title: Inhibition of transforming growth factor-β via the activin receptor-like kinase-5 inhibitor attenuates pulmonary fibrosis.
abstract: Idiopathic pulmonary fibrosis is a chronic pulmonary disease that is characterized by formation of scar tissue in lungs. Transforming growth factor-β (TGF-β) is considered an important cytokine in the pathogenesis of this disease. Hence, the antifibrotic effect of an inhibitor of the TGF-β type I receptor, namely, SB 431542, was investigated in our study. SB 431542 was used to treat TGF-β-treated IMR-90 cells; the expression of α-smooth muscle actin (α-SMA) was detected at the protein level by using an anti-α-SMA antibody, and at the gene level by reverse transcription-quantitative PCR. The effect of the inhibitor on cell proliferation was determined by a cell growth assay. The inhibitor was also administered into bleomycin-treated mice. Histopathological assessment and determination of total collagen levels were carried out to evaluate the severity of lung fibrosis in these mice. Our results demonstrated that treatment with SB 431542 inhibits TGF-β‑induced α-SMA expression in lung fibroblasts, at both the protein and the mRNA levels (P<0.05). However, the inhibitor did not significantly reduce lung fibroblast proliferation. In the bleomycin-induced pulmonary fibrosis mouse model, bleomycin treatment caused important morphological changes, accompanied by an increase in the collagen level of the lungs. Early treatment with SB 431542 prevented the manifestation of histopathological alterations, whereas delayed treatment significantly decreased the collagen level (P<0.05). These results suggest that inhibition of TGF-β signaling, via inhibition of the activin receptor-like kinase-5 (ALK-5) by SB 431542, may attenuate pulmonary fibrosis.
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Rhun Yian
authors.initials: RY
authors.lastname: Koh
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Chooi Ling
authors.initials: CL
authors.lastname: Lim
authors.affiliation: Department of Physiology and Biomedical Sciences, Michigan State University, East Lansing, MI 48837, USA.
authors.forename: Bruce David
authors.initials: BD
authors.lastname: Uhal
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Maha
authors.initials: M
authors.lastname: Abdullah
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Sharmili
authors.initials: S
authors.lastname: Vidyadaran
authors.affiliation: Biotechnology Programme, School of Science and Technology, University Malaysia Sabah, Sabah 88400, Malaysia.
authors.forename: Coy Choke
authors.initials: CC
authors.lastname: Ho
authors.affiliation: Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Heng Fong
authors.initials: HF
authors.lastname: Seow
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; C541116:ACTA2 protein, human; D000199:Actins; D001549:Benzamides; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse; D006909:Hydroxyproline