脓毒症诊治中Ang/Tie信号通路的研究进展
Advances in the study on Ang/Tie signaling pathway in diagnosis and treatment of sepsis
杨航 1戴菁 1王学锋1
作者信息
- 1. 上海交通大学医学院附属瑞金医院检验科,上海 200025
- 折叠
摘要
脓毒症以及伴随的多器官功能障碍是一组常见的临床综合征,其患病率随着人口老龄化逐年上升.全球每年发生2 000万例脓毒症,死亡率为26%.早期准确诊断脓毒症,有利于及时采取针对性的治疗策略,这是降低病死率的关键.内皮细胞是外源病原体或内源性损伤信号的早期作用对象.研究提示,内皮细胞的结构改变与功能活化在脓毒症的发生、发展中发挥重要作用.作为内皮细胞专属信号通路,血管生成素(angiopoietin,Ang)/酪氨酸激酶受体(tyrosine kinase receptor,Tie)在内皮细胞的异常激活和损伤中发挥重要作用.Ang/Tie信号通路主要包括2种位于内皮细胞中的酪氨酸激酶受体(Tie1、Tie2)和4种分泌性糖蛋白配体(Ang-1、Ang-2、Ang-3、Ang-4).机制研究方面,Ang-1可持续性激活Tie2受体,维持细胞与细胞、细胞与基质间的相互作用,支持血管内皮细胞正常的生理功能;Ang-2是Ang-1拮抗剂,可竞争性阻断Ang-1与Tie2受体结合.脓毒症环境下,Ang-1下降,Ang-2升高,Ang-1/Ang-2的比值下降.Ang-2竞争性阻断Ang-1与可溶性Tie2受体结合,内皮细胞处于严重异常激活状态.Ang-2介导肝素酶的释放导致糖萼损伤,可引起血管通透性增加;Ang-2可促进炎症反应;Ang/Tie信号系统失调介导凝血功能障碍,Ang-2升高是弥散性血管内凝血的前哨性事件.临床病情监测方面,Ang-2>5.61 ng/mL,诊断脓毒症的灵敏度为74.36%;Ang-2持续升高,提示内皮功能难以恢复,器官发生功能性改变.早期动态监测Ang-2可用于预测脓毒症相关肺损伤、急性肾损伤.Ang-2/Ang-1比值上升、Ang1/可溶性Tie2比值下降可预测脓毒症患者90 d病死率(ROC曲线面积分别为0.787和0.704).Ang-2和可溶性Tie-2水平下降,则提示脓毒症血浆置换有效.靶向Ang/Tie信号通路的动物实验获得一定成功,但目前临床试验未能获得有价值的结果.脓毒症相关Ang/Tie信号通路有待于进一步深入研究.
Abstract
Sepsis and concomitant multiorgan dysfunction are a group of common clinical syndromes,and their prevalence are increasing year by year due to the increase of the aging population.It reveals that 20 million cases of sepsis occur globally every year,with a mortality rate of 26%.Early diagnosis of sepsis facilitates the adoption of timely and tar-geted therapeutic strategies,which is a key element in reducing mortality.Endothelial cells(EC)are the early targets of ex-ogenous pathogens and endogenous injury signals,and numerous studies suggest that structural changes and functional acti-vation of EC play an important role in the development of sepsis.As an endothelial-exclusive signaling pathway,the angio-poietin(Ang)/tyrosine kinase receptor(Tie)signaling pathway plays an important role in the abnormal activation and injury of EC,and plays a central role in the regulation of dysfunctional changes in the disease process.The Ang/Tie signaling path-way mainly includes two tyrosine kinase receptors(Tie1,Tie2)located in EC and four secreted glycoprotein ligands(Ang-1,Ang-2,Ang-3,Ang-4).Ang-1 sustainably activates the Tie2 receptor,maintaining function between cells,and between cell and matrix,supporting the normal physiological functions of vascular EC.Ang-2 is an Ang-1 antagonist,competitively blocking the binding of Ang-1 to the Tie2 receptor.In a sepsis environment,the ratio of Ang-1/Ang-2 decreases(Ang-1 de-creases,while Ang-2 increases).Ang-2 competitively blocks the binding of Ang-1 to Tie2 receptors,resulting in severe ab-normal activation of EC.Ang-2 mediates the release of heparinase(HPSE),resulting in glycocalyx damage and an increase of vascular permeability.Ang-2 increase may promote inflammatory response.Ang/Tie signaling system dysfunction results in coagulation dysfunction,and Ang-2 elevation is a sentinel event in disseminated intravascular coagulation.In terms of disease monitoring,the sensitivity of Ang-2>5.61 ng/mL for diagnosing sepsis is 74.36%.Continuing rise of Ang-2 indi-cates that patients are in difficulty with restoring endothelial function and normal function in organs.Early dynamic morni-toring of Ang-2 can be used to predict sepsis related lung injury and acute kidney injury.The increase in Ang-2/Ang-1 ratio and Ang-2/soluble Tie ratio are independently correlated with the 90 d-mortality rate of sepsis patients(area under ROC curve is 0.787 and 0.704,respectively).Decrease of Ang-2 and/or Tie-2 in levels indicates good efficay of plasma ex-change in sepsis patients.Targeting the Ang/Tie signaling pathway have achieved certain success in animal experiments,but currently clinical trials have not yielded valuable results.Further in-depth research is needed on the Ang/Tie signaling pathway related to sepsis.
关键词
脓毒症/血管生成素/酪氨酸激酶受体Ang/TieKey words
Sepsis/Angiopoietins/Tyrosine kinase receptor Angli/Tie引用本文复制引用
基金项目
国家自然科学基金面上项目(81970127)
国家自然科学基金面上项目(82270128)
出版年
2024
国家科技期刊平台
NSTL
万方数据