Broken barriers: a new take on sepsis pathogenesis

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.