ) does not [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. On the basis of previous studies[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], compared to non-BPD infants, some particular cytokine levels were upregulated in the first 28 days of life in BPD infants. In the study presented here, we further explored the correlation between the cytokine profile and FiO\u003csub\u003e2\u003c/sub\u003e on day 28. Our results confirm the fact that during the first week of life, infants with BPD had significantly lower IL-10 levels. However, this inflammation is transient and no longer present on days 14–28. Instead, IL-4, IL-6, and IL-8 were increased in the BPD group on days 14–28. Which means Persistent lung inflammation, with an imbalance of pro-inflammatory versus anti-inflammatory mediators, plays a central role in the pathogenesis of BPD along with an arrest of lung growth.IL-6 and IL-8 are pro-inflammatory cytokines. IL-6 is secreted by macrophages, T cells and endothelial cells to stimulate the immune response, leading to the synthesis of a variety of inflammatory mediators, including neutrophils, and secreting a variety of inflammatory mediators to promote inflammation, thus causing airway remodeling. which is an independent risk factor for BPD in premature infants[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The biological function of IL-8 is to mediate neutrophil migration, development and aggravation of inflammatory responses. It has been hypothesized that elevated cord blood IL-8 is associated with death or moderate/severe BPD[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIL-10 is a potent anti-inflammatory cytokine, and an increasing number of studies have shown that IL-10 could be a protective factor against the development of BPD by reducing acute lung injury caused by mechanical stretching [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In addition, inhibiting the activation of nuclear transcription factor-κB (NF-κB) is secondary to hyperoxia injury [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. In our research, the non-BPD group had higher IL-10 on days 2–7, and the difference between the two groups disappeared on days 14–28. This result may suggest that the protective effect of IL-10 decreased over time.\u003c/p\u003e\u003cp\u003eAt the same time, the results of our study showed lower IL-13 on days 14–28 and higher IL-4 in the BPD group than in the non-BPD control group, which suggested that the increased expression of IL-4 may be involved in abnormal lung development and maturation in neonates with BPD and that IL-13 may play a protective role in the development of BPD. Even though IL-13 is associated with the development of bronchial hyperreactivity[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], but it also inhibits inflammatory cytokine production in macrophages andepithelial cells such as TNF-α, IL-6, IL-8 and IL-1β [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and upregulates the anti-inflammatory cytokine[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. At the same time, the action of IL-4 was two-sided effects of lung inflammation, it may inhibits to some aspects of lung inflammation, furthermore, it may induces collagen production and proliferation of subsets of lung fibroblasts[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. It has been clearly demonstrated that nutrition status influences immune cell function in previous research and that immune cell function determines the cellular metabolic state, and the role of cytokines as mediators of weight loss and anorexia or chronic liver disease has been previously proven in studies concerning malignancies, showing an apparent relationship between the levels of IL-6, IL-1 and TNF and neoplastic cachexia [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Is it possible that nutritional status promotes the development of BPD by affecting cytokines? How do it contribute to bpd? Given the above, we attempted to assess the mediation effect of serum cytokines in the development of BPD from nutrition to explore the mechanism of BPD.\u003c/p\u003e\u003cp\u003eFor very low birth weight (VLBW) and extremely low birth weight (ELBW) infants whose alveolar maturity mostly or completely occurs after birth, nutrition supply in the early postnatal period plays a crucial role in respiratory development[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Regarding the association of nutritional support with the development of BPD described by our research, the BPD group had a significantly lower total energy and total protein intake than the non-BPD group within the first week after birth. Malnutrition interferes with pulmonary defenses against volutrauma and infection, all of which are harmful to lung repair, development and maturation. Early sufficient protein supply in premature infants can lower protein breakdown, promote improved protein balance, and increase protein synthesis[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. In a retrospective cohort study of BPD infants, it was found that an energy intake in the range of 120–150 kcal/kg/day and a minimum protein intake of at least 3.5 g/kg/day are needed in BPD infants[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eMoreover, our results show that infants who survived without BPD had a significantly higher intake of enteral feed (including each ingredient and energy) and a lower parenteral intake than infants who developed BPD. In a prospective study, the same association identified that enteral nutrition can reduce the incidence of growth retardation in premature infants with BPD[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The start of enteral nutrition was delayed by the presence of hemodynamic or respiratory instability, which means that such infants may suffer from inflammation of the storm caused by infection, the lungs of shunt caused by PDA, or mechanical stretch caused by mechanical ventilation.\u003c/p\u003e\u003cp\u003eOur results showed dynamic changes in cytokines at different time points. Some cytokines (e.g.IL-4, IL-6, IL-8 and IL-13) showed no significant changes in the early stages but exhibited significant changes in the late stages in premature infants who received insufficient nutrition in the first week of life and subsequently developed BPD. From a comprehensive perspective of the results of the correlation study between cytokines and nutritional support, we supposed that early nutritional support influenced the development of BPD though IL-4, IL-6, IL-8 and IL-13. Then the role of inflammatory mediating effect in nutrition and BPD was further explored in our study. The results show that there is an intermediary relationship between total protein, enteral nutrition (including carbohydrates, energy and proteins) and FiO2 on day 28, which supports the idea that early protein and enteral nutrition deficiency can improve oxygen dependence on day 28 after birth and promote BPD by increasing proinflammatory mediators on days 14–28.\u003c/p\u003e\u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, the occurrence and development of BPD was involving various factors, such as birth weight and gestational age, and these characteristics make difference of complications, such as infections, PDA, mechanical Ventilation time and NRDS etc. (which can in turn affect the inflammatory status) in two group. These clinical complications of premature birth were complex processes involving multiple factors, and multi-stage interactions, in addition, some maternal factors could also affect the inflammatory state of the newborn (e.g. intrauterine infection), nutritional support was only accounts for a part of it. At that same time, nutrition support also affects the occurrence of BPD through various ways, our findings illustrate that serum cytokines mediated a partial association between nutrition support and BPD, which implies that for premature infants, BPD may result from cytokine changes caused by other factors (such as hyperoxia injury and gut microbiota), apart from the mediating role of the change in serum cytokines in nutritional support, which is worthy of further investigation.\u003c/p\u003e\u003cp\u003eOur results provide evidence for BPD control measures in early nutrition and provide hints for exploring the potential mechanisms of these risk factors. Based on these facts, the efforts of clinicians have been focused on effective nutritional treatment strategies. We must note that the sample in our study was very small, and this observation needs to be verified in a larger cohort.\u003c/p\u003e\u003cp\u003eWe are aware of the limitations of our study, as it is a single-center retrospective cohort, and the present study is a cross-sectional study, which could only provide association and by nature could not provide causality. Future longitudinal studies may further verify the serum cytokine mediation effect of nutrition and BPD. Certainly, the design of retrospective data collection and analysis does allow us to generate a hypothesis by identifying significant associations between several variables and the outcomes and it should be well tested by a prospective, randomized clinical trial in future researches. What’s more, cytokine was partly intermediate between nutritional factors and BPD, and we are looking forward more researches to explore other intermediary factors.\u003c/p\u003e\u003cp\u003eHowever, we believe that our data can help support future meta-analysis studies on this hypothesis. Strong evidence indicates that energy and protein intake in the first weeks of life is important in the lung development of premature infants.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur results show that poor nutrition intake is associated with the upregulation of proinflammatory\u003c/p\u003e\u003cp\u003eCytokines also increased the incidence of BPD. Inefficient EN nutrition, total energy and protein intake in the first week of life is associated with FiO2 on Day 28 by mediating serum cytokines.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThe experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration. The collection of cytokine data in this study was approved by the Human Ethics Committee of Peking Union Medical College Hospital, Chinese Academy of Medical Sciences. The ethical review number was ZS-1552. All of the procedures were performed in accordance with the Declaration of Helsinki and relevant policies in China. All parent or legal guardian for this study participation gave their informed consent for publication\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have declared they have no conflicting interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThis work was supported by the Non-profit Central Research Institute Fund of Chinese Academy of Medical Science\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJing-Jing Jiang performed the research, analyzed the data and wrote the paper,\u0026nbsp;Zhen-jie Zhang was responsible for the data curation and investigation, Yun-wei Li was responsible for data curation, Weilin Wan\u0026nbsp;was responsible for methodology, and project administration.\u0026nbsp;Zheng-hong Li\u0026nbsp;as\u0026nbsp;\u003cem\u003eCorresponding Author\u003c/em\u003e designed the research study, review and editing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMourani, P.M. and S.H. Abman, Pulmonary vascular disease in bronchopulmonary dysplasia: pulmonary hypertension and beyond. Curr Opin Pediatr, 2013. 25(3): p. 329-37.\u003c/li\u003e\n\u003cli\u003eJensen, E.A. and B. Schmidt, Epidemiology of bronchopulmonary dysplasia. Birth Defects Res A Clin Mol Teratol, 2014. 100(3): p. 145-57.\u003c/li\u003e\n\u003cli\u003eUberos, J., et al., Early energy restriction in premature infants and bronchopulmonary dysplasia: a cohort study. Br J Nutr, 2020. 123(9): p. 1024-1031.\u003c/li\u003e\n\u003cli\u003ePoindexter, B.B. and C.R. Martin, Impact of Nutrition on Bronchopulmonary Dysplasia. Clin Perinatol, 2015. 42(4): p. 797-806.\u003c/li\u003e\n\u003cli\u003eSpeer, C.P., Inflammation and bronchopulmonary dysplasia. Semin Neonatol, 2003. 8(1): p. 29-38.\u003c/li\u003e\n\u003cli\u003eKaneko, M., et al., Serum cytokine concentrations, chorioamnionitis and the onset of bronchopulmonary dysplasia in premature infants. 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Kenny, The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol, 1986. 51(6): p. 1173-82.\u003c/li\u003e\n\u003cli\u003eThebaud, B., et al., Bronchopulmonary dysplasia. Nat Rev Dis Primers, 2019. 5(1): p. 78.\u003c/li\u003e\n\u003cli\u003eChoo-Wing, R., et al., Developmental differences in the responses of IL-6 and IL-13 transgenic mice exposed to hyperoxia. Am J Physiol Lung Cell Mol Physiol, 2007. 293(1): p. L142-50.\u003c/li\u003e\n\u003cli\u003eYoon, B.H., et al., Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol, 1997. 177(4): p. 825-30.\u003c/li\u003e\n\u003cli\u003eRocha, G., et al., Cord blood levels of IL-6, IL-8 and IL-10 may be early predictors of bronchopulmonary dysplasia in preterm newborns small for gestational age. Dis Markers, 2012. 33(1): p. 51-60.\u003c/li\u003e\n\u003cli\u003eDembinski, J., et al., Modulation of pro- and anti-inflammatory cytokine production in very preterm infants. Cytokine, 2003. 21(4): p. 200-6.\u003c/li\u003e\n\u003cli\u003eTian, X.Y., et al., Biological markers in cord blood for prediction of bronchopulmonary dysplasia in premature infants. Clin Exp Obstet Gynecol, 2014. 41(3): p. 313-8.\u003c/li\u003e\n\u003cli\u003eHawwa, R.L., et al., IL-10 inhibits inflammatory cytokines released by fetal mouse lung fibroblasts exposed to mechanical stretch. Pediatr Pulmonol, 2011. 46(7): p. 640-9.\u003c/li\u003e\n\u003cli\u003eLi, H.D., et al., Exogenous interleukin-10 attenuates hyperoxia-induced acute lung injury in mice. Exp Physiol, 2015. 100(3): p. 331-40.\u003c/li\u003e\n\u003cli\u003eWong, W.S. and D.S. Koh, Advances in immunopharmacology of asthma. 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Vestn Dermatol Venerol, 1976(8): p. 88-9.\u003c/li\u003e\n\u003cli\u003eSantetti, D., et al., Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease. World J Gastroenterol, 2015. 21(29): p. 8927-34.\u003c/li\u003e\n\u003cli\u003ePatel, H.J. and B.M. Patel, TNF-alpha and cancer cachexia: Molecular insights and clinical implications. Life Sci, 2017. 170: p. 56-63.\u003c/li\u003e\n\u003cli\u003eAl-Jebawi, Y., et al., Low caloric intake and high fluid intake during the first week of life are associated with the severity of bronchopulmonary dysplasia in extremely low birth weight infants. J Neonatal Perinatal Med, 2020. 13(2): p. 207-214.\u003c/li\u003e\n\u003cli\u003eMilanesi, B.G., et al., Assessment of early nutritional intake in preterm infants with bronchopulmonary dysplasia: a cohort study. Eur J Pediatr, 2021. 180(5): p. 1423-1430.\u003c/li\u003e\n\u003cli\u003eThiess, T., et al., Correlation of Early Nutritional Supply and Development of Bronchopulmonary Dysplasia in Preterm Infants \u0026lt;1,000 g. Front Pediatr, 2021. 9: p. 741365.\u003c/li\u003e\n\u003cli\u003eGianni, M.L., et al., The role of nutrition in promoting growth in pre-term infants with bronchopulmonary dysplasia: a prospective non-randomised interventional cohort study. BMC Pediatr, 2014. 14: p. 235.\u003c/li\u003e\n\u003cli\u003eUberos, J., et al., Nutrition in extremely low birth weight infants: impact on bronchopulmonary dysplasia. Minerva Pediatr, 2016. 68(6): p. 419-426.\u003c/li\u003e\n\u003c/ol\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":"Serum cytokines, nutritional status, BPD, fraction of inspired oxygen","lastPublishedDoi":"10.21203/rs.3.rs-3237649/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3237649/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eTo verify whether nutritional support is associated with Bronchopulmonary Dysplasia (BPD) by mediating serum cytokines.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe recorded in a retrospective cohort study the intake of enteral nutrition (EN) and parenteral nutrition (PN) in the first week, serum cytokines on Day 2\u0026ndash;7 and Day 14\u0026ndash;28 by examining the nutritional and clinical history of 34 newborns born at gestational age\u0026thinsp;\u0026le;\u0026thinsp;32 weeks admitted to the neonatal intensive care unit from January 2018 to October 2019.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eNon-BPD group (24 infants) had a significantly higher gestational age and higher birth weight than the BPD group (14 infants). Among the infants with non-BPD, total proteins, total energy and EN carbohydrates, EN proteins, EN lipids, and EN energy in the first week intake and IL-4, IL-6, IL-8 on Day 14\u0026ndash;28 and FiO\u003csub\u003e2\u003c/sub\u003e on Day 28 were significantly lower, and IL-10 on Day 2\u0026ndash;7 and IL-13 on Day 14\u0026ndash;28 was significantly higher. Pearson correlation analysis showed a negative correlation between total protein, total energy and EN proteins, EN carbohydrates, EN lipids, and EN energy in the first week with IL-4, IL-6, and IL-8 on Day 14\u0026ndash;28. In mediation analyses, total protein, EN proteins, EN carbohydrates, EN lipid, EN energy, total energy in the first week were related to FiO2 on day 28 partly mediated by IL-6 and IL-8 on Day 14\u0026ndash;28.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eOur results showed that inefficient nutrition, especially EN nutrition intake in the first week of life were associated with BPD by mediating proinflammatory cytokines on Day 14\u0026ndash;28.\u003c/p\u003e","manuscriptTitle":"Serum cytokines in the mediation roles on the relationship between nutritional support and bronchopulmonary dysplasia in premature infants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-10-05 15:10:47","doi":"10.21203/rs.3.rs-3237649/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":"94c19214-4b18-4b70-95f0-7d61fd23a747","owner":[],"postedDate":"October 5th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-04-25T11:19:38+00:00","versionOfRecord":[],"versionCreatedAt":"2023-10-05 15:10:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3237649","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3237649","identity":"rs-3237649","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}