Science Faculty, Department of Biology, 37516Istanbul University, Istanbul, Turkey.
School of Medicine, Koc University Research Center for Translational Medicine (KUTTAM), Koc University, Istanbul, Turkey.
Toxicol Ind Health. 2022 Jun;38(6):330-341. doi: 10.1177/07482337221095638. Epub 2022 May 7.
Air pollution, especially at chronic exposure to high concentrations, is a respiratory risk factor for the development of chronic obstructive pulmonary disease (COPD). E-cadherin, a cell-cell adhesion protein, is involved in the integrity of the alveolar epithelium. Causes of E-cadherin decreases in emphysematous areas with pulmonary cell damage related to COPD are not well understood. We aimed to determine the molecules causing the decrease of E-cadherin and interactions between these molecules. In emphysematous and non-emphysematous areas of lungs from COPD patients (n = 35), levels of E-cadherin, HDACs, Snail, Zeb1, active-β-catenin, p120ctn, and Kaiso were determined by using Western Blot. The interactions of HDAC1, HDAC2, and p120ctn with transcription co-activators and Kaiso were examined by co-immunoprecipitation experiments. The methylation status of the promoter was investigated. E-cadherin, Zeb1, Kaiso, and active-β-catenin were decreased in emphysema, while HDAC1, HDAC2, and p120ctn2 were increased. Snail, Zeb1, Twist, active-β-catenin, Kaiso, and p120ctn co-precipitated with HDAC1 and HDAC2. E-cadherin, Kaiso, and active-β-catenin co-precipitated with p120ctn. HDAC1-Snail and HDAC2-Kaiso interactions were increased in emphysema, but p120ctn-E-cadherin interaction was decreased. The results show that HDAC1-Snail and HDAC2-Kaiso interactions are capable of decreasing the E-cadherin in emphysema. The decreased interaction of p120ctn/E-cadherin leads to E-cadherin destruction. The decreased E-cadherin and its induced degradation in pneumocytes cause impaired repair and disintegrity of the epithelium. Approaches to suppress HDAC1-Snail and HDAC2-Kaiso interactions may help the protection of alveolar epithelial integrity by increasing the E-cadherin stability in pneumocytes.
空气污染，尤其是长期暴露于高浓度污染环境下，是导致慢性阻塞性肺疾病（COPD）的一个呼吸道致病因素。E-钙黏蛋白是一种细胞间黏附蛋白，与肺泡上皮细胞的完整性有关。然而，导致 COPD 患者肺气肿区域 E-钙黏蛋白减少的原因尚不清楚。我们旨在确定导致 E-钙黏蛋白减少的分子，并研究这些分子之间的相互作用。通过 Western blot 检测了 35 例 COPD 患者肺气肿和非肺气肿区域 E-钙黏蛋白、HDACs、Snail、Zeb1、活性-β-catenin、p120ctn 和 Kaiso 的水平。通过免疫共沉淀实验检测了 HDAC1、HDAC2 和 p120ctn 与转录共激活因子和 Kaiso 的相互作用。并对启动子的甲基化状态进行了研究。E-钙黏蛋白、Zeb1、Kaiso 和活性-β-catenin 在肺气肿中减少，而 HDAC1、HDAC2 和 p120ctn2 增加。Snail、Zeb1、Twist、活性-β-catenin、Kaiso 和 p120ctn 与 HDAC1 和 HDAC2 共沉淀。E-钙黏蛋白、Kaiso 和活性-β-catenin 与 p120ctn 共沉淀。在肺气肿中，HDAC1-Snail 和 HDAC2-Kaiso 的相互作用增加，但 p120ctn-E-钙黏蛋白的相互作用减少。结果表明，HDAC1-Snail 和 HDAC2-Kaiso 的相互作用能够减少肺气肿中的 E-钙黏蛋白。p120ctn/E-钙黏蛋白相互作用的减少导致 E-钙黏蛋白的破坏。肺细胞中 E-钙黏蛋白的减少及其诱导的降解导致上皮细胞的修复和完整性受损。抑制 HDAC1-Snail 和 HDAC2-Kaiso 相互作用的方法可能有助于通过增加肺细胞中 E-钙黏蛋白的稳定性来保护肺泡上皮细胞的完整性。
