Correlation of Serum IL-1β, IL-6, and hsCRP levels with Infarct Core and Ischemic Penumbra Volume in Acute Ischemic Stroke

Correlation of Serum IL-1β, IL-6, and hsCRP levels with Infarct Core and Ischemic Penumbra Volume in Acute Ischemic Stroke | 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 Correlation of Serum IL-1β, IL-6, and hsCRP levels with Infarct Core and Ischemic Penumbra Volume in Acute Ischemic Stroke Zhou Jianbo, Li Lin, Ji Xiyang, Zhang Xiaojie, Dai Changfei, Wang Sa, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1882454/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Background During cerebral ischemia, inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β released from the ischemic core may trigger neuronal death in the ischemic penumbra, influencing infarct volume. This study aimed to understand the relationship between serum IL-1β, IL-6, and high-sensitivity C-reactive protein (hs-CRP) levels with infarct core and ischemic penumbra volume in patients with acute ischemic stroke (AIS) and its influence on prognosis. Methods The serum levels of IL-1β, IL-6, and hs-CRP were measured in 65 patients within 24h of AIS onset. The infarcts of the patients were imaged with magnetic resonance imaging and magnetic resonance angiography. Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and core volume on computed tomography perfusion or perfusion-weighted imaging were used to calculate infarct volume and ischemic penumbra volume. The Tan collateral score was calculated with Neusoft Brain Clinical Assistant Ration Evaluate (NeuBrainCARE). Results We found a significant correlation between infarct core volume and serum hs-CRP levels (P < 0.05) and between penumbra volume and IL-6 levels (P < 0.05). Serum IL-6 and hs-CRP levels were positively correlated with NIHSS scores at admission, discharge, and 3 months after discharge. IL-1β levels, Tan collateral score, and ASPECTS showed no correlation with the infarct core volume. Conclusion A significant correlation between hs-CRP and IL-6 levels and infarct and ischemic penumbra volume, respectively, and with NIHSS score shows that these two factors might prove helpful in predicting the extent of neurological damage in AIS patients after 3 months of onset, opening new avenues for treatment. IL-1β IL-6 hs-CRP infarct core volume ischemic penumbra Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Background Ischemic stroke (IS) is the second leading cause of death worldwide and the first leading cause of acquired long-term disability, placing a heavy burden on the global economy.[ 1 ] The pathophysiology of IS is a complex process that results from a sudden decrease or loss of blood circulation to an area of the brain. The subsequent biochemical events eventually lead to neuronal death at the infarction core. However, the larger volume of brain tissue surrounding the ischemic core, the penumbra, can be rescued if cerebral blood flow is promptly restored. Current IS treatment focuses on reducing brain damage by saving the ischemic penumbra. Currently, evidence-based treatments focus on restoring blood flow early (within 4.5 h) to rescue the ischemic penumbra before it gets progressively recruited to form a larger ischemic core. A previous study suggested that if the volume of the infarcted brain tissue is smaller, the neurological outcome will be better.[ 2 ] However, the success rate of early recanalization with intravenous thrombolysis is only about 30%. Compared to intravenous thrombolysis (IVT), the mechanical thrombectomy applied to remove occluded clots significantly improves stroke patients’ prognosis. Although more than 80% of IS patients receive mechanical thrombectomy and achieve early recanalization, about 50% of the patients still do not enjoy functional independence after thrombectomy as the infarct core becomes too large during recanalization.[ 3 ] The two important pathophysiological mechanisms involved in the ischemic damage of neuronal function are oxidative stress and inflammation. Experimental studies have demonstrated that free radical-induced oxidative stress is one of the significant contributors to ischemic lesion and reperfusion-related brain tissue damage. In acute IS (AIS), the damaged brain cells produce reactive oxygen species (ROS) that activate the endothelial cells and cause oxidative stress. This leads to primary vascular damage and promotes acute immune responses associated with the development of an inflammatory response.[ 4 ] In the acute phase of IS, the resident brain immune cells, microglia, are activated. They subsequently invade the peri-infarct and infarct core and induce the expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1 beta (IL-1β), and anti-inflammatory IL-1 receptor antagonist (IL-1Ra). Increased blood-brain barrier permeability results in the infiltration of neutrophils, macrophages, and other leukocytes. The activation of these immune cells further increases the burden of proinflammatory cytokines.[ 5 ] Thus, the resident and infiltrating immune cells in the brain orchestrate a post-stroke inflammatory response. Experimental evidence has shown that targeting some of these inflammatory cytokines, such as TNF, IL-1, IL-6, and IL-10, holds promise.[ 6 – 9 ] IL-6 is released by different cells, such as microglial cells, astrocytes, leukocytes, and endothelial cells, which is a part of the response to brain damage. It stimulates hepatocytes to synthesize acute phase proteins, mainly C-reactive protein (CRP) and fibrinogen[ 10 ]. IL-6 is a key inflammatory marker in stroke. IL-1 mediates IL-6 mRNA expression by increasing intracellular cyclic adenosine monophosphate (cAMP), and numerous studies have shown a significant increase in IL-6 serum level, which occurs within a few hours after the onset of ischemia and lasts for up to 90 days after the stroke.[ 11 ] IL-1β, TNF-α, and IL-6 are the three main pro-inflammatory cytokines that cause and aggravate the inflammatory response after stroke.[ 12 , 13 ] Tuttolomondoa et al .[ 14 ] found that the levels of TNF-α, IL-6, and IL-1β are significantly increased in the plasma of patients with cardioembolic stroke. IL-1 mediates IL-6 mRNA expression by increasing intracellular cAMP. Studies have also shown a significant increase in IL-6 concentration in the serum within a few hours of onset of ischemia, which lasts for up to 90 days after stroke.[ 11 ] Pawluk et al .[ 15 ] suggested that IL-6 has potential prognostic significance for the success of thrombolytic therapy. Hotter[ 16 ] demonstrated that, in a cohort of patients with no infections, the levels of IL-6 are associated with several parameters such as acute diffusion-weighted imaging (DWI) lesion, perfusion deficit, final infarct size, and affection of cortex from acute stroke magnetic resonance imaging (MRI). IL-6, in turn, stimulates hepatocytes to synthesize acute phase proteins, mainly CRP and fibrinogen.[ 10 ] Several studies have shown that elevated high-sensitive CRP (hs-CRP) after stroke is associated with unfavorable outcomes.[ 17 ] Several population-based investigations have demonstrated a correlation between inflammatory biomarkers (such as CRP, fibrinogen, D-dimer, and white blood cell count) and the risk of incident and recurrent stroke. There have been few studies on the relationship between serum levels of inflammatory factors and ischemic penumbra and their impact on the prognosis of patients with AIS.[ 18 ] In addition, the relationship between infarct volume and inflammatory markers has rarely been reported. This study determined if there is a correlation between the serum levels of inflammatory factors IL-1β, IL-6, and hs-CRP with infarct core volume and ischemic penumbra volume in patients with AIS, and evaluated their effects on patients’ prognosis to help in timely recognition of especially vulnerable populations. Patients And Methods Study design and population 65 patients with first-time AIS, admitted within 24h of onset to Xianyang Hospital of Yan’an University (Xianyang City, China) from October 2020 to March 2022, were included in this study. Before inclusion, all patients provided signed informed consent, and the study was approved by the hospital’s ethics committee. The patients were diagnosed with acute cerebral infarction by MRI. Inclusion criteria were: age 18–80 years old (including boundary value), first time acute cerebral infarction of the internal carotid artery system (anterior circulation) according to Chinese guidelines for the diagnosis and treatment of acute ischemic stroke 2018, admitted within 24 h of stroke onset, and followed up with secondary preventive treatment after discharge from the hospital. Exclusion criteria were: computed tomography (CT) or MRI examination of the head showing the presence of intracranial hemorrhagic diseases (e.g., hemorrhagic stroke, epidural hematoma, intracranial hematoma, ventricular hemorrhage, subarachnoid hemorrhage); patients suffering from malignant tumors, diseases of the blood system, immune system, tuberculosis, or moderate-to-severe infections; comorbidity such as dysfunctional organs (e.g., heart, liver, kidney); being unable to cooperate or unwilling to cooperate due to severe mental disorder or mental illness; patients with non-anterior circulation infarction; patients suffering from acute coronary heart disease, heart failure, or myocardial and cardiovascular diseases; and no restricted diffusion on diffusion-weighted MRI sequences(Fig. 1 ). Based on the results of brain MRI with 1.5T (Philips Prodiva; Philips Amsterdam, the Netherlands) or 3.0T (Siemens Verio; Siemens, Munich, Germany) superconducting MRI, the cerebral infarction volume was evaluated. T1-weighted image (T1WI), T2WI, diffusion-weighted imaging (DWI), and MR angiography (MRA) sequences were used for comprehensive diagnosis and Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. Perfusion-weighted imaging (PWI) or CT perfusion (CTP) confirmed the cerebral perfusion. NeuBrainCARE was used to measure the infarct volume on the apparent diffusion coefficient sequence. The hypoperfusion volume was automatically calculated on CTP or PWI sequences via NeuBrainCARE. The ASPECTS was calculated on CT sequences, and the Tan collateral score was calculated on MRA sequences through NeuBrainCARE. Blood was collected from the AIS patients on admission, and the serum levels of IL-1β, IL-6, and hs-CRP were measured. Serum IL-1β and IL-6 levels were measured with the enzyme-linked immunosorbent assay, and hs-CRP concentrations were measured with latex-enhanced immunoturbidimetry. Neurological assessment was conducted using the NIH Stroke Scale (NIHSS). Evaluations at 8 h intervals by two physicians, who have more than 5 years of clinical experience in neurology, with an interval of more than 8 h on the same day. The average value of each evaluation score was taken as the final score. The average scores from each of the 11 items listed in the NIHSS were added to calculate each patient’s total NIHSS score. The scores on the NIHSS range from 0 to 42. The higher the score, the more serious the neurological deficit. Statistical Analyses Correlation analyses were performed between the serum levels of IL-1β, IL-6, and hs-CRP with infarct volume. The relationship between inflammatory factors and neurological function score (NIHSS score) was analyzed at admission, discharge, and 3 months after cerebral infarction. All data were analyzed with SPSS 26.0, and the normality and homogeneity of variance were tested for continuous variables. The data are expressed as the mean ± standard deviation. According to the normality test, the correlation between the two indexes was determined by Pearson’s or Spearman’s correlation analysis. P < 0.05 was considered statistically significant. Results 65 stroke patients (37 males and 28 females) underwent non-thrombolytic therapy. The mean age of the patients without thrombolysis was 61.98 years (range: 37–80 years). The average time from onset to hospitalization was 11.45 ± 6.76 h (range:1–24 h). On admission, the average NIHSS score was 5.60 ± 2.78 (0–12). The clinical characteristics of the patients given non-thrombolytic therapy and their MRI results are listed in Table 1 . After exceeding the thrombolytic time window following admission, these patients were treated with double anticoagulants (aspirin 100 mg/day plus clopidogrel bisulfate 75 mg/day) for intensive lipid-lowering and neuroprotective effects, and improving collateral circulation. Table 1 Clinical characteristics of 65 patients with AIS Characteristics Age (years), mean ± SD (range) 61.98 ± 9.89 (37–80) Male : Female 37:28 Disease course (hour), mean ± SD (range) 11.45 ± 6.76 (1–24) Median length of stay (day), mean ± SD (range) 14.05 ± 4.14 (5–35) NIHSS score on admission, mean ± SD (range) 5.60 ± 2.78 (0–12) History Smoking-n (%) 23 (35.38) Hypertension - n (%) 43(66.15) Diabetes mellitus - n (%) 18 (27.69) Heart disease - n (%) 14 (21.54) Clinical characteristics Limb numbness and weakness - n (%) 21(32.31) Words adverse and vague - n (%) 34 (52.31) Limb weakness and Words vague- n (%) 8 (12.31) Physical clumsiness - n (%) 2(3.08) MRI characteristics Frontal lobe, parietal lobe, temporal lobe- n (%) 24 (36.92) Corpus callosum - n (%) 4 (6.15) Periventricular - n (%) 29 (44.62) Semi-oval center/basal ganglion - n (%) 8 (12.31) Stenosis or occlusion of the anterior cerebral artery - n (%) 30 (46.15) Stenosis or occlusion of the middle cerebral artery - n (%) 28 (43.08) Stenosis or occlusion of internal carotid artery - n (%) 7(10.77) Etiology (TOAST classification) Atherosclerosis - n (%) 40 (61.84) Arteriolar occlusion - n (%) 21 (32.31) Cardioembolism - n (%) 3 (4.62) Undetermined etiology - n (%) 1 (1.54) Values are presented as the mean ± SD (with range in parentheses below) or number (percentage) as appropriate; NIHSS National Institutes of Health Stroke Scale. Correlation between the infarct core volume within 24 h of AIS onset and the serum level of inflammatory factors Correlation analyses showed that the serum levels of IL-1β and IL-6 in the 65 patients, who did not undergo thrombolytic therapy, were not significantly correlated to the infarct core volume within 24 h of onset (P > 0.05). However, there was a significant positive correlation (r = 0.28, P = 0.03) between the infarct core volume and serum hs-CRP levels (Fig. 2 ). Our results showed that serum hs-CRP levels can predict the infarct core volume in AIS. Correlation between the ischemic penumbra volume within 24 h of AIS onset and the serum level of inflammatory factors 41 of 65 non-thrombolytic therapy patients underwent emergency digital subtraction angiography examination of cerebral vessels, as CTP or PWI was not available within 48h. Only 24 patients in this group received CTP or PWI examination. We considered the data of these 24 patients for the correlation study. The analyses showed that the penumbra volume was significantly correlated with serum IL-6 (r = 0.28, P = 0.007) level and not with serum IL-1β or hs-CRP (P > 0.05) level. Thus, serum IL-6 level can predict the volume of ischemic penumbra in AIS (Fig. 3 ). Correlation Between Collateral Circulation Score And Infarct Volume Collateral circulation was assessed from the ASPECTS calculated from the plain CT scans of 30 patients and the Tan scores obtained from the MRA of 36 patients. ASPECTS was 7.57 ± 2.01 (3–10) in the CT sequence, and the Tan collateral score was 1.86 ± 1.07 (0–3) in the MRA sequence via NeuBrainCARE. Correlation analyses showed that the infarct core was not significantly correlated with either the ASPECT score or TAN score (P > 0.05) (Figs. 4 and 5 ). Correlation Between Nihss Scores And Serum Il-1 β, Il-6, And Hs-crp Levels In Ais Patients Correlation between the NIHSS scores and the serum levels of IL-1β, IL-6, and hs-CRP were analyzed at admission, discharge, and at the 3-month follow-up in the 65 patients with AIS. The serum levels of IL-6 and hs-CRP showed a significant positive correlation (P < 0.05) with NIHSS scores at admission, discharge, and also at the 3-month follow-up (P 0.05). This indicates that serum IL-6 and hs-CRP levels in patients with AIS were related to the severity of neurological deficits and might help in the prognosis of patients with AIS (Fig. 6 ). Correlation analyses between the inflammatory factors showed that, at the time of admission, the serum concentrations of IL-6 were positively correlated with hs-CRP (P 0.05). IL-1β drives the IL-6 signaling pathway, and IL-6 binds to the IL-6 receptor on the liver cell membrane, which finally induces the liver to synthesize a series of acute-phase proteins, including the generation of hs-CRP.[ 19 ] Therefore, we speculate that the IL-6 signaling pathway in AIS plays an important role in affecting neurological function after stroke (Fig. 7 ). Discussion Inflammation plays an important role in the pathogenesis of IS. Inflammatory markers such as IL-1, IL-6, CRP, TNF-α, and fibrinogen are upregulated in AIS.[ 17 ] Studies have also associated these inflammatory markers with increased mortality, recurrent vascular risk, and poor functional outcome.[ 15 ] They have been suggested to cause injury to vascular endothelial cells, promote the release of inflammatory factors, and activate the coagulation cascade that can lead to further expansion of the infarct core after stroke.[ 3 , 20 – 23 ] The most studied inflammatory cytokines in AIS are the pro-inflammatory cytokines IL-1β, Il-6, and TNF-α.[ 9 , 17 ] In this study, we did not include TNF-α because the increasing trend of TNF-α, IL-1β, and IL-6 was consistent; for example, a previous study showed within 72 h of neurological sign onset, in a 1-month follow-up period, they assessed NIHSS as primary and plasma levels of TNF-α, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFN-γ, IP-10, MCP-1, 8-isoprostane were increased. The levels of plasma inflammatory markers TNF-α, IL-1β, IL-6, IL-8, and prostaglandin E2 P were significantly decreased in a therapy group after 7 days of intervention,[ 24 ] but the inflammatory factors IL-1β and IL-6 were increased significantly in cerebral ischemia.[ 12 , 13 , 25 , 26 ] Elevated levels of IL-1β after ischemia have been correlated with worsening of the infarct severity. The increased IL-1β levels following cerebral ischemia, in turn, elevate IL-6 level, which has been shown to correlate with brain infarct volume. [ 20 , 21 ] Elevated hs-CRP level is a risk factor and prognostic factor for IS and coronary events.[ 27 ] Our correlation analyses showed a positive association between the serum levels of hs-CRP and infarct core volume. IL-6 levels, on the other hand, have shown a positive correlation with ischemic penumbra. We also observed a positive correlation between the levels of IL-6 and hs-CRP. In addition, the NIHSS score was positively correlated with IL-6 and hs-CRP at all time points (admission, discharge, and 3-month follow-up) considered in this study. The correlation was only observed in patients who did not need thrombolysis therapy. In this study, we observed no significant correlation between the infarct volume or NIHSS score. A significant correlation was also not observed between the inflammatory factors and infarct volume or NIHSS score in the group of patients who underwent thrombolysis therapy. This may be because of the small number of patients. A future study involving more alteplase (rtPA)-treated AIS patients might clarify this discrepancy. Our study showed that the level of the serum IL-6 and hs-CRP within 24 h of onset can be used to predict the severity of neurological function within 3 months. Zhang et al .[ 28 ], in their correlation study among CRP, IL-6, insulin resistance, and cerebral infarction in hypertensive patients, showed that inflammatory factors and insulin resistance were positively correlated with the diameter of cerebral infarction and could aid in the neurological prognosis of the patients. In his study on the prognostic factors of AIS in young Egyptians, Fahmi[ 21 ] demonstrated that IL-6 and infarct diameter are independent predictors of prognosis in young Egyptians. A study on the synergistic effect of IL-6 and infarct size showed the therapeutic benefits of reducing IL-6 level during the early treatment of IS. Previous reports have shown that drugs or cAMP analogs, by increasing intracellular cAMP levels, can enhance IL-1-mediated IL-6 mRNA expression in human lung fibroblasts Though cAMP is not directly involved in the IL-1 signaling path, it can regulate IL-1-mediated activation of the IL-6 gene.[ 10 , 11 ] Reports have also suggested that the drugs increasing intracellular cAMP levels can inhibit the generation of IL-6 induced by rIL-1 in human lung fibroblasts, 27 and that the expression of IL-6 induced by IL-1β in AIS is relatively rare. Our study showed that IL-1β was not correlated with IL-6 or hs-CRP levels in stroke patients. Consistent with earlier reports, the level of IL-6 was correlated with the level of hs-CRP in our study, suggesting that it can not only release CRP in the necrotic tissue of the infarct core but also stimulates the liver to synthesize CRP. IL-6 signaling pathways initiate binding to the membrane-bound IL-6 receptor (IL-6R). The IL-6-IL-6R complex then triggers the dimerization of glycoprotein130 (GP130), which activates the tyrosine kinase (JAK) signaling pathway. 23,24 It has been reported that the specific blocking of this signaling pathway with soluble GP130-FC yields superior results compared to those with neutralizing antibodies of systemic IL-6 or IL-6 R. Studies have shown that IL-6 is a biomarker of disease severity and a prognosis indicator in a cytokine storm, and its expression is superior to that of TNF-α and IL-1.[ 12 – 14 , 26 , 29 ] A small-scale study on the treatment of Takayasu arteritis (TAK) with tocilizumab (TCZ), which targets the IL-6 receptor, showed that coronary atherosclerosis significantly improved after 6 months of treatment with TCZ. Administration of TCZ alone resulted in rapid improvement of cytokine release syndrome and produced effects on serum cytokines such as IL-6, IFN-γ, IL-8, IL-10, and MCP-1.[ 30 ] Drugs or cAMP analogs that increase intracellular cAMP levels can enhance IL-1-mediated IL-6 mRNA expression. Although cAMP is not directly involved in IL-1, it can regulate IL-1-mediated activation of the IL-6 gene.[ 10 , 11 ] The limitation of our study was the relatively lower number of patients included in the correlation study of the penumbra. Another limitation was that only 30 of 65 patients had ASPECTS and 36 had TAN scores because some patients had metal in their bodies and thus could not undergo MRI or head CT before admission to another hospital. In summary, our study showed that the serum hs-CRP level might prove informative in predicting the infarct core volume. The level of serum IL-6 might be predictive of the volume of the ischemic penumbra. The existing literature also shows that treating AIS with the anti-IL-6R antibody TCZ might be more beneficial in reducing ischemic penumbra and improving the prognosis of stroke patients. Thus, planning treatment based on the levels of IL-6 and hs-CRP and using TCZ in patients with very high levels of IL-6 might prove beneficial to AIS patients. Declarations Ethical Approval and Consent to participate The experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Xianyang Hospital of Yan’an University. Written informed consent was obtained from individual or guardian participants Human and Animal Ethics Not applicable. Consent for publication The authors have been informed in writing of the publication of this article, and all the authors agree to publish it. Availability of supporting data Not applicable. Competing interests The authors declare that they have no competing interests. Funding Not applicable. Authors' contributions These authors contributed equally to this work. Acknowledgements We thank Medjaden Inc. for their scientific editing of this manuscript. Authors' information Zhou Jianbo1, Li Lin1, Ji Xiyang, Zhang Xiaojie, Dai Changfei, Wang Sa, Zhang Mijuan, Wei Dong, Zhang Lele, Zhang Guoxun, Yang Xixi, Guo Ming, Wang Bin, Li Fan, Ma Cheng, Zhang Na, Zhang Qun, Chen Ping* 1.Department of Neurology, Xianyang Hospital of Yan’an University,No.38,Wenlin Road, Xianyang 712000,China * Corresponding author: Chen Ping, [email protected] References Herpich F, Rincon F. Management of Acute Ischemic Stroke. Critical care medicine. 2020;48:1654–1663. doi: 10.1097/CCM.0000000000004597 Saver JL. Time is brain–quantified. Stroke. 2006;37:263–266. doi: 10.1161/01.STR.0000196957.55928.ab Baron JC. Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nature reviews Neurology. 2018;14:325–337. doi: 10.1038/s41582-018-0002-2 Pawluk H, Wozniak A, Grzesk G, Kolodziejska R, Kozakiewicz M, Kopkowska E, et al. The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke. Clinical interventions in aging. 2020;15:469–484. doi: 10.2147/CIA.S233909 Malone K, Amu S, Moore AC, Waeber C. Immunomodulatory Therapeutic Strategies in Stroke. Frontiers in pharmacology. 2019;10:630. doi: 10.3389/fphar.2019.00630 Lakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. Journal of translational medicine. 2009;7:97. doi: 10.1186/1479-5876-7-97 Mizuma A, Yenari MA. Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke. Frontiers in neurology. 2017;8:467. doi: 10.3389/fneur.2017.00467 Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nature medicine. 2011;17:796–808. doi: 10.1038/nm.2399 Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy? Acta neuropathologica. 2019;137:693–714. doi: 10.1007/s00401-018-1930-z Zitnik RJ, Zheng T, Elias JA. cAMP inhibition of interleukin-1-induced interleukin-6 production by human lung fibroblasts. The American journal of physiology. 1993;264:L253-260. doi: 10.1152/ajplung.1993.264.3.L253 Kasahara T, Yagisawa H, Yamashita K, Yamaguchi Y, Akiyama Y. IL1 induces proliferation and IL6 mRNA expression in a human astrocytoma cell line: positive and negative modulation by chorela toxin and cAMP. Biochemical and biophysical research communications. 1990;167:1242–1248. doi: 10.1016/0006-291x(90)90657-9 Shaafi S, Sharifipour E, Rahmanifar R, Hejazi S, Andalib S, Nikanfar M, et al. Interleukin-6, a reliable prognostic factor for ischemic stroke. Iranian journal of neurology. 2014;13:70–76. Shenhar-Tsarfaty S, Ben Assayag E, Bova I, Shopin L, Fried M, Berliner S, et al. Interleukin-6 as an early predictor for one-year survival following an ischaemic stroke/transient ischaemic attack. International journal of stroke: official journal of the International Stroke Society. 2010;5:16–20. doi: 10.1111/j.1747-4949.2009.00396.x Tuttolomondo A, Di Sciacca R, Di Raimondo D, Serio A, D'Aguanno G, La Placa S, et al. Plasma levels of inflammatory and thrombotic/fibrinolytic markers in acute ischemic strokes: relationship with TOAST subtype, outcome and infarct site. Journal of neuroimmunology. 2009;215:84–89. doi: 10.1016/j.jneuroim.2009.06.019 Pawluk H, Grzesk G, Kolodziejska R, Kozakiewicz M, Wozniak A, Grzechowiak E, et al. Effect of IL-6 and hs-CRP Serum Levels on Functional Prognosis in Stroke Patients Undergoing IV-Thrombolysis: Retrospective Analysis. Clinical interventions in aging. 2020;15:1295–1303. doi: 10.2147/CIA.S258381 Hotter B, Hoffmann S, Ulm L, Meisel C, Fiebach JB, Meisel A. IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections. Front Neurol. 2019;10:83. doi: 10.3389/fneur.2019.00083 Kirzinger B, Stroux A, Rackoll T, Endres M, Floel A, Ebinger M, et al. Elevated Serum Inflammatory Markers in Subacute Stroke Are Associated With Clinical Outcome but Not Modified by Aerobic Fitness Training: Results of the Randomized Controlled PHYS-STROKE Trial. Frontiers in neurology. 2021;12:713018. doi: 10.3389/fneur.2021.713018 Schuhmann MK, Bieber M, Franke M, Kollikowski AM, Stegner D, Heinze KG, et al. Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice. Journal of neuroinflammation. 2021;18:46. doi: 10.1186/s12974-021-02095-1 Bonar E, Dubin A, Bierczynska-Krzysik A, Noga M, Silberring J, Stalinska K, et al. Identification of major cellular proteins synthesized in response to interleukin-1 and interleukin-6 in human hepatoma HepG2 cells. Cytokine. 2006;33:111–117. doi: 10.1016/j.cyto.2005.12.011 Yang C, Hawkins KE, Dore S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019;316:C135-C153. doi: 10.1152/ajpcell.00136.2018 Fahmi RM, Elsaid AF. Infarction Size, Interleukin-6, and Their Interaction Are Predictors of Short-Term Stroke Outcome in Young Egyptian Adults. J Stroke Cerebrovasc Dis. 2016;25:2475–2481. doi: 10.1016/j.jstrokecerebrovasdis.2016.06.021 Jeong HK, Ji K, Min K, Joe EH. Brain inflammation and microglia: facts and misconceptions. Experimental neurobiology. 2013;22:59–67. doi: 10.5607/en.2013.22.2.59 Tuttolomondo A, Di Raimondo D, Pecoraro R, Arnao V, Pinto A, Licata G. Inflammation in ischemic stroke subtypes. Current pharmaceutical design. 2012;18:4289–4310. doi: 10.2174/138161212802481200 Baram SM, Karima S, Shateri S, Tafakhori A, Fotouhi A, Lima BS, et al. Functional improvement and immune-inflammatory cytokines profile of ischaemic stroke patients after treatment with boswellic acids: a randomized, double-blind, placebo-controlled, pilot trial. Inflammopharmacology. 2019;27:1101–1112. doi: 10.1007/s10787-019-00627-z Nayak AR, Kashyap RS, Kabra D, Purohit HJ, Taori GM, Daginawala HF. Time course of inflammatory cytokines in acute ischemic stroke patients and their relation to inter-alfa trypsin inhibitor heavy chain 4 and outcome. Annals of Indian Academy of Neurology. 2012;15:181–185. doi: 10.4103/0972-2327.99707 Worthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, et al. The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovascular diseases. 2010;30:85–92. doi: 10.1159/000314624 Qiu R, Gao Y, Hou D, Wang Y, Yu C, Wang W, et al. Association between hs-CRP Levels and the Outcomes of Patients with Small-Artery Occlusion. Frontiers in aging neuroscience. 2016;8:191. doi: 10.3389/fnagi.2016.00191 Zhang J, Wu Y, Gao Z. Correlations of C-Reactive Protein (CRP), Interleukin-6 (IL-6), and Insulin Resistance with Cerebral Infarction in Hypertensive Patients. Medical science monitor: international medical journal of experimental and clinical research. 2019;25:1506–1511. doi: 10.12659/MSM.912898 Cojocaru IM, Cojocaru M, Tanasescu R, Iliescu I, Dumitrescu L, Silosi I. Expression of IL-6 activity in patients with acute ischemic stroke. Romanian journal of internal medicine = Revue roumaine de medecine interne. 2009;47:393–396. Pan L, Du J, Liu J, Liao H, Liu X, Guo X, et al. Tocilizumab treatment effectively improves coronary artery involvement in patients with Takayasu arteritis. Clinical rheumatology. 2020;39:2369–2378. doi: 10.1007/s10067-020-05005-7 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-1882454","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":132559195,"identity":"4277e6b0-5e4c-4ade-8a80-b3afbb7e34c7","order_by":0,"name":"Zhou Jianbo","email":"","orcid":"","institution":"Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhou","middleName":"","lastName":"Jianbo","suffix":""},{"id":132559196,"identity":"756fbe82-8d28-4cfc-929a-4d312e25e1cd","order_by":1,"name":"Li Lin","email":"","orcid":"","institution":"Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Lin","suffix":""},{"id":132559197,"identity":"ef933496-83d0-4e63-8905-16f39196bcd2","order_by":2,"name":"Ji Xiyang","email":"","orcid":"","institution":"Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ji","middleName":"","lastName":"Xiyang","suffix":""},{"id":132559198,"identity":"c103d37f-067a-4e94-801d-c3eb87289cdf","order_by":3,"name":"Zhang Xiaojie","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Xiaojie","suffix":""},{"id":132559199,"identity":"3b35a266-b179-47b7-ad94-263b87d06c22","order_by":4,"name":"Dai Changfei","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dai","middleName":"","lastName":"Changfei","suffix":""},{"id":132559200,"identity":"4038c596-cb2f-4ab5-b0da-cac48ca6d47e","order_by":5,"name":"Wang Sa","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wang","middleName":"","lastName":"Sa","suffix":""},{"id":132559201,"identity":"5fd78492-1de1-4c4e-b2df-dbe060b33570","order_by":6,"name":"Zhang Mijuan","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Mijuan","suffix":""},{"id":132559202,"identity":"b924b4da-5946-4ac9-a449-5dbde1d30603","order_by":7,"name":"Wei Dong","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wei","middleName":"","lastName":"Dong","suffix":""},{"id":132559203,"identity":"f9ef8597-6640-44eb-a018-d65dfd32313a","order_by":8,"name":"Zhang Lele","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Lele","suffix":""},{"id":132559204,"identity":"edbfa6b4-3602-4aea-9d17-8204a5e9f213","order_by":9,"name":"Zhang Guoxun","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Guoxun","suffix":""},{"id":132559205,"identity":"b284fc9f-b1d8-47f8-8df5-d06d2993738c","order_by":10,"name":"Yang Xixi","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yang","middleName":"","lastName":"Xixi","suffix":""},{"id":132559206,"identity":"e6906ade-1fae-42ae-9fce-9736d1824886","order_by":11,"name":"Guo Ming","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Guo","middleName":"","lastName":"Ming","suffix":""},{"id":132559207,"identity":"d975665f-647d-41a8-a380-7fcd62428bbf","order_by":12,"name":"Wang Bin","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Wang","middleName":"","lastName":"Bin","suffix":""},{"id":132559208,"identity":"f57a26c9-cfa7-4da2-bd64-e147d2a6ecf2","order_by":13,"name":"Li Fan","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Fan","suffix":""},{"id":132559209,"identity":"9dc80930-c61d-4c71-8c88-c01438c19d9e","order_by":14,"name":"Ma Cheng","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ma","middleName":"","lastName":"Cheng","suffix":""},{"id":132559210,"identity":"0928566b-cbe4-4dba-b9da-f56074e98ed8","order_by":15,"name":"Zhang Na","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Na","suffix":""},{"id":132559211,"identity":"aaf64335-32a8-4e15-adbb-0e54a7dd310e","order_by":16,"name":"Zhang Qun","email":"","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhang","middleName":"","lastName":"Qun","suffix":""},{"id":132559212,"identity":"75527ea1-4133-42fe-9ba4-3f070d8fa84e","order_by":17,"name":"Chen Ping","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYFACxsYHHyok5OTZmw8YgBmEtTA3G844Y2Fs2HMsoRDMaCCohb1NmretIrHhRo7BZxCD4QABDfyzG5sNeNskjBlnpCVunDlPIoGxgfnhoxt4tEjcOdj4QOKchBw7z+PDBh+3SeSxM7AZG+fg0WIgkdhsYFAGtKU9Lc1w5jaJYsYGHjZpAlraJBLYJBIbDuSY/+adA2IQo+VAG1DliRwDY94GIrQA/dJs2HBGAhzIhjOOARnNBPzCP7v94eM/FXXQqKwBMx4+xqeFQQJDhBmfcuxaRsEoGAWjYBSgAQCQyVNWp0dvGQAAAABJRU5ErkJggg==","orcid":"","institution":"Xianyang Hospital of Yan’an University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Ping","suffix":""}],"badges":[],"createdAt":"2022-07-21 15:29:09","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-1882454/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-1882454/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":25848277,"identity":"17ae756b-de1f-439c-9d6d-aa10913470b1","added_by":"auto","created_at":"2022-08-30 15:37:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45326,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of patients included in the analysis.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/9ebec33660d8b2482c6afe35.png"},{"id":25847800,"identity":"08e4775c-9571-4fce-ac4f-d7242c106ec8","added_by":"auto","created_at":"2022-08-30 15:32:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":549014,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation infarct core volume with serum concentrations of IL-1β, IL-6 and hsCRP \u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A-D) Image of a 55-year-old male patient with AIS with the onset of 2 hours. (A) MR DWI sequence images of magnetic resonance showed that there were acute lesions near the left ventricle. (B) The red area was the infarct core measured by NeuBrainCARE in magnetic resonance post-perfusion (threshold of ADC\u0026lt;620, corresponding to the infarct core volume of 4.85 mL).\u0026nbsp;(C) The green area is a low perfusion area (threshold T\u003csub\u003emax\u003c/sub\u003e\u0026gt;6s, corresponding to a low perfusion volume of 42.21 ml) determined by using NeuBrainCARE. (D) Pseudo-color map of T\u003csub\u003emax\u003c/sub\u003e\u0026gt;6s, showing a large area of hypoperfusion. (E-H) Image of a 55-year-old man with cerebral infarction 7 hours after onset. (E) MR DWI sequence images at 7 hours after the onset, showing acute lesions around the left ventricle; (F) Infarct volume measured by NeuBrainCARE on CTP perfusion sequence (threshold value: rCBF\u0026lt;30%, and corresponding infarct core volume: 28.97 ml); (G) Hypoperfusion area measured by NeuBrainCARE on CTP perfusion sequence (threshold value: T\u003csub\u003emax\u003c/sub\u003e\u0026gt;6s, and corresponding hypoperfusion volume: 127.20 ml); (H) Pseudo-color image of T\u003csub\u003emax\u003c/sub\u003e\u0026gt;6s, suggesting a large range of hypoperfusion areas. (I) Serum IL-1 β level was not correlated with infarct core volume (P＞0.05). (J) Serum IL-6 level was not correlated with infarct core volume (P＞0.05); (K)Serum hsCRP level was significantly correlated with infarct core volume (r = 0.28, P = 0.03). （L-N）Serum IL-1 β, IL-6, hsCRP levels were not correlated with infarct core volume(P＞0.05).\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/b5682047679d71a4c86bd168.png"},{"id":25848280,"identity":"be717d30-4b45-4818-b1eb-86290e4db961","added_by":"auto","created_at":"2022-08-30 15:37:04","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":477524,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cspan class=\"ql-cursor\"\u003e\u003c/span\u003e\u003cstrong\u003eCorrelation analysis between ischemic penumbra volume and inflammatory indexes.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A)MR DWI sequence images of 56-year-old men at 7 hours after onset; (B)The MTT sequence image of CTP perfusion showed that the red and yellow parts showed that the MTT was prolonged. (C)The red area was the infarct core volume marked by NeuBrainCARE (the threshold is rCBF\u0026lt;30% contralateral, and the corresponding infarct core volume is 28.97ml ); (D) The green area was the low perfusion volume marked by NeuBrainCARE (the threshold value is T\u003csub\u003emax\u003c/sub\u003e\u0026gt;6s, and the corresponding ischemic penumbra volume is 127.2ml). (E-F) MRI DWI sequence images and PWI perfusion MTT images of 77-year-old men at the first 8 hours of onset, the green, and yellow parts showed that the MTT was prolonged; (G) The red area is the infarct core volume marked by NeuBrainCARE (the threshold is ADC\u0026lt;620, and the corresponding infarct core volume is 4.33ml )； (H) The green area is the low perfusion volume marked by NeuBrainCARE (the threshold value is T\u003csub\u003emax\u003c/sub\u003e\u0026gt;6s, and the corresponding ischemic penumbra volume is 27.91ml). (I) Serum IL-1β level was not correlated with ischemic penumbra volume (P\u0026gt;0.05). (J) Serum IL-6 level was significantly correlated with ischemic penumbra volume (r=0.53, P=0.007). (K) Serum hsCRP level was not correlated with ischemic penumbra volume (P\u0026gt;0.05).\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/7b0bf85c4c544cd86a8e7466.png"},{"id":25848697,"identity":"814b3fc7-7ff0-45c6-903c-6ce2fc0dd515","added_by":"auto","created_at":"2022-08-30 15:42:04","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":63286,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation analyses between collateral circulation score and infarct core volume in 36 patients with AIS.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A) On the right middle cerebral artery, the corresponding filling range was 6.12%, and the TAN score was 0. (B) The right middle cerebral artery was poorly developed, with a corresponding filling range of 74.94% and a TAN score of 2. (C) The TAN score of the 36 patients was 1.86 ± 1.07 (0–3), and Spearman’s correlation analysis showed no significant correlation between the TAN score and the infarct core volume (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e","description":"","filename":"floatimage4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/dd92bd7aa7da808f921ac8e9.jpg"},{"id":25848953,"identity":"b12ab88a-8e42-4ae0-a2c2-cab9acffe226","added_by":"auto","created_at":"2022-08-30 15:47:04","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":94001,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation analysis between ASPECT scores and infarct core volume.\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A) The red area on a non-contrast CT (NCCT) scan of the brain suggests that the density of the blood supply areas in the right lenticular nucleus and M2, M3, M4, M5, and M6 segments of the right middle cerebral artery is decreased, and the corresponding ASPECTS is 4. (B) The red area on a NCCT scan of the brain indicates that the density of the blood supply area of the left caudate nucleus, the internal capsule, the lenticular nucleus and M3 segment of the right middle cerebral artery is decreased, and the corresponding ASPECTS is 6. (C) The ASPECTS of the 30 patients was 7.57 ± 2.01 (3–10), and correlation analyses showed no significant correlation between the infarct core and the ASPECTS (\u003cem\u003eP\u003c/em\u003e\u0026gt;0.05).\u003c/p\u003e","description":"","filename":"floatimage5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/1d7955507c3cefc1cfcf2432.jpg"},{"id":25847803,"identity":"185440d1-88aa-42b6-8d57-51878deb7a06","added_by":"auto","created_at":"2022-08-30 15:32:04","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":332949,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAnalysis of correlation with the levels of IL-1β, IL-6,hsCRP, and NIHSS scores on admission, discharge, and at 3 months after discharge in 65 patients with AIS .\u003c/strong\u003e\u003c/p\u003e\u003cp\u003e(A)The level of IL-1β was not correlated with the NIHSS score on admission after cerebral infarction (P＞0.05);\u0026nbsp;(B)The level of IL-6 was significantly correlated with the NIHSS score on admission after cerebral infarction (P\u0026lt;0.05); (C) The level of HsCRP was positively correlated with the NIHSS score on admission after cerebral infarction (P\u0026lt;0.05).\u003c/p\u003e\u003cp\u003e(D) The level of IL-1β was not correlated with NIHSS score on discharge after cerebral infarction (P＞0.05); (E) The level of IL-6 was not correlated with NIHSS score on discharge after cerebral infarction (P\u0026lt;0.05); (F) The level of HsCRP was not correlated with NIHSS score on discharge after cerebral infarction (P\u0026lt;0.05).\u003c/p\u003e\u003cp\u003e(G) The level of IL-1β was not correlated with NIHSS score at 3 months after discharge (P＞0.05); (H) The level of IL-6 was not correlated with NIHSS score at 3 months after discharge (P\u0026lt;0.05); (I) The level of HsCRP was not correlated with NIHSS score at 3 months after discharge (P\u0026lt;0.05).\u003c/p\u003e","description":"","filename":"floatimage6.png","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/a06840b8ccd79cc041c64abe.png"},{"id":25847806,"identity":"cc88a9d3-cc8d-4765-a83c-e3edc46e7294","added_by":"auto","created_at":"2022-08-30 15:32:04","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":105371,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCorrelation between the level of IL-1β, IL-6, and hsCRP at admission in 65 patients with AIS.\u003c/strong\u003e \u003c/p\u003e\u003cp\u003e(A) There was no correlation between the level of IL-1β and IL-6(P＞0.05). (B) There was no correlation between the level of IL-1β and hsCRP(P＞0.05). (C) There was a correlation between the level of IL-6 and 6hsCRP(P＜0.05).\u003c/p\u003e","description":"","filename":"floatimage7.png","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/d2a4c3ca62d547e6dc686ca6.png"},{"id":28394878,"identity":"73bda126-bbe7-4ba7-95f7-381586c9146f","added_by":"auto","created_at":"2022-10-29 06:44:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2496432,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1882454/v2/ad9f8390-83ad-401c-b283-3526860ade7c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Correlation of Serum IL-1β, IL-6, and hsCRP levels with Infarct Core and Ischemic Penumbra Volume in Acute Ischemic Stroke","fulltext":[{"header":"Background","content":"\u003cp\u003eIschemic stroke (IS) is the second leading cause of death worldwide and the first leading cause of acquired long-term disability, placing a heavy burden on the global economy.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] The pathophysiology of IS is a complex process that results from a sudden decrease or loss of blood circulation to an area of the brain. The subsequent biochemical events eventually lead to neuronal death at the infarction core. However, the larger volume of brain tissue surrounding the ischemic core, the penumbra, can be rescued if cerebral blood flow is promptly restored. Current IS treatment focuses on reducing brain damage by saving the ischemic penumbra. Currently, evidence-based treatments focus on restoring blood flow early (within 4.5 h) to rescue the ischemic penumbra before it gets progressively recruited to form a larger ischemic core. A previous study suggested that if the volume of the infarcted brain tissue is smaller, the neurological outcome will be better.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] However, the success rate of early recanalization with intravenous thrombolysis is only about 30%. Compared to intravenous thrombolysis (IVT), the mechanical thrombectomy applied to remove occluded clots significantly improves stroke patients\u0026rsquo; prognosis. Although more than 80% of IS patients receive mechanical thrombectomy and achieve early recanalization, about 50% of the patients still do not enjoy functional independence after thrombectomy as the infarct core becomes too large during recanalization.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe two important pathophysiological mechanisms involved in the ischemic damage of neuronal function are oxidative stress and inflammation. Experimental studies have demonstrated that free radical-induced oxidative stress is one of the significant contributors to ischemic lesion and reperfusion-related brain tissue damage. In acute IS (AIS), the damaged brain cells produce reactive oxygen species (ROS) that activate the endothelial cells and cause oxidative stress. This leads to primary vascular damage and promotes acute immune responses associated with the development of an inflammatory response.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIn the acute phase of IS, the resident brain immune cells, microglia, are activated. They subsequently invade the peri-infarct and infarct core and induce the expression of pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin 1 beta (IL-1β), and anti-inflammatory IL-1 receptor antagonist (IL-1Ra). Increased blood-brain barrier permeability results in the infiltration of neutrophils, macrophages, and other leukocytes. The activation of these immune cells further increases the burden of proinflammatory cytokines.[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] Thus, the resident and infiltrating immune cells in the brain orchestrate a post-stroke inflammatory response. Experimental evidence has shown that targeting some of these inflammatory cytokines, such as TNF, IL-1, IL-6, and IL-10, holds promise.[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eIL-6 is released by different cells, such as microglial cells, astrocytes, leukocytes, and endothelial cells, which is a part of the response to brain damage. It stimulates hepatocytes to synthesize acute phase proteins, mainly C-reactive protein (CRP) and fibrinogen[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. IL-6 is a key inflammatory marker in stroke.\u003c/p\u003e \u003cp\u003eIL-1 mediates IL-6 mRNA expression by increasing intracellular cyclic adenosine monophosphate (cAMP), and numerous studies have shown a significant increase in IL-6 serum level, which occurs within a few hours after the onset of ischemia and lasts for up to 90 days after the stroke.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] IL-1β, TNF-α, and IL-6 are the three main pro-inflammatory cytokines that cause and aggravate the inflammatory response after stroke.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] Tuttolomondoa \u003cem\u003eet al\u003c/em\u003e.[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] found that the levels of TNF-α, IL-6, and IL-1β are significantly increased in the plasma of patients with cardioembolic stroke. IL-1 mediates IL-6 mRNA expression by increasing intracellular cAMP. Studies have also shown a significant increase in IL-6 concentration in the serum within a few hours of onset of ischemia, which lasts for up to 90 days after stroke.[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Pawluk \u003cem\u003eet al\u003c/em\u003e.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] suggested that IL-6 has potential prognostic significance for the success of thrombolytic therapy. Hotter[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] demonstrated that, in a cohort of patients with no infections, the levels of IL-6 are associated with several parameters such as acute diffusion-weighted imaging (DWI) lesion, perfusion deficit, final infarct size, and affection of cortex from acute stroke magnetic resonance imaging (MRI). IL-6, in turn, stimulates hepatocytes to synthesize acute phase proteins, mainly CRP and fibrinogen.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] Several studies have shown that elevated high-sensitive CRP (hs-CRP) after stroke is associated with unfavorable outcomes.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Several population-based investigations have demonstrated a correlation between inflammatory biomarkers (such as CRP, fibrinogen, D-dimer, and white blood cell count) and the risk of incident and recurrent stroke. There have been few studies on the relationship between serum levels of inflammatory factors and ischemic penumbra and their impact on the prognosis of patients with AIS.[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] In addition, the relationship between infarct volume and inflammatory markers has rarely been reported.\u003c/p\u003e \u003cp\u003eThis study determined if there is a correlation between the serum levels of inflammatory factors IL-1β, IL-6, and hs-CRP with infarct core volume and ischemic penumbra volume in patients with AIS, and evaluated their effects on patients\u0026rsquo; prognosis to help in timely recognition of especially vulnerable populations.\u003c/p\u003e"},{"header":"Patients And Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and population\u003c/h2\u003e \u003cp\u003e65 patients with first-time AIS, admitted within 24h of onset to Xianyang Hospital of Yan\u0026rsquo;an University (Xianyang City, China) from October 2020 to March 2022, were included in this study. Before inclusion, all patients provided signed informed consent, and the study was approved by the hospital\u0026rsquo;s ethics committee. The patients were diagnosed with acute cerebral infarction by MRI.\u003c/p\u003e \u003cp\u003e Inclusion criteria were: age 18\u0026ndash;80 years old (including boundary value), first time acute cerebral infarction of the internal carotid artery system (anterior circulation) according to Chinese guidelines for the diagnosis and treatment of acute ischemic stroke 2018, admitted within 24 h of stroke onset, and followed up with secondary preventive treatment after discharge from the hospital.\u003c/p\u003e \u003cp\u003eExclusion criteria were: computed tomography (CT) or MRI examination of the head showing the presence of intracranial hemorrhagic diseases (e.g., hemorrhagic stroke, epidural hematoma, intracranial hematoma, ventricular hemorrhage, subarachnoid hemorrhage); patients suffering from malignant tumors, diseases of the blood system, immune system, tuberculosis, or moderate-to-severe infections; comorbidity such as dysfunctional organs (e.g., heart, liver, kidney); being unable to cooperate or unwilling to cooperate due to severe mental disorder or mental illness; patients with non-anterior circulation infarction; patients suffering from acute coronary heart disease, heart failure, or myocardial and cardiovascular diseases; and no restricted diffusion on diffusion-weighted MRI sequences(Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eBased on the results of brain MRI with 1.5T (Philips Prodiva; Philips Amsterdam, the Netherlands) or 3.0T (Siemens Verio; Siemens, Munich, Germany) superconducting MRI, the cerebral infarction volume was evaluated. T1-weighted image (T1WI), T2WI, diffusion-weighted imaging (DWI), and MR angiography (MRA) sequences were used for comprehensive diagnosis and Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. Perfusion-weighted imaging (PWI) or CT perfusion (CTP) confirmed the cerebral perfusion. NeuBrainCARE was used to measure the infarct volume on the apparent diffusion coefficient sequence. The hypoperfusion volume was automatically calculated on CTP or PWI sequences via NeuBrainCARE. The ASPECTS was calculated on CT sequences, and the Tan collateral score was calculated on MRA sequences through NeuBrainCARE.\u003c/p\u003e \u003cp\u003eBlood was collected from the AIS patients on admission, and the serum levels of IL-1β, IL-6, and hs-CRP were measured. Serum IL-1β and IL-6 levels were measured with the enzyme-linked immunosorbent assay, and hs-CRP concentrations were measured with latex-enhanced immunoturbidimetry. Neurological assessment was conducted using the NIH Stroke Scale (NIHSS). Evaluations at 8 h intervals by two physicians, who have more than 5 years of clinical experience in neurology, with an interval of more than 8 h on the same day. The average value of each evaluation score was taken as the final score. The average scores from each of the 11 items listed in the NIHSS were added to calculate each patient\u0026rsquo;s total NIHSS score. The scores on the NIHSS range from 0 to 42. The higher the score, the more serious the neurological deficit.\u003c/p\u003e \u003c/div\u003e\n\u003ch2\u003eStatistical Analyses\u003c/h2\u003e\n\u003cp\u003eCorrelation analyses were performed between the serum levels of IL-1β, IL-6, and hs-CRP with infarct volume. The relationship between inflammatory factors and neurological function score (NIHSS score) was analyzed at admission, discharge, and 3 months after cerebral infarction. All data were analyzed with SPSS 26.0, and the normality and homogeneity of variance were tested for continuous variables. The data are expressed as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. According to the normality test, the correlation between the two indexes was determined by Pearson\u0026rsquo;s or Spearman\u0026rsquo;s correlation analysis. \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e65 stroke patients (37 males and 28 females) underwent non-thrombolytic therapy. The mean age of the patients without thrombolysis was 61.98 years (range: 37\u0026ndash;80 years). The average time from onset to hospitalization was 11.45\u0026thinsp;\u0026plusmn;\u0026thinsp;6.76 h (range:1\u0026ndash;24 h). On admission, the average NIHSS score was 5.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.78 (0\u0026ndash;12). The clinical characteristics of the patients given non-thrombolytic therapy and their MRI results are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. After exceeding the thrombolytic time window following admission, these patients were treated with double anticoagulants (aspirin 100 mg/day plus clopidogrel bisulfate 75 mg/day) for intensive lipid-lowering and neuroprotective effects, and improving collateral circulation.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\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\u003eClinical characteristics of 65 patients with AIS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61.98\u0026thinsp;\u0026plusmn;\u0026thinsp;9.89 (37\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale : Female\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37:28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisease course (hour), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.45\u0026thinsp;\u0026plusmn;\u0026thinsp;6.76 (1\u0026ndash;24)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMedian length of stay (day), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.05\u0026thinsp;\u0026plusmn;\u0026thinsp;4.14 (5\u0026ndash;35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIHSS score on admission, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.60\u0026thinsp;\u0026plusmn;\u0026thinsp;2.78 (0\u0026ndash;12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking-n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 (35.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43(66.15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (27.69)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart disease - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (21.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLimb numbness and weakness - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(32.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWords adverse and vague - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (52.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLimb weakness and Words vague- n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (12.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysical clumsiness - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(3.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMRI characteristics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrontal lobe, parietal lobe, temporal lobe- n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (36.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCorpus callosum - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (6.15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePeriventricular - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (44.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSemi-oval center/basal ganglion - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (12.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStenosis or occlusion of the anterior cerebral artery - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30 (46.15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStenosis or occlusion of the middle cerebral artery - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (43.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStenosis or occlusion of internal carotid artery - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(10.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEtiology (TOAST classification)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtherosclerosis - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40 (61.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eArteriolar occlusion - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (32.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardioembolism - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (4.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUndetermined etiology - n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (1.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eValues are presented as the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (with range in parentheses below) or number (percentage) as appropriate; NIHSS National Institutes of Health Stroke Scale.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eCorrelation between the infarct core volume within 24 h of AIS onset and the serum level of inflammatory factors\u003c/b\u003e \u003c/p\u003e \u003cp\u003eCorrelation analyses showed that the serum levels of IL-1β and IL-6 in the 65 patients, who did not undergo thrombolytic therapy, were not significantly correlated to the infarct core volume within 24 h of onset (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). However, there was a significant positive correlation (r\u0026thinsp;=\u0026thinsp;0.28, P\u0026thinsp;=\u0026thinsp;0.03) between the infarct core volume and serum hs-CRP levels (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Our results showed that serum hs-CRP levels can predict the infarct core volume in AIS.\u003c/p\u003e\u003cp\u003e \u003cb\u003eCorrelation between the ischemic penumbra volume within 24 h of AIS onset and the serum level of inflammatory factors\u003c/b\u003e \u003c/p\u003e \u003cp\u003e41 of 65 non-thrombolytic therapy patients underwent emergency digital subtraction angiography examination of cerebral vessels, as CTP or PWI was not available within 48h. Only 24 patients in this group received CTP or PWI examination. We considered the data of these 24 patients for the correlation study. The analyses showed that the penumbra volume was significantly correlated with serum IL-6 (r\u0026thinsp;=\u0026thinsp;0.28, P\u0026thinsp;=\u0026thinsp;0.007) level and not with serum IL-1β or hs-CRP (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) level. Thus, serum IL-6 level can predict the volume of ischemic penumbra in AIS (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \n\u003ch2\u003eCorrelation Between Collateral Circulation Score And Infarct Volume\u003c/h2\u003e\n\u003cp\u003eCollateral circulation was assessed from the ASPECTS calculated from the plain CT scans of 30 patients and the Tan scores obtained from the MRA of 36 patients. ASPECTS was 7.57\u0026thinsp;\u0026plusmn;\u0026thinsp;2.01 (3\u0026ndash;10) in the CT sequence, and the Tan collateral score was 1.86\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07 (0\u0026ndash;3) in the MRA sequence via NeuBrainCARE. Correlation analyses showed that the infarct core was not significantly correlated with either the ASPECT score or TAN score (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\n\u003ch2\u003eCorrelation Between Nihss Scores And Serum Il-1 β, Il-6, And Hs-crp Levels In Ais Patients\u003c/h2\u003e\n\u003cp\u003eCorrelation between the NIHSS scores and the serum levels of IL-1β, IL-6, and hs-CRP were analyzed at admission, discharge, and at the 3-month follow-up in the 65 patients with AIS. The serum levels of IL-6 and hs-CRP showed a significant positive correlation (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) with NIHSS scores at admission, discharge, and also at the 3-month follow-up (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) in the group of patients who did not undergo intravenous thrombolysis treatment. Serum IL-1β level showed no correlation with NIHSS score at either time point considered (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). This indicates that serum IL-6 and hs-CRP levels in patients with AIS were related to the severity of neurological deficits and might help in the prognosis of patients with AIS (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). Correlation analyses between the inflammatory factors showed that, at the time of admission, the serum concentrations of IL-6 were positively correlated with hs-CRP (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). IL-1β showed no correlation with the serum levels of IL-6 or hs-CRP (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). IL-1β drives the IL-6 signaling pathway, and IL-6 binds to the IL-6 receptor on the liver cell membrane, which finally induces the liver to synthesize a series of acute-phase proteins, including the generation of hs-CRP.[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] Therefore, we speculate that the IL-6 signaling pathway in AIS plays an important role in affecting neurological function after stroke (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eInflammation plays an important role in the pathogenesis of IS. Inflammatory markers such as IL-1, IL-6, CRP, TNF-α, and fibrinogen are upregulated in AIS.[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] Studies have also associated these inflammatory markers with increased mortality, recurrent vascular risk, and poor functional outcome.[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] They have been suggested to cause injury to vascular endothelial cells, promote the release of inflammatory factors, and activate the coagulation cascade that can lead to further expansion of the infarct core after stroke.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] The most studied inflammatory cytokines in AIS are the pro-inflammatory cytokines IL-1β, Il-6, and TNF-α.[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] In this study, we did not include TNF-α because the increasing trend of TNF-α, IL-1β, and IL-6 was consistent; for example, a previous study showed within 72 h of neurological sign onset, in a 1-month follow-up period, they assessed NIHSS as primary and plasma levels of TNF-α, IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IFN-γ, IP-10, MCP-1, 8-isoprostane were increased. The levels of plasma inflammatory markers TNF-α, IL-1β, IL-6, IL-8, and prostaglandin E2 P were significantly decreased in a therapy group after 7 days of intervention,[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e] but the inflammatory factors IL-1β and IL-6 were increased significantly in cerebral ischemia.[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] Elevated levels of IL-1β after ischemia have been correlated with worsening of the infarct severity. The increased IL-1β levels following cerebral ischemia, in turn, elevate IL-6 level, which has been shown to correlate with brain infarct volume. [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] Elevated hs-CRP level is a risk factor and prognostic factor for IS and coronary events.[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eOur correlation analyses showed a positive association between the serum levels of hs-CRP and infarct core volume. IL-6 levels, on the other hand, have shown a positive correlation with ischemic penumbra. We also observed a positive correlation between the levels of IL-6 and hs-CRP. In addition, the NIHSS score was positively correlated with IL-6 and hs-CRP at all time points (admission, discharge, and 3-month follow-up) considered in this study. The correlation was only observed in patients who did not need thrombolysis therapy. In this study, we observed no significant correlation between the infarct volume or NIHSS score. A significant correlation was also not observed between the inflammatory factors and infarct volume or NIHSS score in the group of patients who underwent thrombolysis therapy. This may be because of the small number of patients. A future study involving more alteplase (rtPA)-treated AIS patients might clarify this discrepancy.\u003c/p\u003e \u003cp\u003eOur study showed that the level of the serum IL-6 and hs-CRP within 24 h of onset can be used to predict the severity of neurological function within 3 months. Zhang \u003cem\u003eet al\u003c/em\u003e.[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], in their correlation study among CRP, IL-6, insulin resistance, and cerebral infarction in hypertensive patients, showed that inflammatory factors and insulin resistance were positively correlated with the diameter of cerebral infarction and could aid in the neurological prognosis of the patients. In his study on the prognostic factors of AIS in young Egyptians, Fahmi[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] demonstrated that IL-6 and infarct diameter are independent predictors of prognosis in young Egyptians. A study on the synergistic effect of IL-6 and infarct size showed the therapeutic benefits of reducing IL-6 level during the early treatment of IS.\u003c/p\u003e \u003cp\u003ePrevious reports have shown that drugs or cAMP analogs, by increasing intracellular cAMP levels, can enhance IL-1-mediated IL-6 mRNA expression in human lung fibroblasts Though cAMP is not directly involved in the IL-1 signaling path, it can regulate IL-1-mediated activation of the IL-6 gene.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] Reports have also suggested that the drugs increasing intracellular cAMP levels can inhibit the generation of IL-6 induced by rIL-1 in human lung fibroblasts,\u003csup\u003e27\u003c/sup\u003e and that the expression of IL-6 induced by IL-1β in AIS is relatively rare. Our study showed that IL-1β was not correlated with IL-6 or hs-CRP levels in stroke patients. Consistent with earlier reports, the level of IL-6 was correlated with the level of hs-CRP in our study, suggesting that it can not only release CRP in the necrotic tissue of the infarct core but also stimulates the liver to synthesize CRP.\u003c/p\u003e \u003cp\u003eIL-6 signaling pathways initiate binding to the membrane-bound IL-6 receptor (IL-6R). The IL-6-IL-6R complex then triggers the dimerization of glycoprotein130 (GP130), which activates the tyrosine kinase (JAK) signaling pathway.\u003csup\u003e23,24\u003c/sup\u003e It has been reported that the specific blocking of this signaling pathway with soluble GP130-FC yields superior results compared to those with neutralizing antibodies of systemic IL-6 or IL-6 R. Studies have shown that IL-6 is a biomarker of disease severity and a prognosis indicator in a cytokine storm, and its expression is superior to that of TNF-α and IL-1.[\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e] A small-scale study on the treatment of Takayasu arteritis (TAK) with tocilizumab (TCZ), which targets the IL-6 receptor, showed that coronary atherosclerosis significantly improved after 6 months of treatment with TCZ. Administration of TCZ alone resulted in rapid improvement of cytokine release syndrome and produced effects on serum cytokines such as IL-6, IFN-γ, IL-8, IL-10, and MCP-1.[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] Drugs or cAMP analogs that increase intracellular cAMP levels can enhance IL-1-mediated IL-6 mRNA expression. Although cAMP is not directly involved in IL-1, it can regulate IL-1-mediated activation of the IL-6 gene.[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThe limitation of our study was the relatively lower number of patients included in the correlation study of the penumbra. Another limitation was that only 30 of 65 patients had ASPECTS and 36 had TAN scores because some patients had metal in their bodies and thus could not undergo MRI or head CT before admission to another hospital.\u003c/p\u003e \u003cp\u003eIn summary, our study showed that the serum hs-CRP level might prove informative in predicting the infarct core volume. The level of serum IL-6 might be predictive of the volume of the ischemic penumbra. The existing literature also shows that treating AIS with the anti-IL-6R antibody TCZ might be more beneficial in reducing ischemic penumbra and improving the prognosis of stroke patients. Thus, planning treatment based on the levels of IL-6 and hs-CRP and using TCZ in \u003cb\u003epatients\u003c/b\u003e with very high levels of IL-6 might prove beneficial to AIS patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval and Consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe experimental protocol was established, according to the ethical guidelines of the Helsinki Declaration and was approved by the Human Ethics Committee of Xianyang Hospital of \u0026nbsp;Yan’an University. Written informed consent was obtained from individual or guardian participants\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman and Animal Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have been informed in writing of the publication of this article, and all the authors agree to publish it.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThese authors contributed equally to this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank \u003cem\u003eMedjaden\u003c/em\u003e Inc. for their scientific editing of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhou Jianbo1, Li Lin1, Ji Xiyang, Zhang Xiaojie, Dai Changfei, Wang Sa, Zhang Mijuan, Wei Dong, Zhang Lele, Zhang Guoxun, Yang Xixi, Guo Ming, Wang Bin, Li Fan, Ma Cheng, Zhang Na, Zhang Qun, Chen Ping*\u003c/p\u003e\n\u003cp\u003e1.Department of Neurology, Xianyang Hospital of Yan’an University,No.38,Wenlin Road, Xianyang 712000,China\u003c/p\u003e\n\u003cp\u003e* Corresponding author: Chen Ping,[email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eHerpich F, Rincon F. Management of Acute Ischemic Stroke. Critical care medicine. 2020;48:1654\u0026ndash;1663. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/CCM.0000000000004597\u003c/span\u003e\u003cspan address=\"10.1097/CCM.0000000000004597\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSaver JL. Time is brain\u0026ndash;quantified. Stroke. 2006;37:263\u0026ndash;266. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1161/01.STR.0000196957.55928.ab\u003c/span\u003e\u003cspan address=\"10.1161/01.STR.0000196957.55928.ab\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaron JC. Protecting the ischaemic penumbra as an adjunct to thrombectomy for acute stroke. Nature reviews Neurology. 2018;14:325\u0026ndash;337. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/s41582-018-0002-2\u003c/span\u003e\u003cspan address=\"10.1038/s41582-018-0002-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePawluk H, Wozniak A, Grzesk G, Kolodziejska R, Kozakiewicz M, Kopkowska E, et al. The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke. Clinical interventions in aging. 2020;15:469\u0026ndash;484. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/CIA.S233909\u003c/span\u003e\u003cspan address=\"10.2147/CIA.S233909\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalone K, Amu S, Moore AC, Waeber C. Immunomodulatory Therapeutic Strategies in Stroke. Frontiers in pharmacology. 2019;10:630. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fphar.2019.00630\u003c/span\u003e\u003cspan address=\"10.3389/fphar.2019.00630\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLakhan SE, Kirchgessner A, Hofer M. Inflammatory mechanisms in ischemic stroke: therapeutic approaches. Journal of translational medicine. 2009;7:97. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/1479-5876-7-97\u003c/span\u003e\u003cspan address=\"10.1186/1479-5876-7-97\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMizuma A, Yenari MA. Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke. Frontiers in neurology. 2017;8:467. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2017.00467\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2017.00467\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nature medicine. 2011;17:796\u0026ndash;808. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/nm.2399\u003c/span\u003e\u003cspan address=\"10.1038/nm.2399\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy? Acta neuropathologica. 2019;137:693\u0026ndash;714. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00401-018-1930-z\u003c/span\u003e\u003cspan address=\"10.1007/s00401-018-1930-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZitnik RJ, Zheng T, Elias JA. cAMP inhibition of interleukin-1-induced interleukin-6 production by human lung fibroblasts. The American journal of physiology. 1993;264:L253-260. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1152/ajplung.1993.264.3.L253\u003c/span\u003e\u003cspan address=\"10.1152/ajplung.1993.264.3.L253\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKasahara T, Yagisawa H, Yamashita K, Yamaguchi Y, Akiyama Y. IL1 induces proliferation and IL6 mRNA expression in a human astrocytoma cell line: positive and negative modulation by chorela toxin and cAMP. Biochemical and biophysical research communications. 1990;167:1242\u0026ndash;1248. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/0006-291x(90)90657-9\u003c/span\u003e\u003cspan address=\"10.1016/0006-291x(90)90657-9\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShaafi S, Sharifipour E, Rahmanifar R, Hejazi S, Andalib S, Nikanfar M, et al. Interleukin-6, a reliable prognostic factor for ischemic stroke. Iranian journal of neurology. 2014;13:70\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShenhar-Tsarfaty S, Ben Assayag E, Bova I, Shopin L, Fried M, Berliner S, et al. Interleukin-6 as an early predictor for one-year survival following an ischaemic stroke/transient ischaemic attack. International journal of stroke: official journal of the International Stroke Society. 2010;5:16\u0026ndash;20. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/j.1747-4949.2009.00396.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1747-4949.2009.00396.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuttolomondo A, Di Sciacca R, Di Raimondo D, Serio A, D'Aguanno G, La Placa S, et al. Plasma levels of inflammatory and thrombotic/fibrinolytic markers in acute ischemic strokes: relationship with TOAST subtype, outcome and infarct site. Journal of neuroimmunology. 2009;215:84\u0026ndash;89. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jneuroim.2009.06.019\u003c/span\u003e\u003cspan address=\"10.1016/j.jneuroim.2009.06.019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePawluk H, Grzesk G, Kolodziejska R, Kozakiewicz M, Wozniak A, Grzechowiak E, et al. Effect of IL-6 and hs-CRP Serum Levels on Functional Prognosis in Stroke Patients Undergoing IV-Thrombolysis: Retrospective Analysis. Clinical interventions in aging. 2020;15:1295\u0026ndash;1303. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2147/CIA.S258381\u003c/span\u003e\u003cspan address=\"10.2147/CIA.S258381\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHotter B, Hoffmann S, Ulm L, Meisel C, Fiebach JB, Meisel A. IL-6 Plasma Levels Correlate With Cerebral Perfusion Deficits and Infarct Sizes in Stroke Patients Without Associated Infections. Front Neurol. 2019;10:83. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2019.00083\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2019.00083\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKirzinger B, Stroux A, Rackoll T, Endres M, Floel A, Ebinger M, et al. Elevated Serum Inflammatory Markers in Subacute Stroke Are Associated With Clinical Outcome but Not Modified by Aerobic Fitness Training: Results of the Randomized Controlled PHYS-STROKE Trial. Frontiers in neurology. 2021;12:713018. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2021.713018\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2021.713018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchuhmann MK, Bieber M, Franke M, Kollikowski AM, Stegner D, Heinze KG, et al. Platelets and lymphocytes drive progressive penumbral tissue loss during middle cerebral artery occlusion in mice. Journal of neuroinflammation. 2021;18:46. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12974-021-02095-1\u003c/span\u003e\u003cspan address=\"10.1186/s12974-021-02095-1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonar E, Dubin A, Bierczynska-Krzysik A, Noga M, Silberring J, Stalinska K, et al. Identification of major cellular proteins synthesized in response to interleukin-1 and interleukin-6 in human hepatoma HepG2 cells. Cytokine. 2006;33:111\u0026ndash;117. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cyto.2005.12.011\u003c/span\u003e\u003cspan address=\"10.1016/j.cyto.2005.12.011\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang C, Hawkins KE, Dore S, Candelario-Jalil E. Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke. Am J Physiol Cell Physiol. 2019;316:C135-C153. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1152/ajpcell.00136.2018\u003c/span\u003e\u003cspan address=\"10.1152/ajpcell.00136.2018\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFahmi RM, Elsaid AF. Infarction Size, Interleukin-6, and Their Interaction Are Predictors of Short-Term Stroke Outcome in Young Egyptian Adults. J Stroke Cerebrovasc Dis. 2016;25:2475\u0026ndash;2481. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jstrokecerebrovasdis.2016.06.021\u003c/span\u003e\u003cspan address=\"10.1016/j.jstrokecerebrovasdis.2016.06.021\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJeong HK, Ji K, Min K, Joe EH. Brain inflammation and microglia: facts and misconceptions. Experimental neurobiology. 2013;22:59\u0026ndash;67. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5607/en.2013.22.2.59\u003c/span\u003e\u003cspan address=\"10.5607/en.2013.22.2.59\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuttolomondo A, Di Raimondo D, Pecoraro R, Arnao V, Pinto A, Licata G. Inflammation in ischemic stroke subtypes. Current pharmaceutical design. 2012;18:4289\u0026ndash;4310. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.2174/138161212802481200\u003c/span\u003e\u003cspan address=\"10.2174/138161212802481200\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaram SM, Karima S, Shateri S, Tafakhori A, Fotouhi A, Lima BS, et al. Functional improvement and immune-inflammatory cytokines profile of ischaemic stroke patients after treatment with boswellic acids: a randomized, double-blind, placebo-controlled, pilot trial. Inflammopharmacology. 2019;27:1101\u0026ndash;1112. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10787-019-00627-z\u003c/span\u003e\u003cspan address=\"10.1007/s10787-019-00627-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNayak AR, Kashyap RS, Kabra D, Purohit HJ, Taori GM, Daginawala HF. Time course of inflammatory cytokines in acute ischemic stroke patients and their relation to inter-alfa trypsin inhibitor heavy chain 4 and outcome. Annals of Indian Academy of Neurology. 2012;15:181\u0026ndash;185. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.4103/0972-2327.99707\u003c/span\u003e\u003cspan address=\"10.4103/0972-2327.99707\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorthmann H, Tryc AB, Goldbecker A, Ma YT, Tountopoulou A, Hahn A, et al. The temporal profile of inflammatory markers and mediators in blood after acute ischemic stroke differs depending on stroke outcome. Cerebrovascular diseases. 2010;30:85\u0026ndash;92. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1159/000314624\u003c/span\u003e\u003cspan address=\"10.1159/000314624\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQiu R, Gao Y, Hou D, Wang Y, Yu C, Wang W, et al. Association between hs-CRP Levels and the Outcomes of Patients with Small-Artery Occlusion. Frontiers in aging neuroscience. 2016;8:191. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fnagi.2016.00191\u003c/span\u003e\u003cspan address=\"10.3389/fnagi.2016.00191\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang J, Wu Y, Gao Z. Correlations of C-Reactive Protein (CRP), Interleukin-6 (IL-6), and Insulin Resistance with Cerebral Infarction in Hypertensive Patients. Medical science monitor: international medical journal of experimental and clinical research. 2019;25:1506\u0026ndash;1511. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.12659/MSM.912898\u003c/span\u003e\u003cspan address=\"10.12659/MSM.912898\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCojocaru IM, Cojocaru M, Tanasescu R, Iliescu I, Dumitrescu L, Silosi I. Expression of IL-6 activity in patients with acute ischemic stroke. Romanian journal of internal medicine = Revue roumaine de medecine interne. 2009;47:393\u0026ndash;396.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePan L, Du J, Liu J, Liao H, Liu X, Guo X, et al. Tocilizumab treatment effectively improves coronary artery involvement in patients with Takayasu arteritis. Clinical rheumatology. 2020;39:2369\u0026ndash;2378. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10067-020-05005-7\u003c/span\u003e\u003cspan address=\"10.1007/s10067-020-05005-7\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\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":"IL-1β, IL-6, hs-CRP, infarct core volume, ischemic penumbra","lastPublishedDoi":"10.21203/rs.3.rs-1882454/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1882454/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eDuring cerebral ischemia, inflammatory factors such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-1β released from the ischemic core may trigger neuronal death in the ischemic penumbra, influencing infarct volume. This study aimed to understand the relationship between serum IL-1β, IL-6, and high-sensitivity C-reactive protein (hs-CRP) levels with infarct core and ischemic penumbra volume in patients with acute ischemic stroke (AIS) and its influence on prognosis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe serum levels of IL-1β, IL-6, and hs-CRP were measured in 65 patients within 24h of AIS onset. The infarcts of the patients were imaged with magnetic resonance imaging and magnetic resonance angiography. Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and core volume on computed tomography perfusion or perfusion-weighted imaging were used to calculate infarct volume and ischemic penumbra volume. The Tan collateral score was calculated with Neusoft Brain Clinical Assistant Ration Evaluate (NeuBrainCARE).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eWe found a significant correlation between infarct core volume and serum hs-CRP levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) and between penumbra volume and IL-6 levels (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Serum IL-6 and hs-CRP levels were positively correlated with NIHSS scores at admission, discharge, and 3 months after discharge. IL-1β levels, Tan collateral score, and ASPECTS showed no correlation with the infarct core volume.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eA significant correlation between hs-CRP and IL-6 levels and infarct and ischemic penumbra volume, respectively, and with NIHSS score shows that these two factors might prove helpful in predicting the extent of neurological damage in AIS patients after 3 months of onset, opening new avenues for treatment.\u003c/p\u003e","manuscriptTitle":"Correlation of Serum IL-1β, IL-6, and hsCRP levels with Infarct Core and Ischemic Penumbra Volume in Acute Ischemic Stroke","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2022-08-30 15:32:02","doi":"10.21203/rs.3.rs-1882454/v2","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}},{"code":1,"date":"2022-07-27 13:23:14","doi":"10.21203/rs.3.rs-1882454/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":"0a2defdd-9d26-42f1-a3a5-4a9a703e59c2","owner":[],"postedDate":"August 30th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-10-29T06:44:17+00:00","versionOfRecord":[],"versionCreatedAt":"2022-08-30 15:32:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-1882454","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1882454","identity":"rs-1882454","version":["v2"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}