Role of activin-A in cigarette smoke-induced inflammation and COPD

Objective: Activin-A is a pleiotropic cytokine belonging to the TGF-β superfamily and has been implicated in asthma and pulmonary fibrosis. However, the role of activin-A and its endogenous inhibitor, follistatin, in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) is unkown. Methods: We first quantified activin-A and follistatin in lungs of air- or CS-exposed mice and in lungs of patients with COPD by immunohistochemistry, ELISA and qRT-PCR. We subsequently studied the effect of CS on primary human bronchial epithelial cells (HBECs) in vitro. Next, activin-A signalling was antagonized in vivo by administration of follistatin in mice exposed to air or CS for 4 weeks. Results: Protein levels of activin-A were increased in the airway epithelium of patients with COPD compared with never-smokers and smokers. CS-exposed HBECs expressed higher levels of activin-A and lower levels of follistatin. Both mRNA and protein levels of activin-A were increased in lungs of CS-exposed mice, whereas follistatin levels were reduced upon CS exposure. Importantly, administration of follistatin attenuated the CS-induced increase of inflammatory cells and mediators in the bronchoalveolar lavage fluid in mice. Conclusions: These results suggest that an imbalance between activin-A and follistatin contributes to the pathogenesis of CS-induced inflammation and COPD