Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi, 530021, China.
Department of Respiratory Medicine, The First Affiliated Hospital of Guangxi Medical University, 6 Shuangyong Road, Nanning, Guangxi, 530021, China.
Free Radic Biol Med. 2024 Nov 1;224:447-456. doi: 10.1016/j.freeradbiomed.2024.08.036. Epub 2024 Aug 29.
Airway remodeling is an important pathological of airflow limitation in chronic obstructive pulmonary disease (COPD).However,its mechanism still needs to be further clarify.
Animals:Healthy male C57BL/6 mice aged 4-6 weeks were randomly divided into control group and cigarette smoke(CS)group. Mice in the CS group were placed in a homemade glass fumigator, 5 cigarettes/time, 40 min/time, 4 times/day, 5 days/week, for 24 weeks. Mice in the control group were placed in a normal air environment.Cells:BEAS-2B cells were stimulated with 0.1%cigarette smoke extract(CSE).HE staining, immunohistochemical staining and Masson staining were used to observe the pathological of lung tissues, transmission electron microscopy was used to observe the structural of mitochondria in bronchial epithelial cells.Western blotting was used to detect the expression of STAT3,transforming growth factor-β1(TGF-β1),microtubule-associated protein 1A/1B-light chain3(LC3),PINK1,Parkin,E-cadherin,zonula occludens1(ZO-1),vimentin and snail family transcriptional inhibitor1 (Snail1),and MitoSOX Red was used to detect mitochondrial reactive oxygen species(mtROS).
CS exposure causes lung parenchymal destruction and airway remodeling in mice.Compared to the control group,the expression of p-STAT3,TGF-β1 and EMT in the whole lung homogenate of the CS group was increased.Mitochondrial architecture disruption in bronchial epithelial cells of CS mice, with impaired PINK1-Parkin-dependent mitophagy.In vitro experiments showed that CSE exposure led to STAT3 activation, increased TGF-β1,EMT and enhanced PINK1-Parkin-mediated mitophagy.STAT3 inhibition reversed TGF-β1 upregulation induced by CSE and improved CSE-induced EMT and mitophagy.Inhibition of mitophagy improves EMT induced by CSE. Inhibition of mitophagy reduces STAT3-induced EMT.
CS activates the STAT3,and activated STAT3 promotes EMT in bronchial epithelial cells by enhancing PINK1-Parkin-mediated mitophagy and TGF-β1 signaling.Moreover, activated STAT3 can promote EMT directly.This may be one of the mechanisms by which CS causes small airway remodeling in COPD.
气道重塑是慢性阻塞性肺疾病（COPD）气流受限的重要病理学特征。然而，其机制仍需进一步阐明。
动物：4-6 周龄健康雄性 C57BL/6 小鼠随机分为对照组和香烟烟雾（CS）组。CS 组小鼠置于自制玻璃熏气箱中，每次 5 支香烟，每次 40 分钟，每天 4 次，每周 5 天。对照组小鼠置于正常空气环境中。细胞：用 0.1%香烟烟雾提取物（CSE）刺激 BEAS-2B 细胞。HE 染色、免疫组织化学染色和 Masson 染色观察肺组织病理学变化，透射电镜观察支气管上皮细胞中线粒体的结构，Western blot 检测 STAT3、转化生长因子-β1（TGF-β1）、微管相关蛋白 1A/1B-轻链 3（LC3）、PINK1、Parkin、E-钙黏蛋白、闭合蛋白 1（ZO-1）、波形蛋白和蜗牛家族转录抑制剂 1（Snail1）的表达，MitoSOX Red 检测线粒体活性氧（mtROS）。
CS 暴露导致小鼠肺实质破坏和气道重塑。与对照组相比，CS 组全肺匀浆中 p-STAT3、TGF-β1 和 EMT 的表达增加。CS 小鼠支气管上皮细胞中线粒体结构破坏，PINK1-Parkin 依赖性线粒体自噬受损。体外实验表明，CSE 暴露导致 STAT3 激活，增加 TGF-β1、EMT 并增强 PINK1-Parkin 介导的线粒体自噬。STAT3 抑制逆转了 CSE 诱导的 TGF-β1 上调，并改善了 CSE 诱导的 EMT 和线粒体自噬。线粒体自噬抑制改善了 CSE 诱导的 EMT。线粒体自噬抑制降低了 STAT3 诱导的 EMT。
CS 激活 STAT3，激活的 STAT3 通过增强 PINK1-Parkin 介导的线粒体自噬和 TGF-β1 信号通路促进支气管上皮细胞 EMT。此外，激活的 STAT3 可以直接促进 EMT。这可能是 CS 导致 COPD 小气道重塑的机制之一。
