Endothelial cell integrity is a critical component of the body's defense against Acute Lung Injury (ALI) and endothelial dysfunction is fundamental to the pathophysiology of this illness. To this date, mortality for ALI remains unacceptably high and few therapies have any effect on survival. Activated protein C (APC) has recently been shown to improve survival in patients with sepsis, a common cause of ALi, yet the cellular mechanisms underlying this exciting discovery remain unknown. We hypothesize that one beneficial consequence of APC is a phenotypic change that enhances endothelial cell barrier function and decreases endothelial cell permeability. Specific Aim #1 will characterize the time and dose dependent effect of APC in vitro on micro and macrovascular lung EC. with a focus on ). Specific Aim #2, using complementary molecular and protein biochemical techniques, will identify the signal transduction pathways involved in the barrier protective effect of APC. Specific Aim #3 will focus on the interaction between APC and the endothelial cell APC receptor(EPCR) in APC-mediated EC barrier protection. These studies may reveal a new therapy for vascular permeability in ALI.