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首页> 外文期刊>American Journal of Physiology >Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells.
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Cigarette smoke induces MUC5AC mucin overproduction via tumor necrosis factor-alpha-converting enzyme in human airway epithelial (NCI-H292) cells.

机译：香烟烟雾通过人气道上皮细胞（NCI-H292）中的肿瘤坏死因子-α转换酶诱导MUC5AC粘蛋白过度生产。

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摘要

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death in the U.S. Because cigarette smoking is so importantly implicated in the pathogenesis of COPD and because mucus hypersecretion plays such an important role in COPD, understanding of the mechanisms of smoking-induced mucus hypersecretion could lead to new therapies for COPD. Cigarette smoke causes mucin overproduction via EGF receptor (EGFR) in airway epithelial cells, but the cellular mechanism remains unknown. Airway epithelial cells contain EGFR proligands on their surfaces, which can be cleaved by metalloprotease and subsequently bind to EGFR resulting in mucin production. We hypothesize that TNF-alpha-converting enzyme (TACE) is activated by cigarette smoke, resulting in increased shedding of EGFR proligand, leading to EGFR phosphorylation and mucin induction in human airway epithelial (NCI-H292) cells. Here we show that cigarette smoke increases MUC5AC production in NCI-H292 cells, an effect that is prevented by anEGFR-neutralizing antibody and by specific knockdown of transforming growth factor-alpha (TGF-alpha) using small interfering RNA (siRNA) for TGF-alpha, implicating TGF-alpha-dependent EGFR activation in the responses. Cigarette smoke increases TGF-alpha shedding, EGFR phosphorylation, and mucin production, which are prevented by metalloprotease inhibitors (GM-6001 and TNF-alpha protease inhibitor-1) and by specific knockdown of TACE with TACE siRNA, implicating TACE in smoking-induced responses. Furthermore, pretreatment with antioxidants prevents smoking-induced TGF-alpha shedding and mucin production, suggesting that reactive oxygen species is involved in TACE activation. These results implicate TACE in smoking-induced mucin overproduction via the TACE-proligand-EGFR signal pathway in NCI-H292 cells.
机译：慢性阻塞性肺疾病（COPD）在美国是主要的死亡原因之一，因为吸烟与COPD的发病机理息息相关，并且粘液分泌过多在COPD中起着重要的作用，因此了解吸烟诱发的机制粘液分泌过多可能导致COPD的新疗法。香烟烟雾通过气道上皮细胞中的EGF受体（EGFR）引起粘蛋白过量产生，但其细胞机制仍然未知。气道上皮细胞在其表面上含有EGFR配体，可被金属蛋白酶裂解并随后与EGFR结合，从而产生粘蛋白。我们假设香烟烟雾激活了TNF-α转换酶（TACE），导致EGFR配体的脱落增加，导致人气道上皮（NCI-H292）细胞中的EGFR磷酸化和粘蛋白诱导。在这里，我们显示香烟烟雾会增加NCI-H292细胞中MUC5AC的产生，这一作用可通过使用EGFR中和抗体以及使用TGF-β的小干扰RNA（siRNA）特异性抑制转化生长因子-α（TGF-α）来防止。 α，在响应中牵涉TGF-α依赖性EGFR激活。香烟烟雾会增加金属蛋白酶抑制剂（GM-6001和TNF-α蛋白酶抑制剂-1）和TACE与TACE siRNA的特异性结合，从而阻止了TACE-α脱落，EGFR磷酸化和粘蛋白生成，这与吸烟诱导的TACE抑制有关回应。此外，用抗氧化剂进行的预处理可防止吸烟引起的TGF-α脱落和粘蛋白生成，这表明活性氧与TACE活化有关。这些结果表明，TACE通过NCI-H292细胞中的TACE-配体-EGFR信号途径参与吸烟诱导的粘蛋白过量生产。

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