Airway epithelial monolayer integrity is a critical target in COPD

Under healthy conditions, the actin‐myosin II cytoskeleton and apical intercellular junction proteins, such as E‐cadherin, maintain epithelial polarity to separate the apical and basolateral compartments of the epithelium. Even subtle breaches in the monolayer allow for very small proteins to traverse the monolayer and activate epithelial signaling. Such signals include the 5kD, apically restricted protein EGF, which can activate the basolateral EGFR and can release EGFR receptor from the basolateral membrane, allowing it to move to the apical membrane. This leads to a lack of spatial restriction, allowing for promiscuous activation. While alterations in E‐cadherin levels and EGFR activation occur in response to CS exposure and in COPD, the initial mechanisms that lead to disruption in epithelial polarity are largely unknown. We have demonstrated that disrupting the epithelial monolayer by cytoskeletal rearrangements or decreased E‐cadherin, increases EGFR activation. The actin‐myosin cytoskeleton is a principle player in establishing epithelial cell shape and polarity. We observed that CS exposure leads to changes in the subcellular distribution of the myosin II paralogs and a subsequent reduction in E‐cadherin expression in primary human airway epithelium. These changes in the actin‐myosin cytokeletal cause a biphasic effect on the cortical tension of the cells, with acute exposures causing a decrease in cortical tension and repetitive exposures leading to increases. The increased cortical tension corresponds to a reduction in cell‐cell adhesion proteins, potentially due to carboxy‐terminal destabilization of E‐cadherin to the actin cytoskeleton. Histologic sections of airways show decreased E‐cadherin, altered myosin paralog expression, and EGFR activation in COPD patients. In clincial cohorts, E‐cadherin levels inversely correlate with worse emphysema in patients. Thus, low E‐cadherin expression and altered myosin II are strongly associated with chronic bronchitis, although causation remains to be established. By altering these proteins, and breaching epithelial polarization and activating EGFR. EGFR activation, in turn, promotes critical changes in the epithelium and induces mucus production and cell proliferation, helping to drive chronic bronchitis. We have developed an lung restricted, inducible E‐cadherin knockdown using airway adminstration of Adeno‐Cre recombinase in E‐cadherin floxed mice. After seven weeks of E‐cadherin knockdown, histology suggest epithelial remodeling in the mouse indicating loss of cell‐cell adhesion proteins are sufficient to induce epithelial changes. Support or Funding Information NIH T32 HL007534, R01 GM66817, and HL085763