The Emory Alcohol and Lung Biology Center has demonstrated in multiple studies that chronic alcohol abuse causes a previously unrecognized pulmonary oxidant stress that generates dysfunction of multiple cell types. In clinical and animal studies, chronic alcohol ingestion depletes the alveolar lining fluid glutathione (GSH), a critical antioxidant, by -80% and oxidizes the redox potential by 35-50 mV. In Project 2, the goal is to clarify the discrete mechanisms by which chronic alcohol ingestion suppresses alveolar macrophage (AM) maturation and immune function and renders individuals susceptible to serious lung infections such as bacterial pneumonia and tuberculosis. Studies during the first phase of this Center demonstrated that alcohol-induced oxidant stress impairs AM differentiation and surface expression of the receptors necessary to drive phagocytosis and the respiratory burst. These derangements could be rescued by oral supplements of GSH precursors. In addition, Center investigators demonstrated that the alcohol-induced oxidant stress increased the expression of transforming growth factor ^ (TOPp^. Since, TGF(3i can increase expression and activity of NADPH oxidase and ROS from NADPH oxidase can up-regulate TGFpi, we hypothesized that chronic alcohol ingestion up-regulates a feed-forward loop of TGFfr and NADPH oxidase that promotes chronic ROS generation and results in impaired AM terminal differentiation. Consequently, impaired terminal differentiation results in AM with decreased plasma membrane expression of the receptors required for triggering phagocytosis and the respiratory burst, thereby rendering the alveolar space vulnerable to infections.
In Aims 1 -3, a murine model of chronic ethanol ingestion will be employed to examine the relationships between ethanol-induced oxidant stress, NADPH oxidase activation, TGFpi up-regulation, impaired terminal differentiation, and cellular dysfunction in AMs. A unique strength of the Emory Alcohol Center is highlighted through a close collaboration with the Clinical Core in Aim 4, where subjects with or without a history of chronic alcohol abuse will be recruited. After a baseline bronchoalveolar lavage and examination of AMs, subjects will be randomized to treatment with S-adenosylmethionine (SAM) or placebo to determine if SAM can attenuate alcohol-induced derangements in AMs. These studies have the potential to identify novel mechanisms and treatments for pneumonia and lung injury in alcoholic subjects.
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