Alcohol abuse increases the risk of developing the acute respiratory distress syndrome (ARDS) ˜ 3-fold in septic patients. We have shown that chronic ethanol ingestion in rats impairs alveolar epithelial barrier function and increases sepsis-mediated acute lung injury in vivo. Recently we determined that ethanol-induced alveolar epithelial dysfunction is corrected by treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). Interestingly, a Phase II clinical trial from Australia published in 2002 suggested that GM-CSF decreased acute lung injury in patients with severe sepsis. Although that study did not evaluate which of these patients might have had underlying alcohol abuse, these results nevertheless raise the exciting possibility that GM-CSF could be an effective therapy in patients at risk for ARDS. Further, we hypothesize that GM-CSF treatment could be particularly effective in septic patients with underlying alveolar epithelial dysfunction secondary to alcohol abuse. To test this hypothesis experimentally we employed a cecal ligation and perforation (CLP) model of sepsis in rats fed an isocaloric liquid diet containing either ethanol or maltin-dextrin (control diet) for 6 weeks. Rats were treated with recombinant rat GM-CSF (500 ng in saline) or saline vehicle alone intranasally × 3 doses starting 48 hours prior to CLP surgery and then sacrificed after 18 hours of severe sepsis (manifested by hypotension and lactic acidemia). We determined that GM-CSF treatment significantly (p < .05) decreased acute lung injury as reflected by lung edema (wet:dry ratios) and alveolar epithelial protein leak. In fact, ethanol-fed rats treated with GM-CSF had the same (p > .05) degree of sepsis-mediated lung injury as control-fed rats. We conclude that GM-CSF treatment significantly decreases sepsis-mediated acute lung injury in ethanol-fed rats. Based on these findings in a relevant experimental model, we speculate that GM-CSF treatment could significantly decrease the morbidity and even the mortality of acute lung injury in alcoholic patients. Although this needs to be tested in future clinical trials, this targeted approach to alveolar epithelial dysfunction is promising in this vulnerable population who have an ˜ 70% chance of developing ARDS during sepsis and for whom we have no effective therapies other than supportive care.
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