Jiang Zhiming, Zhang Yuke, Zhu Yibing, Li Chong, Zhou Lei, Li Xiaolin, Zhang Fuxiang, Qiu Xianming, Qu Yiqing
Department of Pulmonary and Critical Care Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Department of Pulmonary and Critical Care Medicine, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
Ann Transl Med. 2021 Feb;9(3):223. doi: 10.21037/atm-20-2196.
Epithelial-mesenchymal transition (EMT) is an important characteristic in the remodeling of airways that occurs in chronic obstructive pulmonary disease (COPD). Cigarette smoke is a potential driving factor of this EMT in COPD. However, the mechanisms by which cigarette smoke induce EMT remain uncertain. Cathelicidin has been implicated as a causal factor of airway inflammation and mucus hypersecretion in smoking-related COPD. This study aimed to investigate whether cathelicidin induces EMT to promote airway remodeling in this disease.
Human lung tissue was collected from smokers with COPD and smokers without COPD. The EMT markers E-cadherin and vimentin were examined by immunohistochemistry. Mouse models of COPD were established by taking mice with airway cathelin-related antimicrobial peptide (CRAMP), the murine homologue of cathelicidin, either upregulated or downregulated by intranasal introduction of lentiviral vectors and then exposing them to cigarette smoke. E-cadherin and vimentin expression in the airways of the model mice was examined using immunofluorescence. Tumor necrosis factor alpha (TNF-α) converting enzyme (TACE), transforming growth factor alpha (TGF-α), and epidermal growth factor receptor (EGFR) expression was analyzed by Western blot. Additionally, NCI-H292 human airway epithelial cells, both with and without cathelicidin downregulation, were stimulated with cigarette smoke extract (CSE) and LL-37 synthetic peptide, a bioactive fragment of cathelicidin. This was done to confirm that the TACE/TGF-α/EGFR signaling pathway is activated in humans exposed to cigarette smoke.
Significant EMT was found in the small airways of smokers both with and without COPD, as well as in the airways of COPD model mice. Downregulation of CRAMP in COPD mice, however, ameliorated airway EMT induced by cigarette smoke. Conversely, upregulation of CRAMP enhanced airway EMT ; TACE, TGF-α, and EGFR were found to be involved in this process. , EMT induced by CSE and LL-37 was inhibited by blocking TACE, TGF-α, and EGFR expression.
Cathelicidin promotes airway EMT by activating the TACE/TGF-α/EGFR signaling pathway. This mediates smoking-induced airway remodeling in the pathogenesis of COPD.
上皮-间质转化（EMT）是慢性阻塞性肺疾病（COPD）气道重塑的一个重要特征。香烟烟雾是COPD中这种EMT的潜在驱动因素。然而，香烟烟雾诱导EMT的机制仍不确定。在吸烟相关的COPD中，cathelicidin被认为是气道炎症和黏液高分泌的一个致病因素。本研究旨在调查cathelicidin是否诱导EMT以促进该疾病中的气道重塑。
从患有COPD的吸烟者和未患COPD的吸烟者中收集人肺组织。通过免疫组织化学检测EMT标志物E-钙黏蛋白和波形蛋白。通过鼻内注射慢病毒载体上调或下调气道cathelicidin相关抗菌肽（CRAMP，cathelicidin的小鼠同源物），然后将小鼠暴露于香烟烟雾中，建立COPD小鼠模型。使用免疫荧光检测模型小鼠气道中E-钙黏蛋白和波形蛋白的表达。通过蛋白质印迹分析肿瘤坏死因子α（TNF-α）转换酶（TACE）、转化生长因子α（TGF-α）和表皮生长因子受体（EGFR）的表达。此外，用香烟烟雾提取物（CSE）和cathelicidin的生物活性片段LL-37合成肽刺激下调和未下调cathelicidin的NCI-H292人气道上皮细胞，以证实TACE/TGF-α/EGFR信号通路在暴露于香烟烟雾的人中被激活。
在患有和未患COPD的吸烟者的小气道以及COPD模型小鼠的气道中均发现明显的EMT。然而，COPD小鼠中CRAMP的下调改善了香烟烟雾诱导的气道EMT。相反，CRAMP的上调增强了气道EMT；发现TACE、TGF-α和EGFR参与了这一过程。阻断TACE、TGF-α和EGFR的表达可抑制CSE和LL-37诱导的EMT。
Cathelicidin通过激活TACE/TGF-α/EGFR信号通路促进气道EMT。这在COPD发病机制中介导吸烟诱导的气道重塑。
