This project will study the mechanisms responsible for microvascular thrombosis in experimental models of sepsis. Sepsis, a systemic response to an infection, is the main cause of death in adult intensive care units in the United States, and microvascular thrombosis is a severe complication of the disease. The main model we will use involves bacterial endotoxin (lipopolysaccharide, LPS), which mediates many manifestations of patients with a common form of sepsis. In addition, we will use a clinically relevant model of human polymicrobial sepsis of abdominal origin, cecal ligation and perforation (CLP). Our preliminary data demonstrate that both sepsis models enhance microvascular thrombosis in vivo;in this project, we will explore the molecular mechanisms involved. Our central hypothesis is that LPS-induced stimulation of toll-like receptor 4 (TLR4) on endothelial cells mediates microvascular thrombosis in endotoxemia, by a mechanism dependent on the platelet adhesive molecule, glycoprotein Ibct. We propose four aims:
in aim 1, we will identify which LPS receptors mediate enhancement of microvascular thrombosis in vivo.
In aim 2, we will determine whether bone marrow- or non-bone marrow-derived cells mediate LPS- induced responses in vivo.
In aim 3, we will use an ex vivo flow system to examine the effects of endotoxemia and CLP on platelet activation and adhesion to specific adhesion molecules (e.g.-vWf, P- selectin, fibrinogen) under physiologic flow.
In aim 4, we will use the in vivo model to define the platelet and endothelial adhesion molecules responsible for LPS- and CLP-enhanced microvascular thrombosis. Completion of these aims will broaden our understanding of the mechanisms of microvascular thrombosis in models of human sepsis. This will allow identification of novel therapeutic targets for microvascular thrombosis in this disease. Our long-term goal is to apply the knowledge gained from these studies to allow optimal management of patients with sepsis and their associated microvascular alterations. Relevance to public health: Sepsis, the body's response to an infection, is a major cause of death in the U.S. Our goal is to understand the causes of a severe complication of this illness, clots in tiny blood vessels. This information would help develop new treatments for patients with this devastating illness.
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