Chronic Alcohol Ingestion Primes the Lung for Bleomycin-Induced Fibrosis in Mice
Chronic Alcohol Ingestion Primes the Lung for Bleomycin-Induced Fibrosis in Mice
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DOI：
10.1111/acer.12232
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发表时间：
2014-02-01
影响因子：
3.2
通讯作者：
Guidot, David M.
中科院分区：
文献类型：
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作者：
Sueblinvong, Viranuj;Kerchberger, Vern E.;Guidot, David M.
背景酒精滥用会增加急性肺损伤（ALI）的风险。在实验模型和临床研究中，长期摄入酒精会导致气道氧化应激和谷胱甘肽消耗，并增加肺部纤维化的有效诱导剂转化生长因子 β-1 (TGF1) 的表达。因此，我们假设酒精摄入会促进实验性 ALI 后的异常纤维化，而用谷胱甘肽前体 s-腺苷甲硫氨酸 (SAMe) 治疗可以减轻这些影响。 方法 3 个月大的 C57BL/6 小鼠在饮用水中喂食标准乔瓦醇 (20% v/v)，持续 8 周，并在最后 4 周喂食 SAMe (4% w/v)。通过气管内滴注博莱霉素（2.5单位/kg）诱导ALI，并在第7天和第14天对肺进行组织学评估纤维化情况，并在第14天评估细胞外基质蛋白和TGF1的表达。结果摄入酒精在7天时对肺部炎症没有明显影响，但在博来霉素治疗后第14天，肺组织胶原沉积、羟脯氨酸含量、以及将活化的 TGF1 释放到气道中。相比之下，补充 SAMe 通过降低肺部 TGF1 表达，完全减轻了酒精诱导的这些异常纤维化变化的引发。与此同时，SAMe 降低了体外肺成纤维细胞酒精诱导的 TGF1 和 Smad3 mRNA 表达。结论这些新的实验结果表明，长期摄入酒精使实验小鼠肺部在博莱霉素诱导的 ALI 后易发生纤维化，并且这些效应可能是由酒精介导的氧化应激及其诱导和激活 TGF1 驱动的。
BackgroundAlcohol abuse increases the risk for acute lung injury (ALI). In both experimental models and in clinical studies, chronic alcohol ingestion causes airway oxidative stress and glutathione depletion and increases the expression of transforming growth factor beta-1 (TGF1), a potent inducer of fibrosis, in the lung. Therefore, we hypothesized that alcohol ingestion could promote aberrant fibrosis following experimental ALI and that treatment with the glutathione precursor s-adenosylmethionine (SAMe) could mitigate these effects.MethodsThree-month-old C57BL/6 mice were fed standard chowalcohol (20% v/v) in their drinking water for 8weeks and SAMe (4% w/v) during the last 4weeks. ALI was induced by intratracheal instillation of bleomycin (2.5 units/kg), and lungs were assessed histologically at 7 and 14days for fibrosis and at 14days for the expression of extracellular matrix proteins and TGF1.ResultsAlcohol ingestion had no apparent effect on lung inflammation at 7days, but at 14days after bleomycin treatment, it increased lung tissue collagen deposition, hydroxyproline content, and the release of activated TGF1 into the airway. In contrast, SAMe supplementation completely mitigated alcohol-induced priming of these aberrant fibrotic changes through decreased TGF1 expression in the lung. In parallel, SAMe decreased alcohol-induced TGF1 and Smad3 mRNA expressions by lung fibroblasts in vitro.ConclusionsThese new experimental findings demonstrate that chronic alcohol ingestion renders the experimental mouse lung susceptible to fibrosis following bleomycin-induced ALI, and that these effects are likely driven by alcohol-mediated oxidative stress and its induction and activation of TGF1.