Chronic alcohol abuse increases the risk of developing acute lung injury approximately three-fold. In both experimental animal models and in selected clinical studies in human subjects, chronic ethanol ingestion produces chronic oxidative stress within the alveolar microenvironment, as reflected by profound depletion of the antioxidant, glutathione. This chronic oxidative stress leads to diverse defects within the alveoli, most notably alveolar epithelial barrier disruption and alveolar macrophage dysfunction, which render the lung susceptible to injury during acute inflammatory stresses such as sepsis, pneumonia, or trauma. Many of the alveolar epithelial and macrophage functions that are impaired in the alcoholic lung are normally regulated within the alveolar space by granulocyte-macrophage colony-stimulating factor (GM-CSF). This competitive renewal addresses the hypothesis that chronic alcohol abuse impairs GM-CSF responsiveness of the alveolar epithelium and macrophages, thereby rendering the lung susceptible to injury. A related hypothesis to be tested is that treatment with recombinant GM-CSF can overcome GM-CSF hyporesponsiveness in the alcoholic lung and decrease the incidence and/or severity of acute lung injury in alcoholic patients. In four integrated aims this project will determine: 1) the mechanisms by which ethanol-induced oxidative stress impairs GM-CSF receptor expression and selected downstream GM-CSF-dependent functions in alveolar epithelial cells and macrophages in ethanol-fed rats, 2) the role of lung-specific expression of GM-CSF in ethanol-mediated lung dysfunction by examining alveolar epithelial cell and macrophage function in ethanol-fed transgenic mice that under-express or over-express GM-CSF within the alveolar epithelium, and comparing these to the parent strain mice with normal GM-CSF expression, 3) the mechanisms by which exogenous GM-CSF treatment restores alveolar epithelial and macrophage functions in chronic ethanol-fed rats, using both isolated cells in vitro as well as integrated cell functions in vivo, 4) the optimal dosing and timing of GM-CSF therapy in an established model of sepsis-mediated lung injury in vivo in ethanol-fed rats. Experimental findings indicate that the """"""""alcoholic lung"""""""" is a remarkably consistent phenotype in mice, rats, and in humans. Therefore, this proposal exploits existing transgenic mouse constructs that enable the performance of critical experiments that are not possible in the rat model, and complement these experiments with physiological studies that are far more feasible in the rat model. Further, parallel studies in these two species increase the likelihood that any novel insights will ultimately translate to the clinical setting. The ultimate goal of this project is to develop human recombinant GM-CSF as a therapy for patients at high risk for acute lung injury as a consequence of chronic alcohol abuse.
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