炎症小体NLRP3相关炎症因子IL-1β、IL-18与脑小血管病相关性研究
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摘要
目的检测脑小血管病(CSVD)患者血清中炎症小体相关炎症因子IL~(-1)β、IL~(-1)8浓度,建立炎症小体NLRP3与CSVD之间的潜在关联。方法纳入CSVD患者50例和同期具有脑血管病危险因素,但头颅影像学检查正常的患者(主要指头颅磁共振平扫及弥散成像)30例。采集血样标本,使用双抗体夹心法对血清IL~(-1)β、IL~(-1)8浓度进行检测,比较其与CSVD的相关性。结果 CSVD组IL~(-1)β血清浓度(19.21±3.77ng·L~(-1))比对照组(16.56±2.84ng·L~(-1))高(P<0.05);CSVD组IL~(-1)8血清浓度(73.38±19.27ng·L~(-1))比对照组(70.70±2.84ng·L~(-1))高,但差异无统计学意义(P>0.05)。以CSVD为因变量,以年龄、性别、高血压、糖尿病、冠心病、既往卒中史、吸烟史、饮酒史、颈动脉内膜增厚、颈动脉斑块形成、血同型半胱氨酸、糖化血红蛋白、空腹血糖、三酰甘油、低密度脂蛋白、总胆固醇、IL~(-1)β、IL~(-1)8为自变量,进行Logistic回归分析。IL~(-1)β、年龄、吸烟是CSVD的危险因素(B=0.446,OR=1.562,P=0.003;B=0.166,OR=1.180,P=0.007;B=4.107,OR=0.016,P=0.010)。结论血清IL~(-1)β浓度升高与CSVD有相关性;IL~(-1)β、年龄、吸烟是脑小血管病的危险因素。
Objective To investigate the potential association between NLRP3 inflammasome and cerebral small vessel disease(CSVD)by detecting the concentrations of NLRP3-related inflammatory factors IL~(-1)β and IL~(-1)8 in CSVD patients. Method Fifty patients diagnosed with CSVD and collected 30 cases with cerebrovascular disease risk factors, however, the skull imaging examination of the normal patients(mainly refers to the head of the nuclear magnetic flat sweep and dispersion). The blood specimens were collected, and the concentrations of serum IL~(-1)β and IL~(-1)8 were detected by using double antibody sandwich method, and their correlations with CSVD were compared. Results The serum concentration of IL~(-1)β in CSVD group was higher(19.21±3.77 ng·L~(-1)) than the control group(16.56±2.84 ng·L~(-1)), showing statistically significant difference(P<0.05). Similarly, the serum concentration of IL~(-1)8 in CSVD group was higher(73.38±19.27 ng·L~(-1)) than the control group(70.70±2.84 ng·L~(-1)),but showed no significance. Logistic regression analysis was carried out by using CSVD as dependent variable, and age,gender, hypertension, diabetes, coronary heart disease, previous history of stroke, smoking history, drinking history,carotid artery intima thickening, carotid artery plaque formation, serum homocysteine, glycosylated hemoglobin, fasting venous blood glucose, triglycerides, low density lipoprotein, total cholesterol, IL~(-1)β, IL~(-1)8 as independent variables.The results showed that IL~(-1)β, age and smoking were the risk factors for CSVD(B=0.446, OR=1.562, P=0.003;B=0.166, OR=1.180, P=0.007; and B=4.107, OR=0.016, P=0.010). Conclusion These findings suggested a correlation between the concentrations of serum IL~(-1)β and CSVD. Also IL~(-1)β, age and smoking are considered as the risk factors for CSVD.
Objective To investigate the potential association between NLRP3 inflammasome and cerebral small vessel disease(CSVD)by detecting the concentrations of NLRP3-related inflammatory factors IL~(-1)β and IL~(-1)8 in CSVD patients. Method Fifty patients diagnosed with CSVD and collected 30 cases with cerebrovascular disease risk factors, however, the skull imaging examination of the normal patients(mainly refers to the head of the nuclear magnetic flat sweep and dispersion). The blood specimens were collected, and the concentrations of serum IL~(-1)β and IL~(-1)8 were detected by using double antibody sandwich method, and their correlations with CSVD were compared. Results The serum concentration of IL~(-1)β in CSVD group was higher(19.21±3.77 ng·L~(-1)) than the control group(16.56±2.84 ng·L~(-1)), showing statistically significant difference(P<0.05). Similarly, the serum concentration of IL~(-1)8 in CSVD group was higher(73.38±19.27 ng·L~(-1)) than the control group(70.70±2.84 ng·L~(-1)),but showed no significance. Logistic regression analysis was carried out by using CSVD as dependent variable, and age,gender, hypertension, diabetes, coronary heart disease, previous history of stroke, smoking history, drinking history,carotid artery intima thickening, carotid artery plaque formation, serum homocysteine, glycosylated hemoglobin, fasting venous blood glucose, triglycerides, low density lipoprotein, total cholesterol, IL~(-1)β, IL~(-1)8 as independent variables.The results showed that IL~(-1)β, age and smoking were the risk factors for CSVD(B=0.446, OR=1.562, P=0.003;B=0.166, OR=1.180, P=0.007; and B=4.107, OR=0.016, P=0.010). Conclusion These findings suggested a correlation between the concentrations of serum IL~(-1)β and CSVD. Also IL~(-1)β, age and smoking are considered as the risk factors for CSVD.
引文
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[19]Ragino YI,Chernyavski AM,Polonskaya YV,et al.Activity of the inflammatory process in different types of unstable atherosclerotic plaques[J].Bull Exp Biol Med,2012,153(2):186-189.
[20]Yu M,Wen N,Wenzhon Z,et al.Effect of repeated ischaemic preconditioning on TLR4 and proinflammatory cytokines TNF-αand IL-1βin myocardial ischaemia-reperfusion injury in a rat model[J].Arch Med Sci,2010,6(6):843-847.
[21]Lamkanfi M,Malireddi RK,Kanneganti TD,et al.Fungal zymosan and mannan activate the cryopyrin inflammasomep[J].J Biol Chen,2009,284(31):20574-20581.
[22]Pelegrin P,Surprenant A.Pannexin-1 couples to maitotoxin-and nigericin-induced interlecukin-1 beta relase through a dye uptakeindependent path-way[J].J Biol Chem,2007,282(4):2386-2394.
[23]Mattson MP,Meffert MK.Roles for NF-kappaB in nerve cell survival,plasticity,and disease[J].Cell Death Differ,2006,13(5):852-860.
[24]Pradillo JM,Denes A,Greenhalgh AD,et al.Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inlfammation in comorbid rats[J].J Cereb Blood Flow Metab,2012,32(9):1810-1819.
[25]Weber MD,Frank MG,Tracey KJ,et al.Stress induces the dangerassociated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats:apriming stimulus of microglia and the NLRP3inflammasome[J].J Neurosci,2015,35(1):316-324.
[26]Walsh JG,Muruve DA,Paver C.Inflammasomes in the CNS[J].Nat Rev Neurosci,2014,15(2):84-97.
[2]脑小血管病诊治专家共识组.脑小血管病诊治专家共识[J].中国临床医生,2014,42(1):84-87.
[3]Moran C,Phan TG,Srikanth VK.Cerebral small vessel disease:a review of clinical,radiological,and histopathological phenotypes[J].Int J Stroke,2012,7(1):36-46.
[4]Berrocal-Izquierdo N,Bioque M,Bernardo M.Is cerebrovascular disease a silent condition in patients with chronic schizo-phreniarelated disorders[J].Int Clin Psychopharmacol,2017,32(2):80-86.
[5]唐杰,付建辉.脑小血管病的发病机制[J].国际脑血管病杂志,2013,21(4):293-298.
[6]Wiseman S,Marlborough F,Doubal F,et al.Blood markers of coagulation,fibrinolysis,endothelial dysfunction and inflamation in lacunar stroke versus non-lacunar stroke and non-stroke:systematic review and meta-analysis[J].CerebrovascDis,2014,37(1):64-75.
[7]王玉梅,商亚珍.血管性痴呆的研究进展[J].承德医学院学报,2011,28(3):320-322.
[8]Satio K,Suyama K,Nishida K,et al.Early increases in TNF-α,IL-6and IL-1 beta levels following transent cerebral in gerbil barin[J].Neurosci Lett,1996,206(2-3):149-152.
[9]陈小莉,林建东,刘宁,等.雷米普利对大鼠急性肺损伤时白细胞介素-1β浓度的影响[J].中华急诊医学杂志,2001,10(5):300-302.
[10]Davies CA,Loddick SA,Joulmond S,et al.The progression and to pographic distribution of interlerkin-1βexpression after permanent middle cerebral artery occlusion in the rat[J].J Cereb Blood Flow Metab,1999,19(1):87-98.
[11]Davis BK,Wen H,Ting JP.The inflammasome NLRs in immunity,inflammation,and associated diseases[J].Ann Rev Immunol,2011,29:707-735.
[12]Lavine SD,Hofan FM,Zlokovic BV.Circulation antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury[J].J Cereb Blood Flow Metab,1998,18(1):52-58.
[13]Shcielke GP,Yang GY,Shivers BD,et al.Reduced ischemic brain injury in interleukin-1βconverting enzyme-deficient mice[J].Cereb Blood Flow Metab,1998,18(2):180-185.
[14]Huang J,Upadhyay UM,Tamargo RJ.Inflamation in stroke and focal cerebral ischemia[J].Surgical Neurology,2006,66(3):232-245.
[15]Shcielke GP,Yang GY,Shivers BD,et al.Reduced ischemic brain injury in interleukin-1βConverting enzyme-deficient mice[J].Cereb Blood Flow Metab,1998,18(2):180-185.
[16]Sahar S,Dwarakanath RS,Reddy MA,et al.Angiotensin II enhances interleukin-18 mediated inlfamatory gene expression in vascular smooth muscle cells:a novel cross-talk in the pathogenesis of atherosclerosis[J].CircRes,2005,96(10):1064-1071.
[17]Blauw GJ,Lagaay AM,Smel AH,et al.Stroke,statins,and cholesterol:a meta-analysis of randomized placebo-controlled,double-blind trials with HMG-COA reductase inhibitors[J].Stroke,1997,28(5):946-950.
[18]Ait-Oufella H,Taleb S,Mallat Z,et al.Recent advances on the role of cytokines in atherosclersis[J].Arterioscler Thromb Vasc Biol,2011,31(5):969-979.
[19]Ragino YI,Chernyavski AM,Polonskaya YV,et al.Activity of the inflammatory process in different types of unstable atherosclerotic plaques[J].Bull Exp Biol Med,2012,153(2):186-189.
[20]Yu M,Wen N,Wenzhon Z,et al.Effect of repeated ischaemic preconditioning on TLR4 and proinflammatory cytokines TNF-αand IL-1βin myocardial ischaemia-reperfusion injury in a rat model[J].Arch Med Sci,2010,6(6):843-847.
[21]Lamkanfi M,Malireddi RK,Kanneganti TD,et al.Fungal zymosan and mannan activate the cryopyrin inflammasomep[J].J Biol Chen,2009,284(31):20574-20581.
[22]Pelegrin P,Surprenant A.Pannexin-1 couples to maitotoxin-and nigericin-induced interlecukin-1 beta relase through a dye uptakeindependent path-way[J].J Biol Chem,2007,282(4):2386-2394.
[23]Mattson MP,Meffert MK.Roles for NF-kappaB in nerve cell survival,plasticity,and disease[J].Cell Death Differ,2006,13(5):852-860.
[24]Pradillo JM,Denes A,Greenhalgh AD,et al.Delayed administration of interleukin-1 receptor antagonist reduces ischemic brain damage and inlfammation in comorbid rats[J].J Cereb Blood Flow Metab,2012,32(9):1810-1819.
[25]Weber MD,Frank MG,Tracey KJ,et al.Stress induces the dangerassociated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats:apriming stimulus of microglia and the NLRP3inflammasome[J].J Neurosci,2015,35(1):316-324.
[26]Walsh JG,Muruve DA,Paver C.Inflammasomes in the CNS[J].Nat Rev Neurosci,2014,15(2):84-97.