Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, No. 74, Linjiang Road, Yuzhong District, Chongqing, 400010, China.
J Appl Toxicol. 2012 Apr;32(4):282-92. doi: 10.1002/jat.1679. Epub 2011 May 4.
Cigarette smoking is strongly implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Mucus hypersecretion is the key manifestation in patients with COPD and mucin 5AC (MUC5AC) is a major component of airway mucus. Hypoxia inducible factor-1 (HIF-1) is a transcriptional factor which can be stimulated to bind to the MUC5AC promoter and induce MUC5AC promoter activation. Previous studies have reported that activation of HIF-1α pathways by cigarette smoke contributes to the development of COPD. We hypothesize that cigarette smoke up-regulates HIF-1α production and HIF-1 activity through epidermal growth factor receptor (EGFR)-activated signal cascades pathways, leading to mucin production in human airway epithelial cells (16HBE). We show that cigarette smoke increases HIF-1α production, HIF-1 activity and MUC5AC expression. These effects are prevented by small interfering RNA (siRNA) for HIF-1α, indicating that cigarette smoke-induced mucin production is HIF-1α-dependent. Cigarette smoke activates extracellular signal-regulated kinase 1/2 (ERK1/2) and phosphatidylinositol 3-kinase (PI3K) signal pathways, both of which are inhibited by gefitinib (an inhibitor of EGFR), suggesting that cigarette smoke-activated signal pathways are mediated by EGFR in 16HBE cells. Furthermore, pretreatment with gefitinib and the pharmacological inhibitors of PI3K (LY294002) and ERK1/2 (PD98059) prevented cigarette smoke-mediated Akt and ERK1/2 phosphorylation responses, HIF-1α production, HIF-1 activity and MUC5AC expression. These observations demonstrate an important role for EGFR-mediated signaling pathways in regulating cigarette smoke-induced HIF-1 activation and MUC5AC expression. Our results suggest that cigarette smoke activates EGFR-mediated signaling pathways, leading to HIF-1α production and HIF-1 activation, resulting in mucin expression in human airway epithelial cells.
吸烟与慢性阻塞性肺疾病（COPD）的发病机制密切相关。黏液过度分泌是 COPD 患者的主要表现，黏蛋白 5AC（MUC5AC）是气道黏液的主要成分。缺氧诱导因子-1（HIF-1）是一种转录因子，可被刺激与 MUC5AC 启动子结合，诱导 MUC5AC 启动子激活。先前的研究表明，香烟烟雾激活 HIF-1α 途径有助于 COPD 的发展。我们假设，香烟烟雾通过表皮生长因子受体（EGFR）激活的信号级联途径上调 HIF-1α 的产生和 HIF-1 活性，导致人气道上皮细胞（16HBE）中黏蛋白的产生。我们发现，香烟烟雾增加了 HIF-1α 的产生、HIF-1 活性和 MUC5AC 的表达。这些效应被 HIF-1α 的小干扰 RNA（siRNA）所阻止，表明香烟烟雾诱导的黏蛋白产生依赖于 HIF-1α。香烟烟雾激活细胞外信号调节激酶 1/2（ERK1/2）和磷脂酰肌醇 3-激酶（PI3K）信号通路，这两种通路都被吉非替尼（EGFR 抑制剂）抑制，提示 16HBE 细胞中香烟烟雾激活的信号通路是由 EGFR 介导的。此外，吉非替尼预处理以及 PI3K（LY294002）和 ERK1/2（PD98059）的药理抑制剂预处理可防止香烟烟雾介导的 Akt 和 ERK1/2 磷酸化反应、HIF-1α 的产生、HIF-1 活性和 MUC5AC 的表达。这些观察结果表明，EGFR 介导的信号通路在调节香烟烟雾诱导的 HIF-1 激活和 MUC5AC 表达中起着重要作用。我们的结果表明，香烟烟雾激活 EGFR 介导的信号通路，导致 HIF-1α 的产生和 HIF-1 的激活，从而导致人气道上皮细胞中黏蛋白的表达。
