Neutrophil-endothelial interactions and barrier function in sepsis

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DESCRIPTION (provided by applicant): Sepsis continues to be a leading cause of mortality in the ICU. The root cause of mortality can be traced directly to multisystem organ failure caused by damage to the vasculature that supplies these organs. Vascular damage is due in part to uncontrolled leukocyte interaction with endothelium. The challenge in designing an immuno-centric intervention is to avoid complete suppression. In spite of systemic hyper-inflammation, trials using corticosteroids have failed. A more targeted and deliberate approach is needed. A common feature of the exaggerated inflammatory response during sepsis is the accumulation of activated neutrophils within the microvasculature of organs such as liver, kidney, brain, spleen and lung leading to cell mediated tissue damage and organ failure. The underlying mechanisms that lead to the accumulation of neutrophils in the vasculature with ensuing damage to barrier function are not known. The overarching hypothesis is that protection of the vascular endothelium from the damage induced by the activated neutrophils will facilitate a return to vascular homeostasis and in turn protect the parenchyma from an excessive invasive inflammatory response. We will (1) determine the mechanisms by which the endothelial glycocalyx layer regulates neutrophil-endothelial cell interaction during sepsis, (2) investigate whether neutrophil-derived microparticles protect endothelial barrier function, and (3) investigate whether neutrophil diapedesis contributes to damage of the vascular basement membrane and is associated vascular permeability due to a loss of barrier function. If transmigration and degranulatory activities of neutrophils were controlled without being obviated, a more physiological response to infection/injury would ensue. Thus, understanding how to control vascular damage through manipulation of neutrophil extravasation has potential applications in many acute/chronic inflammatory settings including sepsis.