This grant renewal is an extension of our studies on the structural determinants of vascular permeability in the lung. The long-range objective is to identify the components of the tight and adhering junctions which regulate the permeability barrier in the pulmonary endothelium. Although proteins specific for the two types of endothelial junctions have been recently identified, no information currently exists regarding their distribution in different segments of the pulmonary vasculature and their relationship to structure and function of the endothelial permeability barrier. Using colloidal gold techniques and antibodies, which recognize ZO-1 and Plakoglobin, two junction-specific proteins, we will determine, by morphometry and immuno electron microscopy, the distribution of these components of the endothelial junctional complex in various segments of the rat pulmonary vascular system. In a rat model of H202-induced pulmonary edema we will correlate increased endothelial permeability with selective loss of junctional components as detected by immuno electron microscopy and freeze-fracture techniques. These studies are expected to provide new insight in the pathogenesis of a variety of human pulmonary diseases such as the Adult Respiratory Distress Syndrome (ARDS), oxygen toxicity and ischemia-reperfusion injury in which oxygen derivatives and H202 in particular, are released by activated neutrophiles or endothelial cells.
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