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.
The airway epithelium is subjected to insults such as cigarette smoke (CS), a primary cause of Chronic Obstructive Pulmonary Disease (COPD) and serves as an excellent model to study cell plasticity. Both CS-exposed and COPD-patient derived epithelia (CHBE) display quantitative evidence of cellular plasticity, with loss of specialized apical features and a transcriptional profile suggestive of partial epithelial to mesenchymal transition, albeit with distinct cell motion indicative of cellular unjamming. These injured/diseased cells have an increased fraction of polymerized actin, due to loss of the actin-severing protein, cofilin-1. Decreasing polymerized actin restores the jammed state in both CHBE and CS exposed epithelia, indicating that the fraction of polymerized actin is critical in unjamming the epithelia. Kinetic energy spectral analysis suggests that loss of cofilin-1 results in unjamming, similar to that seen with both CS exposure and in CHBE cells. Our data suggest that in response to chronic injury, although epithelial cells display evidence of pEMT, their movement is more consistent with cellular unjamming. Inhibitors of actin polymerization rectify the unjamming features of the monolayer.
Cellular plasticity is generally defined as the ability of a cell to adapt in response to stimuli. The airway epithelium is subjected to chronic environmental insults and therefore serves as an excellent model to study plasticity. Large patient to patient variability has limited our understanding of epithelial plasticity in chronic obstructive pulmonary disease (COPD). Globally, COPD is the 4th leading cause of death, and insults such as cigarette smoke (CS) is the main causes of disease etiology as it quantitatively alters both structure and function of airway epithelial cells. We observed that the epithelium injured from CS, has a disrupted barrier with decreased ciliary function and monolayer height, and a transcriptional shift towards mesenchymal markers with preserved apical‐basal polarity, which resembles cells derived from COPD patients. We found that the cells in the monolayer unjam, with a kinetic energy much higher than seen with epithelial to mesenchymal transition (EMT), indicating that the cells are not mesenchymal. This cellular movement occurs with increases in the velocity correlation length implicating cell shape and stiffness as fundamental to the injury; analysis suggests decreasing cell stiffness can push the cells to jam. We also observed that basal oxygen consumption rate (OCR) of CS exposed epithelia is lower than air exposed cells, indicating reduced metabolic activity. As both cells exposed to tobacco and cells from COPD patients have increased polymerized actin, which would increase cell stiffness, strategies to shift the actin towards more G‐actin could serve as a strategy to improve monolayer integrity. Moreover, cells from patients with COPD have lower levels of the actin binding protein, Cofilin‐1, which can also alter mitochondrial function. Inhibiting actin polymerization (Latrunculin A) to decrease cell stiffness pushes the epithelium back towards a jammed state and potentially alter mitochondrial function, attesting to cell‐intrinsic properties of stiffness in monolayer integrity.
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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