摘要
目的失控的炎症反应是脓毒症的主要发病机制。近期发现G蛋白偶联受体-174(GPR174)在免疫反应的调控和自身免疫性疾病的发病过程中具有重要的作用。本研究探讨GPR174基因多态性与汉族人群脓毒症易感性的相关性和机制。方法收集2005年5月至2017年12月入住复旦大学附属中山医院急诊重症监护室(ICU)575例脓毒症和579例非脓毒症的患者进行病例对照研究,利用ABI 7900平台TaqMan Real-time PCR方法对GPR174基因的SNP rs3827440进行基因测序,酶联免疫吸附法(ELISA)测定TNF-α、IL-1β、IL-6和IL-10的浓度。建立CLP脓毒症小鼠模型,观察Gpr174基因敲除后(GPR74 KO)对脓毒症小鼠生存率和炎症反应的影响。结果GPR174基因rs3827440与汉族人群脓毒症的易感性显著相关。脓毒症患者携带TT/T基因型/等位基因比例明显高于ICU非脓毒症对照组,Logistic回归分析纠正性别因素差异有统计学意义(OR=1.68,95%CI:1.19-2.20,P=0.0004)。进一步研究发现,脓毒症患者外周血IL-6和TNF-α的浓度与基因型有关,携带TT/T基因型患者外周血IL-6和TNF-α浓度显著髙于携带CC/C基因型的患者,去除混杂因素后差异有统计学意义(P<0.05)。动物实验发现,与野生型小鼠相比,Gpr174 KO小鼠脓毒症的生存率明显升高,血清中炎症介质TNF-α、IL-6、IL-1β的表达明显降低,抗炎因子IL-10明显升高(P<0.01)。结论GPR174通过调控炎症反应,影响脓毒症的发病和易感性。
Objective Dysregulated host immune responses contribute to the pathogenesis of sepsis.G protein-coupled receptor 174(GPR174)was found to be involved in the immune responses and associated with the susceptibility to autoimmune diseases.This study aimed to investigate the association of GPR174 variants with sepsis susceptibility and the contribution of GPR174 in sepsis development.Methods From May 2005 to December 2017,a total of 575 sepsis patients and 579 non-septic controls admitted to our Emergency ICU were enrolled in this case-control study.The non-synonymous SNP rs3827440 in GPR174 was genotyped using TaqMan Real-time PCR assays on ABI7900 platform.Then the correlation between rs3827440 and serum levels of interleukin(IL)-6 and tumor necrosis factor-αlpha(TNF-α)were investigated in septic patients.Gpr174-deficient mice were generated and subjected to cecal ligation and puncture(CLP).The concentrations of inflammatory cytokines were measured by enzyme-linked immunosorbent assay(ELISA).Results Rs3827440 TT/T genotype in GPR174 was positively associated with sepsis risk after logistic regression analysis adjusted for sex[odds ratio(OR)=1.68,95%confidence interval(CI):1.19-2.20,P=0.0004].IL-6 and TNF-α serum levels in female TT and male T allele carriers of septic patients were significantly higher than those in female CC and male C allele carriers(P<0.05).Preclinical validation of Gpr 174 gene was performed in Gprl 74 knockout(KO)mice using CLP models.Gprl74 KO mice had higher survival rate.Moreover,Gprl74 KO mice had significantly decreased serum concentrations of IL-1β,IL-6 and TNF-α compared with WT mice,while the levels of IL-10 was increased(P<0.01).Conclusions GPR174 as a novel sepsis susceptibility gene in Chinese Han population is involved in the development and physiopathology of sepsis.
作者
王建李
仇冬则
胡延妍
童朝阳
宋振举
Wang Jianli;Qiu Dongze;Hu Yanyan;Tong Chaoyang;Song Zhenju(Department of Emergency Medicine,Zhongshan Hospital,Fudan University,Shanghai,200032;Department of Integrative Medicine,Zhongshan Hospital,Fudan University,Shanghai,200032)
出处
《中华急诊医学杂志》
CAS
CSCD
北大核心
2020年第6期815-819,共5页
Chinese Journal of Emergency Medicine
基金
国家自然科学基金(81471840,81171837)
上海市卫健委重要薄弱学科建设项目(2016ZB0202)。
