Department of Environmental Health and Engineering, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Department of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Commun Biol. 2022 Oct 29;5(1):1149. doi: 10.1038/s42003-022-04150-w.
Epithelial cells line the lung mucosal surface and are the first line of defense against toxic exposures to environmental insults, and their integrity is critical to lung health. An early finding in the lung epithelium of patients with chronic obstructive pulmonary disease (COPD) is the loss of a key component of the adherens junction protein called E-cadherin. The cause of this decrease is not known and could be due to luminal insults or structural changes in the small airways. Irrespective, it is unknown whether the loss of E-cadherin is a marker or a driver of disease. Here we report that loss of E-cadherin is causal to the development of chronic lung disease. Using cell-type-specific promoters, we find that knockout of E-cadherin in alveolar epithelial type II but not type 1 cells in adult mouse models results in airspace enlargement. Furthermore, the knockout of E-cadherin in airway ciliated cells, but not club cells, increase airway hyperreactivity. We demonstrate that strategies to upregulate E-cadherin rescue monolayer integrity and serve as a potential therapeutic target.
上皮细胞排列在肺黏膜表面，是抵御环境损伤的第一道防线，其完整性对肺健康至关重要。在慢性阻塞性肺疾病（COPD）患者的肺上皮细胞中，早期发现的一个关键特征是黏着连接蛋白 E-钙黏蛋白（E-cadherin）的一个关键成分丢失。这种减少的原因尚不清楚，可能是由于管腔损伤或小气道的结构改变。无论如何，尚不清楚 E-cadherin 的丢失是疾病的标志物还是驱动因素。在这里，我们报告称 E-cadherin 的丢失是导致慢性肺病发展的原因。使用细胞类型特异性启动子，我们发现，在成年小鼠模型中，敲除肺泡上皮细胞 II 型（而非 I 型）中的 E-cadherin 会导致肺泡腔扩大。此外，敲除气道纤毛细胞中的 E-cadherin（而非 club 细胞）会增加气道高反应性。我们证明，上调 E-cadherin 的策略可以挽救单层完整性，并可作为一种潜在的治疗靶点。
