School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
Chem Biol Interact. 2022 Jan 5;351:109763. doi: 10.1016/j.cbi.2021.109763. Epub 2021 Nov 28.
Air pollution has been linked to emphysema in chronic obstruction pulmonary disease (COPD). However, the underlying mechanisms in the development of emphysema due to air pollution remain unclear. The objective of this study was to investigate the role of components of the Hippo signaling pathway for E-cadherin-mediated contact inhibition of proliferation in the lungs after air pollution exposure. E-Cadherin-mediated contact inhibition of proliferation via the Hippo signaling pathway was investigated in Sprague-Dawley (SD) rats whole-body exposed to air pollution, and in alveolar epithelial A549 cells exposed to diesel exhaust particles (DEPs), E-cadherin-knockdown, and high-mobility group box 1 (HMGB1) treatment. Underlying epithelial differentiation, apoptosis, and senescence were also examined, and the interaction network among these proteins was examined. COPD lung sections were used to confirm the observations in rats. Expressions of HMGB1 and E-cadherin were negatively regulated in the lungs and A549 cells by air pollution, and this was confirmed by knockdown of E-cadherin and by treating A549 cells with HMGB1. Depletion of phosphorylated (p)-Yap occurred after exposure to air pollution and E-cadherin-knockdown, which resulted in decreases of SPC and T1α. Exposure to air pollution and E-cadherin-knockdown respectively downregulated p-Sirt1 and increased p53 levels in the lungs and in A549 cells. Moreover, the protein interaction network suggested that E-cadherin is a key activator in regulating Sirt1 and p53, as well as alveolar epithelial cell differentiation by SPC and T1α. Consistently, downregulation of E-cadherin, p-Yap, SPC, and T1α was observed in COPD alveolar regions with particulate matter (PM) deposition. In conclusion, our results indicated that E-cadherin-mediated cell-cell contact directly regulates the Hippo signaling pathway to control differentiation, cell proliferation, and senescence due to air pollution. Exposure to air pollution may initiate emphysema in COPD patients.
空气污染与慢性阻塞性肺疾病（COPD）中的肺气肿有关。然而，由于空气污染导致肺气肿的潜在机制尚不清楚。本研究的目的是研究 Hippo 信号通路中细胞黏附连接的 E-钙黏蛋白成分在空气污染暴露后对肺的增殖抑制作用。通过 Hippo 信号通路的 E-钙黏蛋白介导的细胞接触抑制增殖作用，在全身体暴露于空气污染的 Sprague-Dawley（SD）大鼠和肺泡上皮 A549 细胞中进行了研究，还研究了柴油机排气颗粒（DEP）、E-钙黏蛋白敲低和高迁移率族蛋白 1（HMGB1）处理。还检查了潜在的上皮分化、细胞凋亡和衰老，并检查了这些蛋白质之间的相互作用网络。使用 COPD 肺切片来证实大鼠中的观察结果。空气污染使肺和 A549 细胞中的 HMGB1 和 E-钙黏蛋白的表达受到负调控，通过 E-钙黏蛋白敲低和用 HMGB1 处理 A549 细胞得到证实。暴露于空气污染和 E-钙黏蛋白敲低后，磷酸化（p）-Yap 耗竭，导致 SPC 和 T1α 减少。空气污染和 E-钙黏蛋白敲低分别下调肺和 A549 细胞中的 p-Sirt1 并增加 p53 水平。此外，蛋白质相互作用网络表明，E-钙黏蛋白是通过 SPC 和 T1α 调节 Sirt1 和 p53 以及肺泡上皮细胞分化的关键激活物。一致地，在具有颗粒物（PM）沉积的 COPD 肺泡区域观察到 E-钙黏蛋白、p-Yap、SPC 和 T1α 的下调。总之，我们的结果表明，E-钙黏蛋白介导的细胞-细胞接触直接调节 Hippo 信号通路，以控制由于空气污染导致的分化、细胞增殖和衰老。空气污染可能会引发 COPD 患者的肺气肿。
