Chronic alcohol abuse predisposes individuals to pneumonia and increases the risk ˜4-fold of developing the acute respiratory distress syndrome. Although it has been recognized for decades that alcohol abuse impairs alveolar macrophage function, we have more recently shown that alcohol abuse also causes previously unrecognized severe redox stress and alveolar epithelial dysfunction. Recently, we determined that chronic ethanol ingestion in a rat model decreases alveolar macrophage expression of the receptor for granulocyte-macrophage colony-stimulating factor (GM-CSF) and decreases downstream expression of the master transcription factor PU.1 that ultimately transduces GM-CSF signaling necessary for macrophage function. Remarkably, treatment with recombinant GM-CSF in vivo restored GM-CSF receptor expression, PU.1 nuclear binding, and phagocytic function in the alveolar macrophages of ethanol-fed rats. It has been assumed that GM-CSF receptor expression, and signaling via PU.1, is restricted to hematopoietic cells. However, we determined that GM-CSF treatment also restored alveolar epithelial barrier function, in both in vivo and in vitro model systems, suggesting that the GM-CSF receptor, and perhaps PU.1, is expressed in this "nonhematopoietic " cell type. To test this speculation we analyzed gene and protein expression of PU.1 and of the GM-CSF receptor (both the GM-CSFRa and GM-CSFRb subunits), as well as PU.1 nuclear binding, in freshly isolated alveolar epithelial type II cells from rats 6 ethanol ingestion for 6 weeks. We found that type II cells expressed GM-CSFRa, GM-CSFRb, and PU.1 by PCR. Further, both GM-CSFRa and GM-CSFRb proteins were expressed in type II cells as determined by flow cytometry, and PU.1 protein was expressed as determined by Western blot and EMSA. Importantly, ethanol ingestion decreased cellular expression of both GM-CSFRa and GM-CSFRb protein and decreased both PU.1 protein expression and nuclear binding. Finally, we surveyed the entire airway epithelium by immunohistochemistry using antibodies to both GM-CSFRa and GM-CSFRb in rat tracheal, bronchial, and alveolar epithelia. We determined that both GM-CSFRa and GM-CSFRb are expressed throughout the airway epithelium. In summary, we report for the first time that the lung epithelium expresses GM-CSF signaling components and that chronic ethanol ingestion impairs their expression. We speculate that alcohol abuse disrupts lung epithelial (and macrophage) function by dampening GM-CSF signaling, thereby rendering alcoholics more susceptible to acute lung injury as well as pneumonia.
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