Cigarette smoke (CS) is the primary cause of chronic obstructive pulmonary disease (COPD), a devastating disease characterized by progressive lung function, afflicting 13% of the world’s population and causing 150,000 deaths annually in the United States. Although the focus has been on inflammation, aggressive anti-inflammatories have not served as disease modifiers suggesting additional strategies are needed. The lung epithelia, the first cells exposed to CS, play a critical role in COPD pathogenesis. We have found that alterations in the actin cytoskeleton impact barrier integrity, drive tissue remodeling, and inflammatory signals in the airway, and impaired repair and regeneration in the alveoli, ultimately leading to tissue loss and impaired lung function. In line with our work, others have shown that actin cytoskeletal reorganization is critical in the early stages of disease development and present throughout the disease, regardless of severity. This underscores the significance of the actin cytoskeleton in the pathogenesis of COPD and suggests that interventions targeting this pathway may hold promise for treating or abrogating disease. We have optimized a chronic cigarette smoke exposure model for normal human differentiated primary epithelial cells, which quantitatively replicates the cellular and molecular events observed in epithelia derived from COPD patients. With these robust models, we have identified molecular events involving epithelial structure and energetics relevant to both airway and alveolar dysfunction in COPD.

Our in vitro chronic CS exposure model increases actin assembly in lung epithelial cells from healthy donors recapitulating actin dynamics observed in COPD. Additionally, inhibiting actin assembly in CS-injured and COPD-derived cells improves airway monolayer and alveolar integrity, highlighting the critical role of actin dynamics in chronic lung disease. This is due to decreased cofilin-1, a key actin-severing protein. Restoration of cofilin-1 improves epithelial function. We propose that identifying mechanisms to increase and optimize active cofilin-1 will address a critical gap in knowledge to open new avenues for COPD intervention.

Our CS-injury model recapitulates the mitochondrial disruption and altered cellular energetics present in COPD cells. Our preliminary data indicate that COPD/CS-induced cofilin-1 loss alters mitochondrial dynamics and energetics. We hypothesize that decreases in cofilin-1 repress oxidative phosphorylation, promoting glycolysis. While mitochondrial energetics are well known to be disrupted in COPD, identifying cytoskeletal mechanisms regulating mitochondrial morphology and energetics is unexplored in COPD and can improve epithelial integrity throughout the lung.

We hypothesize that decreased cofilin-1 leads to epithelial plasticity that drives both airway and alveolar disease by increasing actin polymer mass in epithelial cells, altering the cellular structure and influencing cellular metabolism to cause tissue damage in COPD. We will dissect the contribution of cofilin-1 loss on COPD pathogenesis through its effects on epithelial integrity and mitochondrial dynamics. These novel studies provide preclinical and translational data to target actin dynamics for therapeutic gains.

Supported by: NHLBI R01HL124099