Ischemia/reperfusion injury (I/RI) is a common clinical event associated with a myriad of disorders and has potentially serious consequences. Significant evidence exists that the tissue damage associated with I/RI results, at least in part, from activated leukocytes recruited during reperfusion. Mucosal surfaces at anatomically distinct sites, such as the intestine and lung, are lined by a single layer of epithelial cells. Since these tissues are essentially exposed to the outside environment, barrier function of this protective epithelium plays a central role in inflammatory disorders such as I/RI. Essentially nothing is known about the role of epithelial cells during I/RI. Using a well characterized epithelial model system, preliminary data indicates that conditions which mimic I/RI in vitro, namely hypoxia/reoxygenation, elicits only minor changes in epithelial barrier function but results in dramatic and clinically important increases in epithelial-neutrophil interactions. Thus, we hypothesize that epithelia play a crucial role in the development of clinical syndromes associated with mucosal I/RI.
Three specific aims are designed to investigate this hypothesis. First, we propose to examine in detail these interesting findings supporting the crucial interaction of neutrophils and epithelia during hypoxia/reoxygenation. Biochemical crosstalk between epithelia and neutrophils will be defined under these conditions and we will generate important probes to determine the impact of such interactions. Next, we will define basic epithelial physiologic changes during hypoxia/reoxygenation. Preliminary data reveal that important physiologic differences may exist between epithelia and other cell types, such as endothelia, during hypoxia. Lastly, we will examine the physiological regulation of hypoxia-elicited changes in neutrophil-epithelial interactions. Pilot data suggest that mediators present in the intestinal micoenvironment in vivo may impede neutrophil-elicited damage to intestinal epithelia. These studies will shed important light on this increasingly important issue and will define future strategies for development of potential therapies of I/RI.
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