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Acta Pharmacol Sin. 2007 Mar;28(3):382-91.

Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation.

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1
Department of Pulmonary Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100071, China.

Abstract

AIM:

Myofibroblasts play important roles in the pathogenesis of lung fibrosis. Transforming growth factor (TGF)-beta 1 has been widely recognized as a key fibrogenic cytokine. The major signaling pathway of (TGF)-beta(1) is through cytoplasmic Smad proteins. Our study investigated the role of individual (TGF)-beta(1)/Smad signal proteins in mediating alpha-smooth muscle actin (alpha-SMA) gene expression, which is a well-known key marker of myofibroblast differentiation.

METHODS:

We transiently cotransfected alpha-SMA promoter-luciferase fusion plasmid (p895-Luc) and Smad expression plasmids and measured Luc activity in (TGF)-beta(1)-treated human fetal lung fibroblasts. We induced Smad3 knockout mice lung fibrosis by bleomycin. alpha-SMA protein expression was assessed by Western blotting. Collagen protein was analyzed by measuring hydroxyprolin. Myofibroblast morphology was assessed by immunohistochemistry.

RESULTS:

We found that the overexpression of Smad3, not Smad2 markedly increased (TGF)-beta(1)-induced alpha-SMA promoter activity and alpha-SMA protein expression in vitro, whereas the overexpression of dominant negative mutant Smad3 and Smad7 repressed (TGF)-beta(1)-induced alpha-SMA gene expression. Compared to wild-type mice, Smad3 knockout mice showed attenuated lung fibrosis after bleomycin treatment, manifested by lower collagen production and myofibroblast differentiation.

CONCLUSION:

Our study suggested (TGF)-beta(1)/Smad3 is a major pathway which regulated the myofibroblast differentiation. This result indicates a potential significance for future attempts of attenuating the progression of human lung fibrosis by the inhibition of the Smad3 cascade.

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