Reperfusion of the ischemic intestine results in the infiltration of large numbers of neutrophils into the mucosal interstitium that is accompanied by extensive mucosal injury including disruption of the interstitium, edema, and epithelial cell necrosis. Several recent studies demonstrate a strong correlation between mucosal injury and neutrophil infiltration suggesting that neutrophils may play an active role in mediating some of the mucosal injury observed in the reperfused gut. Hypothesis: We propose that reactive oxygen metabolites generated by activated neutrophils may degrade the mucosal interstitial matrix and injure the epithelium directly via oxidative mechanisms and/or indirectly via the oxidative activation of latent proteases and inactivation of certain protease inhibitors. In order to test this hypothesis we intend to: 1. Characterize the effects of activated neutrophils toward the individual components of the interstitial matrix and subepithelial basement membrane in the absence or presence of intestinal interstitial fluid (lymph). 2. Characterize the interaction between activated neutrophils and the basement membrane synthesized by ileal epithelial cells in vitro in the absence or presence of interstitial fluid (lymph). 3. Investigate the cytotoxic activity of activated neutrophils toward ileal, epithelial cells in the absence or presence of interstitial fluid (lymph). 4. Determine the effect that neutrophils may have on the ability of an epithelial monolayer to restrict movement of macromolecules in the absence or presence of interstitial fluid (lymph). The proposed studies will increase our understanding of the mechanisms by which inflammatory neutrophils mediate degradation of the mucosal interstitium and epithelium injury in the reperfused intestine. Because reperfusion of ischemic intestine induces an acute inflammatory response, data obtained from these studies may be important in understanding the mechanisms of tissue injury associated with other forms of inflammation.
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