| Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis. | |
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MedLine Citation:
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PMID: 17274978 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Activin receptor-like kinase 5 (ALK5) is a type I receptor of transforming growth factor (TGF)-beta. ALK5 inhibition has been reported to attenuate the tissue fibrosis including pulmonary fibrosis, renal fibrosis and liver fibrosis. To elucidate the inhibitory mechanism of ALK5 inhibitor on pulmonary fibrosis in vivo, we performed the histopathological assessment, gene expression analysis of extracellular matrix (ECM) genes and immunohistochemistry including receptor-activated Smads (R-Smads; Smad2/3), CTGF, myofibroblast marker (alpha-smooth muscle actin; aSMA) and type I collagen deposition in the lung using Bleomycin (BLM)-induced pulmonary fibrosis model. ALK5 inhibitor, SB-525334 (10 mg/kg or 30 mg/kg) was orally administered at twice a day. Lungs were isolated 5, 7, 9 and 14 days after BLM treatment. BLM treatment led to significant pulmonary fibrotic changes accompanied by significant upregulation of ECM mRNA expressions, Smad2/3 nuclear translocation, CTGF expression, myofibroblast proliferation and type I collagen deposition. SB-525334 treatment attenuated the histopathological alterations in the lung, and significantly decreased the type I and III procollagen and fibronectin mRNA expression. Immunohistochemistry revealed that SB-525334 treatment showed significant attenuation in Smad2/3 nuclear translocation, decrease in CTGF-expressing cells, myofibroblast proliferation and type I collagen deposition. These results suggest that ALK5 inhibition attenuates R-Smads activation thereby attenuates pulmonary fibrosis. |
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Authors:
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Hiroyuki Higashiyama; Daisuke Yoshimoto; Toshihiko Kaise; Shigeki Matsubara; Masatoshi Fujiwara; Hideo Kikkawa; Satoshi Asano; Mine Kinoshita |
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Publication Detail:
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Type: Journal Article Date: 2006-12-24 |
Journal Detail:
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Title: Experimental and molecular pathology Volume: 83 ISSN: 0014-4800 ISO Abbreviation: Exp. Mol. Pathol. Publication Date: 2007 Aug |
Date Detail:
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Created Date: 2007-06-05 Completed Date: 2007-08-06 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0370711 Medline TA: Exp Mol Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 39-46 Citation Subset: IM |
Affiliation:
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Pharmacology Department, Tsukuba Research Laboratories, GlaxoSmithKline KK, 43 Wadai, Tsukuba, Ibaraki, 300-4247, Japan. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Active Transport, Cell Nucleus Activin Receptors, Type I / antagonists & inhibitors*, metabolism* Animals Bleomycin / pharmacology* Cell Proliferation Collagen Type I / metabolism Connective Tissue Growth Factor Extracellular Matrix Proteins / genetics Gene Expression Regulation / drug effects Immediate-Early Proteins / metabolism Immunohistochemistry Intercellular Signaling Peptides and Proteins / metabolism Male Mice Mice, Inbred BALB C Protein Kinase Inhibitors / pharmacology* Protein-Serine-Threonine Kinases Pulmonary Fibrosis / chemically induced, enzymology*, pathology* RNA, Messenger / genetics Receptors, Transforming Growth Factor beta / antagonists & inhibitors*, metabolism* Smad2 Protein / metabolism Smad3 Protein / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Collagen Type I; 0/Ctgf protein, mouse; 0/Extracellular Matrix Proteins; 0/Immediate-Early Proteins; 0/Intercellular Signaling Peptides and Proteins; 0/Protein Kinase Inhibitors; 0/RNA, Messenger; 0/Receptors, Transforming Growth Factor beta; 0/Smad2 Protein; 0/Smad2 protein, mouse; 0/Smad3 Protein; 0/Smad3 protein, mouse; 11056-06-7/Bleomycin; 139568-91-5/Connective Tissue Growth Factor; EC 2.7.1.11/TGF-beta type I receptor; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 2.7.11.30/Activin Receptors, Type I |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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