Overexpression of prothymosin α induces pulmonary emphysema by inhibition of TGF-β signalling pathway

• Main Authors: Chih-HauSu, 蘇秉驊
• Other Authors: Chao-Liang Wu
• Format: Others
• Language: en_US
• Published: 2010
• Online Access: http://ndltd.ncl.edu.tw/handle/52654485912178620936

博士 === 國立成功大學 === 基礎醫學研究所 === 98 === Emphysema is the major type of chronic obstructive pulmonary disease (COPD), characterised by permanent airflow restriction resulting from enlargement of alveolar airspace and loss of lung elasticity. Despite being the main risk factor, only about 20% of cigarette smokers develop emphysema. Therefore, there may be unidentified genes which predispose to smoking-induced emphysema. Prothymosin α (ProT) is an acidic protein associated with cell proliferation, apoptosis, oxidative stress, immunomodulation and acetylation. Despite its many effects, the exact physiologic role of ProT remains poorly understood. Here we investigated the relevance of ProT in emphysema. We showed that overexpression of ProT leads to pulmonary emphysema in transgenic mice. Importantly, we also detected ProT overexpression in the lung epithelium from patients with emphysema. In the emphysematous lung epithelium from human and mouse samples, phosphorylated Smad2/3 levels were reduced and levels of the inhibitory Smad, Smad7, were increased, resulting in downregulation of TGF-β signalling and, in turn, increases in the production of MMP-12 and MMP-2, which are known to be associated with emphysema. Moreover, overexpression of ProT increases the acetylation, stability and activity of Smad7, which can antagonize TGF-β signalling. We have uncovered a pathway in which acetylation mediated by ProT overexpression causes emphysema through activation of Smad7. Moreover, our results implicate the possible relevance of ProT to emphysema and reinforce the importance of TGF-β signalling in the pathogenesis of emphysema.