Cigarette smoke disrupts monolayer integrity by altering epithelial cell-cell adhesion and cortical tension

Abstract

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality. Cigarette smoke (CS) drives disease development and progression. The epithelial barrier is damaged by CS with increased monolayer permeability. However, the molecular changes that cause this barrier disruption and the interaction between adhesion proteins and the cytoskeleton are not well defined. We hypothesized that CS alters monolayer integrity by increasing cell contractility and decreasing cell adhesion in epithelia. Normal human airway epithelial cells and primary COPD epithelial cells were exposed to air or CS, and changes measured in protein levels. We measured the cortical tension of individual cells and the stiffness of cells in a monolayer. We confirmed that the changes in acute and subacute in vitro smoke exposure reflect protein changes seen in cell monolayers and tissue sections from COPD patients. Epithelial cells exposed to repetitive CS and those derived from COPD patients have increased monolayer permeability. E-cadherin and β-catenin were reduced in smoke exposed cells as well as in lung tissue sections from patients with COPD. Moreover, repetitive CS caused increased tension in individual cells and cells in a monolayer, which corresponded with increased polymerized actin without changes in myosin IIA and IIB total abundance. Repetitive CS exposure impacts the adhesive intercellular junctions and the tension of epithelial cells by increased actin polymer levels, to further destabilize cell adhesion. Similar changes are seen in epithelial cells from COPD patients indicating that these findings likely contribute to COPD pathology.

Cigarette smoke-induced malignant transformation via STAT3 signalling in pulmonary epithelial cells in a lung-on-a-chip model

“…The degeneration of cell adhesion affects its interaction with the actin cytoskeleton, which subsequently leads to the initiation of intracellular signalling cascades. Recent studies demonstrated that E-cadherin and β-catenin were reduced in both cell lines and epithelial cells derived from COPD patients exposed to repetitive CS [32][33][34]. In the present study, Western blot showed that after continuous CSE exposure (20 µg/ mL and 50 µg/mL), the expression levels of E-cadherin and (Fig.…”

Anemia and Adverse Outcomes in a Chronic Obstructive Pulmonary Disease Population with a High Burden of Comorbidities. An Analysis from SPIROMICS

“…ORIGINAL RESEARCH E-cadherin in COPD is not clear, but decreased expression of E-cadherin on the epithelium is associated with a higher risk for development of COPD in the setting of cigarette smoke exposure (33)(34)(35)(36). Analysis of the SPIROMICS cohort showed that higher serum E-cadherin levels were associated with lower percent emphysema (37). It is possible that increased lung inflammation and epithelial injury leads to lower E-cadherin levels specifically in the epithelium, but higher released or soluble levels of E-cadherin.…”

Precision medicine in COPD: where are we and where do we need to go?

“…Small airway fibrosis and obliteration probably contribute to physiological airway dysfunction and occur earlier than any development of emphysema. One potential mechanism contributing to small airway fibrosis/obliteration involves altered epithelial integrity [ 64 , 65 ]. Triggers such as cigarette smoke and other environmental air pollutants can trigger these changes to cause inflammation implicated in COPD where cytokine expression increases, mucus production increases and permeability increases in airways [ 66 ].…”