Ethanol stimulates the expression of fibronectin in lung fibroblasts via kinase-dependent signals that activate CREB
Ethanol stimulates the expression of fibronectin in lung fibroblasts via kinase-dependent signals that activate CREB
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DOI：
10.1152/ajplung.00003.2004
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发表时间：
2005-05-01
影响因子：
4.9
通讯作者：
Guidot, D
中科院分区：
文献类型：
--
作者：
Roman, J;Ritzenthaler, JD;Guidot, D
乙醇使肺在脓毒症等损伤情况下易受急性肺损伤。介导这种效应的机制尚不清楚，但组织重塑的激活被认为是这一过程的关键。我们发现，大鼠慢性乙醇摄入增加了纤维连接蛋白的表达，这是一种与急性肺损伤有关的基质糖蛋白。在培养的NIH/3 T3细胞和原代大鼠和小鼠肺成纤维细胞中，乙醇以剂量和时间依赖性方式诱导纤连蛋白mRNA和蛋白表达。蛋白激酶C和丝裂原活化蛋白激酶的抑制剂，并与磷酸化和增加的DNA结合的转录因子cAMP反应元件结合蛋白，其次是增加纤连蛋白基因的转录，防止乙醇的影响。发现成纤维细胞表达α（7）烟碱乙酰胆碱受体（nAChR），α-银环蛇毒素和甲基乌头碱（α（7）nAChR的抑制剂）可消除乙醇对纤连蛋白的诱导作用。然而，乙醇能够诱导从α（7）nAChR敲除小鼠分离的原代肺成纤维细胞中的纤连蛋白mRNA和蛋白质。乙醇诱导的纤连蛋白反应依赖于乙醇代谢，因为乙醇脱氢酶抑制剂4-甲基吡唑消除了这种作用，而乙醛诱导了这种作用。这些观察结果表明，乙醇或乙醇代谢物通过诱导不依赖于α（7）亚基的nAChR传递的特异性信号刺激肺成纤维细胞产生纤连蛋白，这可能代表了乙醇使肺易受急性肺损伤的机制。
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 alpha(7) nicotinic acetylcholine receptor (nAChR), and ethanol induction of fibronectin was abolished by alpha-bungarotoxin and methyllcaconitine, inhibitors of alpha(7) nAChRs. However, ethanol was able to induce fibronectin mRNA and protein in primary lung fibroblasts isolated from alpha(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 alpha(7)-subunit, and this might represent a mechanism by which ethanol renders the lung susceptible to acute lung injury.