Intestinal ischemia and reperfusion is a common condition in the critically ill and it has been implicated as an important factor in the etiology of a variety of pathologic conditions, including multiple failure, inflammatory bowel disease, and the acute respiratory distress syndrome. The overall goal of this Program Project Grant is to define the mechanisms that underlie the inflammatory responses and microvascular dysfunction that are associated with reperfusion of the ischemic intestine. This program formalizes and extends existing collaborative efforts among ten investigators with an active interest in the pathobiology of intestinal ischemia. Support is requested for six projects, three scientific cores, and an administrative core. The proposed work will focus on the molecular, biochemical, structural, and physiological responses of microvascular endothelium to ischemia and reperfusion. Project 1 will assess the factors that are responsible for the increased expression of endothelial cell adhesion molecules in the postischemic intestine. Project 2 will focus on the mechanisms that account for the protection against reperfusion injury that is afforded by prior exposure of the gut to brief periods of vascular occlusion (ischemic preconditioning). Project 3 will determine how reperfusion of the ischemic intestine results in leukosequestration and endothelial barrier dysfunction in the pulmonary microcirculation. Project 4 will determine whether leukocytes diminish the barrier function of endothelial cells by disrupting the organization and integrity of the cadherin-cytoskeletal complex. Project 5 will address the hypothesis that mitochondria are largely responsible for the oxidative stress observed in endothelial cells exposed to anoxia-reoxygenation. Project 6 will focus on the cellular and molecular mechanisms by which nitric oxide protects microvascular endothelium against ischemia/reperfusion injury. These projects will be supported by facilities in the Cell Culture Core (Core B), Biochemistry/Molecular Biology Core (Core C), and morphology/Imaging Core (Core D). This coordinated effort involves a multidisciplinary approach aimed at elucidating the mechanisms responsible for intestinal ischemia/reperfusion injury at the molecular, cellular, single microvessel and organ levels. The ultimate goal of the Program Project is to obtain the fundamental knowledge that is needed to improve the diagnosis and treatment of ischemic disorders of the bowel.
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