Inhibition of transforming growth factor-β via the activin receptor-like kinase-5 inhibitor attenuates pulmonary fibrosis

Koh,Rhun  Yian; Lim,Chooi  Ling; Uhal,Bruce  David; Abdullah,Maha; Vidyadaran,Sharmili; Ho,Coy  Choke; Seow,Heng  Fong

doi:10.3892/mmr.2015.3193

Inhibition of transforming growth factor-β via the activin receptor-like kinase-5 inhibitor attenuates pulmonary fibrosis

Authors:
- Rhun Yian Koh
- Chooi Ling Lim
- Bruce David Uhal
- Maha Abdullah
- Sharmili Vidyadaran
- Coy Choke Ho
- Heng Fong Seow
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Affiliations: Department of Pathology, Faculty of Medicine and Health Sciences, University Putra Malaysia, Serdang, Selangor 43400, Malaysia, Department of Physiology and Biomedical Sciences, Michigan State University, East Lansing, MI 48837, USA, Biotechnology Programme, School of Science and Technology, University Malaysia Sabah, Sabah 88400, Malaysia
Published online on: January 13, 2015 https://doi.org/10.3892/mmr.2015.3193
Pages: 3808-3813

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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.

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