Members of the Emory Alcohol and Lung Biology Center unveiled a strong association between ethanol abuse and susceptibility to acute lung injury. We hypothesized that one mechanism by which ethanol promotes acute lung injury relates to the activation of tissue remodeling characterized by both increased expression and degradation of lung extracellular matrices. We set out to investigate this during the prior funding period and showed that chronic exposure to ethanol in rodents leads to the activation in lung of matrix metalloproteinases and increased collagen fragmentation, increased expression of Transforming Growth Factor-pi (TGFp), and increased expression of fibronectin, a matrix glycoprotein implicated in injury and repair. We also showed evidence of activation of lung tissue remodeling in otherwise 'healthy' alcoholics. More importantly, these studies unveiled the lung fibroblast as a target for ethanol. Thus, we now propose to explore the mechanisms by which ethanol affects fibroblast functions, the signaling pathways triggered, and the potential role of extracellular matrices as modulators of these events. Interestingly, we found that ethanol-induced oxidative stress via oxidation of thiol disulfide couples activates non-neuronal nicotinic acetylcholine receptors (nAChRs) and triggers TGF|31/Smad3 signaling followed by the induction of genes involved in control of matrix expression and myofibroblast transdifferentiation. We also found that this pathway results in the deposition of fibronectin-rich matrices that help sustain the 'alcoholic phenotype', whereas peroxisome proliferator activated receptors-gamma (PPARy) downregulate these responses. These novel observations led us to postulate that in lung fibroblasts, ethanol-induced oxidative stress triggers redox signaling via nAChRs that leads to TGFp1/Smad3 signaling. In turn, TGFp1/Smad3 signaling promotes alterations in fibroblast phenotype and the production of fibronectin-rich extracellular matrices that render the lung susceptible to fibroproliferation in the setting of acute lung injury. These events are counterbalanced by PPARy. This hypothesis will be tested in aims designed to: 1) Identify the nAChRs responsible for mediating the effects of ethanol in lung fibroblasts. 2) Examine the role of TGFp1/Smad3 signaling in ethanol-induced susceptibility to acute lung injury. 3) Explore the mechanisms by which fibroblast-derived fibronectin-rich matrices contribute to the ethanol-induced effects. 4) Determine the role of PPARy in downregulating ethanol-induced fibroblast activation and matrix expression, and examine how manipulation of this pathway in vivo affects ethanolrelated consequences. Lav summary: This project will examine how chronic exposure to alcohol activates lung fibroblasts and promotes acute lung injury.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Specialized Center (P50)
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Special Emphasis Panel (ZAA1)
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Emory University
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