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

Abstract

Activin-A is a pleiotropic cytokine belonging to the transforming growth factor-b 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 unknown.We first quantified activin-A and follistatin in the lungs of air-or cigarette smoke-exposed mice and in the lungs of patients with COPD by immunohistochemistry, ELISA and quantitative real-time PCR. We subsequently studied the effect of cigarette smoke on primary human bronchial epithelial cells in vitro. Next, activin-A signalling was antagonised in vivo by administration of follistatin in mice exposed to air or cigarette smoke for 4 weeks.Protein levels of activin-A were increased in the airway epithelium of patients with COPD compared with never-smokers and smokers. Cigarette smoke-exposed human bronchial epithelial cells expressed higher levels of activin-A and lower levels of follistatin. Both mRNA and protein levels of activin-A were increased in the lungs of cigarette smoke-exposed mice, whereas follistatin levels were reduced upon cigarette smoke exposure. Importantly, administration of follistatin attenuated the cigarette smoke-induced increase of inflammatory cells and mediators in the bronchoalveolar lavage fluid in mice.These results suggest that an imbalance between activin-A and follistatin contributes to the pathogenesis of cigarette smoke-induced inflammation and COPD. @ERSpublications Imbalance of activin-A and FST in favour of activin-A signalling in COPD patients cigarette smokeexposed mice http://ow.ly/qMqVN For editorial comments see page 954.

Activin-A: active in inflammation in COPD

“…In conclusion, the study of VERHAMME et al [9] sheds light on the role of activin-A and follistatin in COPD, and motivates further investigation. Persistent and exaggerated production of activin-A might be a key factor provoking persistent inflammation in COPD.…”

“…The authors conclude that activin-A is not an innocent bystander but plays an active role in cigarette smoke induced pulmonary inflammation [9].…”

“…In this issue, VERHAMME et al [9] demonstrate for the first time that activin-A is an important regulator of cigarette smoke-induced inflammation in COPD. They found that activin-A is elevated and activated in the airway epithelium, airway smooth muscle and alveolar macrophages of COPD patients.…”

Activin-A is overexpressed in severe asthma and is implicated in angiogenic processes

“…Both TGF-β and activin-A signalling pathways have been shown to be activated upon allergen provocation in asthma [21,22]. Emerging evidence underscores the potential impact of activin-A on the regulation of airway inflammation and remodelling [22][23][24][25][26][27]. Previous studies by our group and others have demonstrated an anti-inflammatory role for activin-A in various settings [28][29][30][31], while other studies have shown opposing effects [23,24].…”

“…Emerging evidence underscores the potential impact of activin-A on the regulation of airway inflammation and remodelling [22][23][24][25][26][27]. Previous studies by our group and others have demonstrated an anti-inflammatory role for activin-A in various settings [28][29][30][31], while other studies have shown opposing effects [23,24]. Interestingly, although the effects of activin-A on airway vascularisation have never been addressed, investigation of its angiogenic effects on other tissues has also produced conflicting results [32][33][34].…”