Activation of STAT3 in the COPD airway epithelium

Rationale The mechanisms driving epithelial pathology in COPD are steadily being unveiled, confirming a role for inflammation in the disease. This study explored the IL-6/STAT3 axis, previously reported to link inflammation and epithelial-to-mesenchymal transition, two features of COPD at the airway epithelium level. Methods Bronchoalveolar lavage fluid (BALF) and surgical lung tissue were obtained from non-smoker controls, smokers and COPD patients. The activation of STAT3 and IL-6 levels were measured in these samples. Primary air-liquid interface (ALI) cultures were carried out from non-smokers, smokers and COPD patients and IL-6 release and STAT3 mRNA levels were assessed. BEAS-2B cell cultures were exposed to sputum supernatants from COPD patients versus non-smokers, with and without a pan-gp130 blocking monoclonal antibody. Finally, primary ALI cultures from non-smokers were exposed to IL-6 versus vehicle and assessed for epithelial-to-mesenchymal transition and cell differentiation. Results IL-6 and Tyr705-phospho-STAT3 levels were increased in samples from COPD patients compared to controls, both in BALF and in the airway epithelium, as well as in ALI cultures. BEAS-2B cells exposed to COPD sputum supernatants displayed STAT3 activation that was inhibited by the pan-gp130 blocking monoclonal antibody. In addition, stimulation of ALI cultures with IL-6 induced increased vimentin expression and fibronectin release and reduced the expression of apical junctional complexes proteins, indicating epithelial-to-mesenchymal transition. Finally, no impact on airway cell differentiation was observed. Conclusions The IL-6/STAT3 axis is activated in the COPD airway epithelium, presumably contributing to epithelial-to-mesenchymal transition.