Prematurely born human infants often develop chronic lung disease (CLD), in which inflammation is a key upstream event. The ability to overcome and resolve the adverse effects of lung inflammation may in fact determine whether an infant will go on to develop CLD or not. The mechanisms that negatively regulate and terminate inflammation, both in the lung and elsewhere, are poorly understood. Upon injection with LPS, a bacterial endotoxin, mice lacking Bcr and Abr die of sepsis with lung injury because they are unable to down regulate and resolve an episode of acute inflammation. These two related proteins negatively regulate a small GTPase, Rac. Macrophages Iacking A br a nd B cr contain elevated Ievels o f active R ac. Active R ac stimulates multiple functions of inflammatory cells including phagocytosis, motility and reactive oxygen species production. Based on our preliminary data, we hypothesize that Bcr and Abr negatively regulate inflammation in the lung through their action on Rac. Our studies are aimed at deciphering the tempo-spatial events (cell types, recruitment kinetics, interactions, cytokines) that lead to increased lung injury in mice lacking Abr and Bcr, after exposure to insults that are relevant to the pathogenesis of human CLD, and to simultaneously seek therapies to down regulate this process. We propose to 1) determine LPS-evoked kinetics of myeloid cell mobilization and cytokine production in mice without Abr and Bcr 2) investigate proinflammatory cytokine-induced gene expression involving Abr and Bcr in alveolar macrophages, including TGF-131 3) examine the role of the lung endothelium in the pulmonary injury seen in mice lacking Abr and Bcr 4) investigate if unresolved inflammation and CLD will develop in newborn mice lacking Abr and Bcr after exposure to mild hyperoxia and LPS 5) explore lentiviral and peptide strategies to terminate LPS-induced inflammation based on Abr, Bcr and Rac. Studies will be performed using primary alveolar macrophages, endothelial cells and null mutant mice. The data obtained from our experiments will provide insight into mechanisms that exist to resolve inflammation, which have never been explored. Moreover, new therapies for pulmonary inflammation will be tested. Because inflammation is a major upstream factor in the development of CLD, our studies directly relate to the Program Project's main theme of seeking to understand and ultimately cure CLD.
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