Cigarette smoke synergistically enhances respiratory mucin induction by proinflammatory stimuli
Cigarette smoke synergistically enhances respiratory mucin induction by proinflammatory stimuli
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DOI：
10.1165/rcmb.2005-0259oc
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发表时间：
2006-08-01
影响因子：
6.4
通讯作者：
Swinney, David C.
中科院分区：
文献类型：
--
作者：
Baginski, Tomasz K.;Dabbagh, Karim;Swinney, David C.
与慢性阻塞性肺疾病（COPD）相关的致病因素，如香烟烟雾、促炎细胞因子和细菌感染，可以在体外和体内单独诱导呼吸道粘蛋白。由于这些因素共同存在于COPD患者的肺部是常见的，我们假设吸烟可以放大细菌外产物和促炎细胞因子对粘蛋白的诱导，导致粘蛋白的过量产生。我们证明了香烟烟雾提取物（CSE）协同增加了LPS或tnf - α诱导的人气道上皮NCI-H292细胞MUC5AC粘蛋白的基因表达和蛋白产生。CSE还增强了表皮生长因子受体（EGFR）配体tgf - α和amphiregulin诱导的MUC5AC粘蛋白的表达和产生，以及LPS和tnf - α诱导的tgf - α和amphiregulin的表达和/或释放。此外，（4-[（3-溴苯基）氨基]-6,7-二氨基喹唑啉），一种有效的EGFR抑制剂，阻断了MUC5AC粘蛋白的协同诱导。H2O2模拟了CSE的协同作用，而抗氧化剂n -乙酰- l-半胱氨酸则阻止了CSE对MUC5AC粘蛋白的协同诱导。在lps诱导的气道炎症大鼠模型中，同时吸入香烟烟雾增加了支气管肺泡灌洗液的粘蛋白含量、muc5AC基因表达和气道粘膜细胞化生。这些结果表明，吸烟有可能通过与COPD发病机制相关的促炎刺激协同放大呼吸道粘蛋白的诱导，并导致COPD患者观察到的粘蛋白过量产生。
Pathogenic factors associated with chronic obstructive pulmonary disease (COPD), such as cigarette smoke, proinflammatory cyto-kines, and bacterial infections, can individually induce respiratory mucins in vitro and in vivo. Since co-presence of these factors is common in lungs of patients with COPD, we hypothesized that cigarette smoke can amplify mucin induction by bacterial exoproducts and proinflammatory cytokines, resulting in mucin hyperproduction. We demonstrated that cigarette smoke extract (CSE) synergistically increased gene expression and protein production of MUC5AC mucin induced by LPS or TNF-alpha in human airway epithelial NCI-H292 cells. CSE also enhanced expression and production of MUC5AC mucin induced by epidermal growth factor receptor (EGFR) ligands TGF-alpha and amphiregulin, as well as LPS- and TNF-alpha-induced expression and/or release of TGF-alpha and amphiregulin. Furthermore, (4-[(3-bromophenyl)amino]-6,7-diaminoquinazoline), a potent inhibitor of EGFR, blocked synergistic induction of MUC5AC mucin. H2O2 mimicked the synergistic effects of CSE, while antioxidant N-acetyl-L-cysteine prevented synergistic induction of MUC5AC mucin by CSE. In a rat model of LPS-induced airway inflammation, concurrent cigarette smoke inhalation enhanced mucin content of the bronchoalveolar lavage fluid, muc5AC gene expression, and mucous cell metaplasia in the airways. These results suggest that cigarette smoke has the potential to synergistically amplify induction of respiratory mucins by proinflammatory stimuli relevant to COPD pathogenesis and contribute to mucin hyperproduction observed in patients with COPD.