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Ethanol stimulates the expression of fibronectin in lung fibroblasts via kinase-dependent signals that activate CREB

Division of Pulmonary, Allergy, and Critical Care Medicine, Departments of ¹Medicine and ³Pediatrics, Emory University School of Medicine, and ²Atlanta Veterans Affairs Medical Center, Atlanta, Georgia

Submitted 7 January 2004 ; accepted in final form 6 January 2005

Ethanol renders the lung susceptible to acute lung injury in the setting of insults such as sepsis. The mechanisms mediating this effect are unknown, but activation of tissue remodeling is considered key to this process. We found that chronic ethanol ingestion in rats increased the expression of fibronectin, a matrix glycoprotein implicated in acute lung injury. In cultured NIH/3T3 cells and in primary rat and mouse lung fibroblasts, ethanol induced fibronectin mRNA and protein expression in a dose- and time-dependent fashion. The effect of ethanol was prevented by inhibitors of protein kinase C and mitogen-activated protein kinases and was associated with the phosphorylation and increased DNA binding of the transcription factor cAMP response element binding protein, followed by increased transcription of the fibronectin gene. Fibroblasts were found to express ₇ nicotinic acetylcholine receptor (nAChR), and ethanol induction of fibronectin was abolished by -bungarotoxin and methyllcaconitine, inhibitors of ₇ nAChRs. However, ethanol was able to induce fibronectin mRNA and protein in primary lung fibroblasts isolated from ₇ nAChR knockout mice. The ethanol-induced fibronectin response was dependent on ethanol metabolism since 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, abolished the effect and acetaldehyde induced it. These observations suggest that ethanol or ethanol metabolites stimulate lung fibroblasts to produce fibronectin by inducing specific signals transmitted via nAChRs independent of the _7-subunit, and this might represent a mechanism by which ethanol renders the lung susceptible to acute lung injury.

extracellular matrix; tissue remodeling; signal transduction; gene transcription; nicotinic acetylcholine receptors; lung injury; cAMP response element binding protein

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