Faculty of Medicine, University of Toronto, and Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario M5S 1A8, Canada.
Sci Transl Med. 2011 Jun 22;3(88):88ps25. doi: 10.1126/scitranslmed.3002011.
Despite intense research into the pathogenesis of sepsis, the current therapy for this devastating syndrome is primarily supportive and mortality remains high. The paucity of specific therapies is not for lack of effort; countless clinical trials in sepsis patients have failed despite promising preclinical data obtained from in vitro and animal models. Human sepsis is characterized by diffuse microvascular leak and tissue edema-features that have been largely ignored in animal models. Moreover, there have been no clinical trials of agents designed to prevent or treat leaky vasculature. Recent compelling evidence suggests that the breakdown in endothelial barrier function plays a crucial role in the pathogenesis of sepsis. In particular, these data suggest that preventing vascular leak can reduce mortality from sepsis. In this Perspective, we highlight the endothelial barrier as a new target for sepsis therapeutics, examining three potential strategies: enhancement of endothelial junctions; reinforcement of the endothelial cytoskeleton; and modulation of endothelial activation.
尽管人们对败血症的发病机制进行了深入研究，但目前对这种严重综合征的治疗主要还是支持性的，死亡率仍然很高。缺乏特效疗法并不是因为没有努力；尽管从体外和动物模型中获得了有希望的临床前数据，但无数针对败血症患者的临床试验都失败了。人类败血症的特征是弥漫性微血管渗漏和组织水肿——这些特征在动物模型中基本上被忽略了。此外，还没有针对旨在预防或治疗渗漏血管的药物进行临床试验。最近令人信服的证据表明，内皮屏障功能的破坏在败血症的发病机制中起着关键作用。特别是，这些数据表明，防止血管渗漏可以降低败血症的死亡率。在本观点中，我们将内皮屏障作为败血症治疗的一个新靶点，探讨了三种潜在的策略：增强内皮连接；强化内皮细胞骨架；以及调节内皮细胞激活。
