title: Inhibition of activin receptor-like kinase 5 attenuates bleomycin-induced pulmonary fibrosis.
abstract: 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.
authors.affiliation: Pharmacology Department, Tsukuba Research Laboratories, GlaxoSmithKline KK, 43 Wadai, Tsukuba, Ibaraki, 300-4247, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Higashiyama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yoshimoto
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kaise
authors.forename: Shigeki
authors.initials: S
authors.lastname: Matsubara
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Hideo
authors.initials: H
authors.lastname: Kikkawa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Asano
authors.forename: Mine
authors.initials: M
authors.lastname: Kinoshita
mesh_terms: D021581:Active Transport, Cell Nucleus; D030201:Activin Receptors, Type I / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D049109:Cell Proliferation; D024042:Collagen Type I / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D017874:Immediate-Early Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: C526318:CCN2 protein, mouse; D024042:Collagen Type I; D016326:Extracellular Matrix Proteins; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D001761:Bleomycin; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse