Division of Respiratory Medicine, Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Basic Clin Pharmacol Toxicol. 2011 Jul;109(1):63-72. doi: 10.1111/j.1742-7843.2011.00686.x. Epub 2011 Mar 16.
Mucus hypersecretion is an important manifestation in patients with chronic obstructive pulmonary diseases (COPD). Cigarette smoke is importantly implicated in the pathogenesis of COPD. Previous studies have shown that cigarette smoke-induced MUC5AC (a major component of airway mucus) expression involving ErbB1 (EGF receptor) signalling pathway. Recently, it has been reported that cigarette smoke induces ErbB3 activation in airway epithelia to secret mucus, and the ligand of ErbB3, neuregulin (NRG) 1β, induces MU5AC expression in human bronchial epithelial cells. In the present study, we have suggested that NRG1β/ErbB3 signalling is activated by cigarette smoke, resulting in the activation of a variety of signal cascade pathways, leading to mucin production in human bronchial epithelial (16HBE) cells. We show that cigarette smoke increases NRG1β release, ErbB3 phosphorylation and MUC5AC production. These effects are prevented by an ErbB3-neutralizing antibody and by specific knockdown using small interfering RNA (siRNA) for NRG1β, implicating NRG1β-dependent ErbB3 activation in the responses. Cigarette smoke activates ERK1/2, c-Jun N-terminal kinase (JNK) mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3-K) signalling pathways, which are also inhibited by an ErbB3-neutralizing antibody and NRG1β siRNA, indicating the regulation of cigarette smoke-activated pathways by NRG1β/ErbB3 signalling. Furthermore, pre-treatments with metalloprotease inhibitor (TNF-α protease inhibitor-1) and specific knockdown of TNF-α-converting enzyme (TACE) with TACE siRNA prevented cigarette smoke-induced NRG1β release, ErbB3 phosphorylation and mucin production, suggesting the role of TACE in cigarette smoke-mediated NRG1β/ErbB3 signalling activation. These results suggest that NRG1β/ErbB3 signalling regulates cigarette smoke-induced mucin overproduction via the MAPK and PI3K signal pathways in 16HBE cells.
黏液过度分泌是慢性阻塞性肺疾病（COPD）患者的重要表现。香烟烟雾在 COPD 的发病机制中起着重要作用。先前的研究表明，香烟烟雾诱导 MUC5AC（气道黏液的主要成分）表达涉及 ErbB1（EGF 受体）信号通路。最近，有报道称香烟烟雾诱导气道上皮细胞中的 ErbB3 激活以分泌黏液，而 ErbB3 的配体神经调节蛋白 1β（NRG1β）诱导人支气管上皮细胞中的 MU5AC 表达。在本研究中，我们提出 NRG1β/ErbB3 信号通路被香烟烟雾激活，导致多种信号级联途径的激活，导致人支气管上皮（16HBE）细胞中粘蛋白的产生。我们发现香烟烟雾增加了 NRG1β 的释放、ErbB3 的磷酸化和 MUC5AC 的产生。这些作用可以被 ErbB3 中和抗体和针对 NRG1β 的小干扰 RNA（siRNA）特异性敲低所阻止，表明 NRG1β 依赖性 ErbB3 激活参与了这些反应。香烟烟雾激活 ERK1/2、c-Jun N 末端激酶（JNK）丝裂原激活蛋白激酶（MAPK）和磷脂酰肌醇 3-激酶（PI3-K）信号通路，这些通路也被 ErbB3 中和抗体和 NRG1β siRNA 抑制，表明 NRG1β/ErbB3 信号调节香烟烟雾激活的途径。此外，金属蛋白酶抑制剂（TNF-α 蛋白酶抑制剂-1）预处理和 TNF-α 转化酶（TACE）的特异性 siRNA 敲低可阻止香烟烟雾诱导的 NRG1β 释放、ErbB3 磷酸化和粘蛋白产生，表明 TACE 在香烟烟雾介导的 NRG1β/ErbB3 信号激活中发挥作用。这些结果表明，NRG1β/ErbB3 信号通过 16HBE 细胞中的 MAPK 和 PI3K 信号通路调节香烟烟雾诱导的粘蛋白过度产生。
