SIS3, a specific inhibitor of smad3, attenuates bleomycin-induced pulmonary fibrosis in mice

Juanjuan Shou; Jingjing Cao; Shanshan Zhang; Ruicong Sun; Mengmeng Zhao; Keqiang Chen; Shao Bo Su; Jianhua Yang; Tianshu Yang

doi:10.1016/j.bbrc.2018.06.072

SIS3, a specific inhibitor of smad3, attenuates bleomycin-induced pulmonary fibrosis in mice

Biochem Biophys Res Commun. 2018 Sep 5;503(2):757-762. doi: 10.1016/j.bbrc.2018.06.072. Epub 2018 Jun 27.

Authors

Juanjuan Shou¹, Jingjing Cao¹, Shanshan Zhang¹, Ruicong Sun¹, Mengmeng Zhao¹, Keqiang Chen², Shao Bo Su³, Jianhua Yang¹, Tianshu Yang⁴

Affiliations

¹ Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Immunology, Tongji University School of Medicine, Shanghai, China.
² Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
³ Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
⁴ Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China; Department of Immunology, Tongji University School of Medicine, Shanghai, China. Electronic address: tianshuy@tongji.edu.cn.

PMID: 29913150
DOI: 10.1016/j.bbrc.2018.06.072

Abstract

Pulmonary fibrosis (PF) is a fatal respiratory disease with no effective medical treatments available. TGF-β/Smads signaling has been implicated to play an essential in the pathogenesis of PF, in which Smad3 act as the integrator of pro-fibrosis signals. In this study, we determined the effect of SIS3, a specific inhibitor of Smad3, in an experimental mouse model of lung fibrosis. We observed that SIS3 treatment significantly reduced bleomycin (BLM)-induced pathological changes and collagen deposition in the lung as indicated by Masson staining, real-time PCR and hydroxyproline content assay. As expected, the levels of Smad3 phosphorylation were decreased in the lung of mice treated with SIS3. Furthermore, SIS3 treatment also suppressed BLM-induced infiltration of inflammatory cells in the lung. Taken together, our results suggest that SIS3 ameliorated BLM-induced PF in mouse lungs. Thus, targeting Smad3 with SIS3 may be an effective approach for treatment of fibrotic disorders.

Keywords: Inflammation; Pulmonary fibrosis; Smad3; Transforming growth factor beta.

Publication types

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

MeSH terms

Animals
Bleomycin
Collagen Type I / analysis
Inflammation / chemically induced
Inflammation / drug therapy
Inflammation / pathology
Isoquinolines / therapeutic use*
Lung / drug effects*
Lung / pathology
Male
Mice
Mice, Inbred C57BL
Phosphorylation / drug effects
Pulmonary Fibrosis / chemically induced
Pulmonary Fibrosis / drug therapy*
Pulmonary Fibrosis / pathology
Pyridines / therapeutic use*
Pyrroles / therapeutic use*
Smad3 Protein / analysis
Smad3 Protein / antagonists & inhibitors*

Substances

6,7-dimethyl-2-(2E)-3-(1-methyl-2-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl-prop-2-enoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride
Collagen Type I
Isoquinolines
Pyridines
Pyrroles
Smad3 Protein
Smad3 protein, mouse
Bleomycin