The pathogenesis of necrotizing enterocolitis remains unknown but infectious agents, enteral alimentation, and mesenteric ischemia have often been invoked as primary initiators of the disease. Despite the prevailing opinion that feeding does play a role in the pathogenesis of enterocolitis, little is known about 1) postprandial responses of blood flow and oxygenation in the developing intestine, 2) the relationships among hemodynamics, oxygenation, and mucosal injury during ischemia and reperfusion in the presence of luminal nutrients, and 3) the contribution of individual nutrient components to intestinal injury during ischemia and reperfusion. Therefore, the overall objective of this proposal is to systemically characterize the changes in intestinal blood flow, oxygenation, and mucosal injury during feeding and ischemia in developing piglet intestine. The proposed studies will address the following specific questions: 1) What are the hemodynamic and oxygenation responses during feeding in developing intestine? Do these responses change with age and with nutrient composition of the test meal? Are the responses different for mother's milk compared to formula? 2) What changes occur in mucosal pO2 and mucosal blood flow during perfusion with luminal nutrients in developing intestine? Is there a significantly greater decrease in villous pO2 during feeding in newborn as compared to older age groups or as a function of luminal nutrient composition? 3) What are the relationships among oxygen consumption, tissue pO2, blood flow, and mucosal permeability during ischemia and reperfusion in the presence of luminal nutrients in developing intestine? Is the newborn intestine capable of regulating its blood flow as tissue pO2 decreases? Can the magnitude of mucosal injury induced by ischemia and reperfusion be correlated with villous pO2? If so, is the villous pO2 at which mucosal injury is detected higher in newborn intestine compared to older age groups? An isolated, autoperfused loop of ileum in piglets of ages 1 day, 3 days, 2 weeks, and 1 month will be utilized to measure total and fractionated blood flow, arteriovenous oxygen difference, venous pressure, and capillary pressure. Oxygen uptake, and total, pre-capillary, and post-capillary resistances will be calculated from the measured variables. Villous pO2 will be measured with an oxygen micro-electrode and mucosal blood flow by hydrogen gas clearance. Blood-to-lumen clearance of 51 chromium EDTA will be used to measure changes in mucosal permeability. Histologic damage will be assessed with light microscopy. The results of these studies should significantly extend current knowledge about the responses of the developing intestine to feeding and hemodynamic stress and may also provide useful information regarding the interactions of enteral feeding, blood flow, and necrotizing enterocolitis.
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