Epithelial Plasticity in COPD Epithelia Is Associated with Mitochondrial Dysfunction

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.