Toll样受体信号转导通路介导的脑缺血耐受

许多预处理措施均可诱导脑缺血耐受,如短暂的全身或局部脑缺血、缺氧、内毒素、促炎细胞因子、麻醉剂等。耐受可在数分钟内快速形成(快速耐受),亦可在数小时至数天内迅速建立起神经保护状态(延迟耐受)。缺血造成组织细胞损伤,损伤的组织细胞释放一些内源性的激活物激活Toll样受体(Toll-like receptors,TLR s)炎症信号传导通路,诱发炎症反应,加重缺血损伤。在延迟缺血耐受的形成过程中,预处理激活TLR s信号通路,诱发轻微炎症,同时生成一些反馈抑制物(如抗炎细胞因子、诱饵受体和TLR s信号通路抑制剂)抑制随后严重缺血所造成的炎症反应,从而形成延迟耐受;快速耐受的形成可能是由于预处理因素影响了膜的流动性,改变了脂质筏的结构从而抑制了TLRs炎症信号通路。对脑缺血耐受发生机制的理解有助于预防和治疗脑缺血损伤。

Cerebral ischemic tolerance mediated by toll like receptor signal transduction pathway

Aim Cerebral ischemic tolerance can be induced by a variety of preconditioning stimuli,such as transient global and focal ischemia,hypoxia,and administration of lipopolysaccharide(LPS),proinflammatory cytokines,anesthetics.Tolerance can be established with two forms: a rapid form in which the trigger induces tolerance to ischemia within minutes and a delayed form in which development of protection takes several hours or days.During ischemia,inflammatory reaction was initiated by toll-like receptors(TLRs) that recognize host-derived molecules released from injured tissues and cells,which exacerbates ischemic injury.In the delayed form of tolerance,the preconditioning stimuli first triggers the TLRs inflammatory pathway,leading not only to inflammation but also to simultaneous upregulation of feedback inhibitors(such as anti-inflammatory cytokines,decoy receptors,and signaling inhibitors),which reduced the inflammatory response to subsequent severe ischemia.The rapid tolerance is achieved by direct interference with membrane fluidity,causing change of lipid rafts leading to inhibition of TLRs signaling pathways.The comprehension of mechanism of cerebral ischemic tolerance highlights new avenues for future prevention and treatment of ischemic brain injury