Loss of E-cadherin is causal to pathologic changes in chronic lung disease
Baishakhi Ghosh, Jeffrey Loube, Shreeti Thapa, Hurley Ryan, Erin Capodanno, Daniel Chen, Carter Swaby, Si Chen, Saborny Mahmud, Mirit Girgis, Kristine Nishida, Linyan Ying, Pratulya Pragadaraju Chengala, Ethan Tieng, Michael Burnim, Ara Wally, D. Ryan Bhowmik, Michael Zaykaner, Bonnie Yeung‐Luk, Wayne Mitzner, Shyam Biswal, Venkataramana K. Sidhaye
Abstract
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.