Salt and water transport by lung epithelial cells is critical for normal clearance of fluid in the developing and mature lungs. A delicate balance between alveolar fluid secretion and absorption results in a thin fluid layer on the surface of the airways that helps promote pulmonary gas exchange and mucociliary clearance of foreign particles from the lung. The alveolar epithelial barrier formed by lung epithelial cells and tight junctions between the cells play a key role in this process, and disruption of the barrier function can result in alveolar flooding. Chronic alcohol exposure appears to compromise the alveolar barrier. Nonetheless, compensatory increases in salt transport in the alcoholic lung appear to be sufficient to maintain approximately normal levels of airway surface fluid. However, alcoholic lungs when challenged by any significant stress (like major trauma or sepsis) are much more likely to develop edema implying that the salt and water transport mechanisms cannot respond to increased demand as nonalcoholic lungs can. It is hypothesized that alcohol-induced changes in epithelial barrier function and transport mechanisms predispose the lungs to acute edematous lung injury. While there is now substantial evidence that the maintenance of salt and water transport is a strongly regulated, energy-dependent process, the pathways for salt and water transport are not clearly defined in the normal lung, let alone how they are modified in the alcoholic lung. It does seem likely that some regulatory mechanism controlling the response of lung salt and water transport stress is abnormal in alcoholic lungs. It is hypothesized that abnormal glucocorticoid and TGF-beta responsiveness of lung epithelial cells prevents stress-induced increases in lung salt and water transport in alcoholic lungs.There are three specific aims of this proposal.
The first aim i s to determine if transport characteristics of the alcoholic lung are different from normal lung.
The second aim i s to determine how transport in stressed alcoholic lung differs from normal and alcoholic lung.
The third aim to elucidate the cellular mechanisms responsible for alcohol-induced changes in lung transport. These experiments will improve our understanding of how chronic alcohol exposure alters alveolar fluid balance under normal and stressful conditions, and help in devising therapeutic strategies to prevent edematous lung injury.
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