Postdoctoral Fellowship: Lyn in Sepsis

Sepsis accounts for over a third of all hospital deaths. The current therapy for sepsis is primarily supportive and mortality remains high (30-50%). Numerous promising preclinical data support the common view that excessive inflammation drives high mortality in sepsis. Yet, over 40 clinical trials designed to block cytokines or inflammatory pathways have failed. Preclinical studies have been focusing on the immune system, might overlook a key element inherent in the human syndrome Whereas microvascular leak and tissue edema, hallmarks of human sepsis, have been largely ignored in animal models. No clinical trial has been designed to target leaky vasculature. Recently, several investigators provided compelling evidence that improved endothelial barrier function was associated with an improvement in survival. These data point microvascular leak as a determinant factor in the outcome of sepsis. We have shown that mice with genetic deficiency of Lyn, a Src family kinases (SKF), had increased vascular permeability and higher mortality in response to LPS-induced endotoxemia. The SFKs, such as c-Src and Yes, generally promote vascular leak in response to LPS or VEGF. In contrast, expression of a constitutively active mutant of Lyn enhanced barrier function, which suggests Lyn could be a potential player to ameliorate vascular leak and thus improve survival in sepsis. However, the mechanism that leads to the loss or improvement of microvascular barrier function is poorly understood in sepsis. In the proposal, I will test the hypothesis Lyn protects against sepsis-induced vascular leak by enhancing endothelial barrier function. Research Subjects