Ischemia and reperfusion is a regional circulatory disorder that elicits microvascular and immune responses that are characteristic of acute inflammatory conditions, such as multiple organ system failure and organ transplantation. The overall objective of this Program Project Grant (program project) is to define the mechanisms that underlie the inflammatory responses, microvascular dysfunction, and parenchymal cell injury that result when the intestine and/or liver are exposed to ischemia and reperfusion. The program formalizes and extends existing collaborations among thirteen investigators with an active interest in the pathobiology of ischemia/reperfusion (I/R) injury. Support is requested for five projects, three scientific cores, and an administrative core. The molecular, biochemical, structural, and functional responses of microvascular endothelial cells to I/R is a major focus of the work outlined in this program project. Project 0004 will address the potential roles of superoxide and nitric oxide (NO), as well as reduced shear rates, in mediating I/R-induced platelet-endothelial cell adhesion in intestinal venules and define the importance of platelets in modulating the recruitment of leukocytes and endothelial barrier dysfunction in postischemic venules. Project 0007 will focus on the mechanisms whereby acute ethanol consumption promotes the development of a sustained defensive (or protected) phenotype in the intestine such that the gut exhibits enhanced resistance to the deleterious consequences of I/R for 24 to 48 hrs after ingestion. Project 0006 will determine the mechanisms by which hepatic I/R-induced oxidative stress creates an imbalance between NF-kB-dependent expression of potentially injurious cytokines and protective proteins in favor of the former resulting in liver injury. Project 0010 will examine the mechanisms that allow Kupffer cells and hepatocytes to modulate the responses of hepatic endothelial cells to hypoxia-reoxygenation, including NF-kB activation, inflammatory cytokine expression, and E-selectin upregulation. Project 0009 will determine how matrix metalloprotease (MMPs) synthesis and activation are regulated in posthypoxic endothelial cells, and how MMPs contribute to the endothelial barrier dysfunction that is associated with I/R. These projects will be supported by services provided by an, Cell Biology/Morphology Core (9001), Molecular Biology/Biochemistry Core (9002) and a Mutant Mouse Resource Facility (9003). This coordinated effort involves a multidisciplinary approach aimed at elucidating the mechanisms responsible for I/R-induced inflammation and microvascular dysfunction at the molecular, cellular, single microvessel and organ levels.
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