Novel Mechanisms for Maintaining Endothelial Barrier Function in Sepsis

The pathophysiology of multiple disease states, including sepsis,1,2 hypertension,1 atherosclerosis,3–5 and ischemia-reperfusion injury,6 is characterized by loss of the endothelial barrier function leading to the accumulation of plasma-borne proteins, tissue edema, and cell death. Importantly therapeutic strategies that inhibit loss of endothelial barrier function have been associated with strategies that improve outcomes.7 There is growing understanding of the role of adherens in maintaining the integrity of the endothelial barrier function8 and the molecular pathways that regulate adheren expression.9 Article see p 2728 Treatment strategies that have been shown to enhance endothelial barrier function have typically focused on preventing endothelial activation,10 inhibiting endothelial cell free radical generation,6 and targeting intracellular kinases.11 Many studies demonstrate that upregulation or prevention of Rac1 inhibition during endothelial cell activation leads to preserved endothelial barrier function.11 In addition to edema, sepsis is characterized by endothelial activation, and the generation of microemboli attributed to the upregulation of the tissue factor–mediated clotting cascade further complicates the clinical course of sepsis.12 Preclinical studies have demonstrated that the cytokine cascade induced by sepsis adversely affects endothelial and intimal barrier functions.1 In addition to decreasing endothelial barrier function, the cytokine cascades have been shown to activate the clotting cascade through endothelial cell tissue factor expression.10 This upregulation of tissue factor can lead activation of the extrinsic coagulation cascade and, because of the generation of factors Xa and Va, …