The objectives of this research proposal are to first, study PMN migration across the alveolar septum, especially PMN migration from alveolar air spaces to the interstitium and second, to define the role of lung endothelial and epithelial ICAM-1 in regulating PMN migration in inflamed lungs and its consequent effects on long injury. The lung contains a large alveolar surface area that is exposed constantly to inflammatory stimuli as well as a large marginated pool of neutrophils. The regulation of neutrophil migration in the lung is critical for maintaining the integrity of the delicate alveolar septum. The alveolar epithelium has an extraordinary high expression of ICAM-1, an adhesion molecule known to effect stable binding of PMNs to cell surfaces and thought to play an important role in regulating PMN extravasation into inflamed tissues. The expression of ICAM-1 on lung epithelial cells in situ can be modified by hyperoxic exposure and proinflammatory cytokines. We hypothesize that alveolar epithelial surface ICAM-1 is involved in regulating PMN migration in the lung. There are six specific aims in this research proposal. 1. Study the role of epithelial ICAM-1 on PMN trans-epithelial migration in an in vitro epithelial culture system. 2. Demonstrate migration of PMNs from alveolar air spaces into the interstitium under physiological conditions and study the subsequent clearance of interstitial PMNs. 3. Define the effects of selected proinflammatory cytokines on ICAM-1 of specific lung cells. 4. Define the role of iCAM-1 in regulating neutrophil clearance from the alveolar surface in mouse lungs that have either a normal or modified distribution pattern of iCAM-1. 5. Define the time course of changes in ICAM-1 expression and the corresponding course of neutrophil invasion in the development of pulmonary inflammation. 6. Test the effectiveness of anti-ICAM-1 antibodies in preventing neutrophil infiltration and protect against lung injury. Successful completion of these aims will enhance our understanding of the mechanisms controlling the development of neutrophil dependent lung injury during inflammation.
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