The lung epithelia, the first cells exposed to CS, play a critical role in COPD pathogenesis. While the loss of the junctional protein, E-cadherin, in COPD regardless of severity is well-recognized, our group has demonstrated that cell-specific loss of E-cadherin is sufficient to cause both airway remodeling and alveolar destruction observed in COPD tissues. Moreover, we have demonstrated that overexpression of E-cadherin abrogates alveolar tissue destruction in mouse models of COPD. This underscores the significance of the epithelium in the pathogenesis of COPD and suggests that interventions targeting this pathway may hold promise for treating the disease. To address these questions, we have optimized several complementary models: 1) a chronic cigarette smoke exposure model for normal human differentiated primary epithelial cells that quantitatively replicates the cellular and molecular events observed in epithelia derived from COPD patients, 2) mouse exposures, and 3) exposure of precision-cut lung slices from human tissues to CS. With these robust models, we have identified a role for E-cadherin in cell proliferation impacting repair and regeneration relevant to both airway and alveolar dysfunction in COPD.

We have found that loss of E-cadherin in AT2 cells is sufficient to cause emphysema, while loss in ciliated epithelium results in airway remodeling and reactivity. Interestingly we find that, apart from its role in cell-cell adhesion, loss of E-cadherin decreases cell proliferation. We hypothesize E-cadherin is essential in promoting regional progenitor cell proliferation critical for tissue repair after cellular injury, and in its absence, cells experience irreversible growth arrest due to cellular senescence (see Fig. 1). Identifying the role of E-cadherin in cell proliferation will open new avenues for COPD intervention. We propose that loss of E-cadherin causes senescence through an interplay of signaling cascades and compromised mechanosensing pathways. Furthermore, we have evidence that loss of E-cadherin alters cellular energetics. Loss of E-cadherin impacts mitochondrial membrane potential and oxidative phosphorylation, promoting glycolysis. While mitochondrial energetics are disrupted in COPD, mechanisms by which progenitor cell defects in E-cadherin affect mitochondrial morphology and cellular metabolism are unexplored in COPD. Furthermore, detailed cell-specific contribution to spatial metabolomics will be performed to delineate the alveolar and airway metabolic consequences of regional progenitor loss of E-cadherin.

We will dissect the contribution of E-cadherin loss on COPD pathogenesis through its effects on cellular senescence-reducing reparative mechanisms. As we have evidence that E-cadherin loss in COPD is partly due to epigenetic reprogramming from enhancer element methylation, we will study strategies to specifically target these elements to modulate E-cadherin transcription. These novel studies provide preclinical and translational data to target E-cadherin for therapeutic gains.

Supported by: NHLBI R01HL151107