Knockout of E-cadherin in adult mouse epithelium results in emphysema and airway disease

Ghosh, B.; Loube, J.; Thapa, S.; Capodanno, E.; Mahmud, S.; Girgis, M.; Chen, S.; Nishida, K.; Ying, L.; Swaby, C.; Wally, A.; Bhowmik, D. R.; Zaykaner, M. E.; Mitzner, W.; Sidhaye, V. K.

doi:10.1101/2021.07.18.452342

bioRxiv · 10.1101/2021.07.18.452342

Knockout of E-cadherin in adult mouse epithelium results in emphysema and airway disease

Ghosh, B.·Loube, J.·Thapa, S.·Capodanno, E.·Mahmud, S.·Girgis, M.·Chen, S.·Nishida, K.·Ying, L.·Swaby, C.·Wally, A.·Bhowmik, D. R.·Zaykaner, M. E.·Mitzner, W.·Sidhaye, V. K.

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Abstract

Chronic obstructive pulmonary disease (COPD) is a devastating lung disease, characterized by a progressive decline in lung function, alveolar loss (emphysema), and airflow limitation due to excessive mucus secretion (chronic bronchitis), that can occur even after the injurious agent is removed. It is slated to rise to the 3rd leading cause of death due to chronic disease by 2030 globally, and the 4th leading cause of death due to chronic disease in the USA. While there is substantial evidence indicating loss of E-cadherin in the lung epithelium of patients with COPD, it is not known if this is causal to the disease. We investigated if loss of E-cadherin can result in lung disease using in both in vitro models of primary, differentiated human cells and in mouse models. Using a cell type-specific promoter using Cre/LoxP mice system to knock-out E- cadherin in ciliated and alveolar epithelial cell (Type 1 and Type 2) populations in adult mouse models, we determined that loss of E-cadherin caused airspace enlargement, as well as increased airway hyperresponsiveness indicating that it does have a causative role in causing COPD. Strategies to upregulate CDH1 (encodes for E-cadherin) in CHBEs and cigarette-smoke injured NHBEs can rescue the dysfunctional epithelium.

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Ghosh, B., Loube, J., Thapa, S., Capodanno, E., Mahmud, S., Girgis, M., Chen, S., Nishida, K., Ying, L., Swaby, C., Wally, A., Bhowmik, D. R., Zaykaner, M. E., Mitzner, W., Sidhaye, V. K.. 2021-07-18. Knockout of E-cadherin in adult mouse epithelium results in emphysema and airway disease. https://doi.org/10.1101/2021.07.18.452342

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