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Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation.
Acta Pharmacol Sin. 2007 Mar; 28(3):382-91.AP

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.

Authors+Show Affiliations

Department of Pulmonary Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100071, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17303001

Citation

Gu, Li, et al. "Effect of TGF-beta/Smad Signaling Pathway On Lung Myofibroblast Differentiation." Acta Pharmacologica Sinica, vol. 28, no. 3, 2007, pp. 382-91.
Gu L, Zhu YJ, Yang X, et al. Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation. Acta Pharmacol Sin. 2007;28(3):382-91.
Gu, L., Zhu, Y. J., Yang, X., Guo, Z. J., Xu, W. B., & Tian, X. L. (2007). Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation. Acta Pharmacologica Sinica, 28(3), 382-91.
Gu L, et al. Effect of TGF-beta/Smad Signaling Pathway On Lung Myofibroblast Differentiation. Acta Pharmacol Sin. 2007;28(3):382-91. PubMed PMID: 17303001.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation. AU - Gu,Li, AU - Zhu,Yuan-Jue, AU - Yang,Xiao, AU - Guo,Zi-Jian, AU - Xu,Wen-Bing, AU - Tian,Xin-Lun, PY - 2007/2/17/pubmed PY - 2009/5/1/medline PY - 2007/2/17/entrez SP - 382 EP - 91 JF - Acta pharmacologica Sinica JO - Acta Pharmacol Sin VL - 28 IS - 3 N2 - 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. SN - 1671-4083 UR - https://www.unboundmedicine.com/medline/citation/17303001/Effect_of_TGF_beta/Smad_signaling_pathway_on_lung_myofibroblast_differentiation_ L2 - https://doi.org/10.1111/j.1745-7254.2007.00468.x DB - PRIME DP - Unbound Medicine ER -