Chronic alcohol exposure in rats induces oxidative stress in the lung via the angiotensin II pathway and elicits an increase in expression of the profibrotic mediator, transforming growth factor β1 (TGF-β1). In addition, fibronectin expression is increased in the lungs of alcohol-fed rats. These data strongly suggest that profibrotic mechanisms are activated in response to chronic alcohol exposure, and if true, this would suggest that alcohol abuse might increase the risk of fibrotic lung diseases. Consistent with this hypothesis, we have recently determined that alcohol ingestion increases TGF-β1 expression and collagen deposition in an experimental model of obliterative bronchiolitis (OB) following tracheal transplantation in rats. Another profibrotic cytokine, interleukin-13 (IL-13), has been shown to be an important mediator of tissue remodeling/fibrosis in the lung and may act upstream of the TGF-β1 pathway. We hypothesized that alterations in the expression of IL-13 or its receptors could contribute to alcohol-mediated amplification of profibrotic mediators in the alcoholic lung. To test this hypothesis, we analyzed whole lungs and type II alveolar epithelial cells isolated from alcohol-fed rats, as well as mouse lung fibroblasts exposed to alcohol in vitro, for various components of the IL-13 signaling pathway. Gene expression of IL-13, along with the α1 and α2 subunits of its receptor (IL-13Rα1 and IL-13Rα2), was examined by assessing mRNA levels by RT-PCR. In parallel, IL-13Rα2 protein expression was determined by immunostaining. We found that IL-13Rα2 protein was expressed in the whole lung, lung fibroblasts, and type II epithelial cells. RT-PCR analyses indicated that whole lung expresses all three components of the IL-13 signaling pathway. Although lungs from alcohol-fed rats displayed decreased IL-13 mRNA expression, IL-13Rα1 expression was increased, and a marked elevation in IL-13Rα1mRNA expression was observed in alcohol-treated primary lung fibroblasts. Associated with the increase in IL-13Rα1 mRNA in lung fibroblasts was an increase in α-smooth muscle actin protein expression, suggesting fibroblast transdifferentiation into myofibroblasts, which is a cardinal feature of fibrotic diseases such as idiopathic pulmonary fibrosis and bronchiolitis obliterans. These data suggest that IL-13 and its receptors play a role in alcohol-mediated activation of profibrotic mechanisms. In particular, we speculate that alcohol abuse increases IL-13Rα1 expression, which could heighten the response of cells in the lung to IL-13, thereby amplifying TGF-β1-induced fibroblast activation and subsequent tissue remodeling.
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