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 organ failure, necrotizing enterocolitis, and inflammatory bowel disease. The overall objective of this Program Project Grant is to define the events that ultimately lead to the mucosal dysfunction that is observed during ischemia and following reperfusion of the adult and neonatal intestine. This program will formalize and extend existing collaborative efforts among nine investigators with an active interest in the pathobiology of intestinal ischemia. The Program will employ a multidisciplinary approach to elucidate the mechanisms underlying the structural, biochemical and physiological responses of the mucosal epithelium, interstitial matrix, vascular smooth muscle and microvascular endothelium to ischemia and reperfusion. The proposed work will focus on both the early (minutes to hours) and late events (days) associated with ischemia and reperfusion, including tissue hypoxia, leukocyte adhesion and emigration from the microvasculature, epithelia cell dysfunction, endothelial and epithelial cell injury, interstitial matrix and basement membrane degradation, decreased sensitivity of arterioles to circulating vasoconstrictors, increased mucosal permeability, mucosal ulceration, and finally mucosal regeneration and repair. Project 1 will characterize the decrement and recovery of mucosal function (lipid absorption) and its relation to the morphological changes that occur during the first few days following a brief period of mesenteric ischemia. Project 2 will assess the responses of the intestinal vasculature and mucosal permeability to ischemia- reperfusion in the developing intestine during feeding. Project 3 will study the mechanisms underlying the altered responsiveness of the intestinal microvasculature to vasoconstrictors following ischemia- reperfusion. Project 4 will determine how the variations in vascular shear forces that occur during ischemia and reperfusion influence leukocyte adhesion and emigration in mesenteric venules. Project 5 will focus on the mechanisms by which neutrophils adhere to and injure cultured vascular endothelium exposed to anoxia-reoxygenation. Project 6 will examine how interstitial fluid protects the interstitial matrix, basement membrane, and epithelial cells from the products of neutrophil activation. These projects will be supported by facilities in the Administrative Core, (Core A) Cell Culture Core (Core B), Biochemistry Core (Core C), and Morphology COre (Core D). This coordinated effort is aimed at elucidating the mechanisms that are responsible for the mucosal dysfunction and injury associated with intestinal ischemia and reperfusion, with the ultimate goal of providing the fundamental knowledge needed to improve the diagnosis and treatment of ischemic disorders of the bowel.
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