Several studies by our lab and other groups at the Emory Alcohol and Lung Biology Center have shown that chronic ethanol abuse predisposes the lung to injury. We have identified Bronchiolitis Obliterans Syndrome (BOS) as another serious clinical condition that may be affected by chronic alcohol abuse. BOS is an airway obstruction disease that primarily affects lung transplant recipients, however it is also prevalent in patients who are exposed to particular toxins and infections. Compelling preliminary data show that chronic ethanol ingestion by donor rats exacerbates obliterative bronchiolitis (OB) in a rodent heterotopic tracheal transplant model. We propose that chronic alcohol abuse by transplant donors may predispose the donor lung to BOS by decreasing granulocyte/macrophage colony stimulating factor (GM-CSF)-mediated epithelial integrity via the TGFbeta1 signaling pathway. This is relevant in the context of lung transplantation as many organ donors are otherwise young healthy individuals who die in alcohol-related accidents. This proposal has three overall goals: (1) to determine the effect of donor ethanol ingestion on OB; (2) to investigate the role of GMCSF; and (3) to investigate the role of TGFbeta1 in the pathogenesis of experimental-induced OB.
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