Derrone Targeting the TGF Type 1 Receptor Kinase Improves Bleomycin-Mediated Pulmonary Fibrosis through Inhibition of Smad Signaling Pathway

Author:

Molagoda Ilandarage Menu Neelaka12ORCID,Sanjaya Sobarathne Senel1ORCID,Lee Kyoung Tae3,Choi Yung Hyun4ORCID,Lee Joyce H.5ORCID,Lee Mi-Hwa6ORCID,Kang Chang-Hee6,Lee Chang-Min5,Kim Gi-Young5ORCID

Affiliation:

1. Department of Marine Life Sciences, Jeju National University, Jeju 63243, Republic of Korea

2. Department of Bioprocess Technology, Rajarata University of Sri Lanka, Mihintale 50300, Sri Lanka

3. Forest Bioresources Department, Forest Microbiology Division, National Institute of Forest Science, Suwon 16631, Republic of Korea

4. Department of Biochemistry, College of Korean Medicine, Dongeui University, Busan 47227, Republic of Korea

5. Department of Molecular Microbiology and Immunology, Division of Biology and Medicine, Brown University, 185 Meeting St., Providence, RI 02912, USA

6. Nakdonggang National Institute of Biological Resources, Sangju 37242, Republic of Korea

Abstract

Transforming growth factor-β (TGF-β) has a strong impact on the pathogenesis of pulmonary fibrosis. Therefore, in this study, we investigated whether derrone promotes anti-fibrotic effects on TGF-β1-stimulated MRC-5 lung fibroblast cells and bleomycin-induced lung fibrosis. Long-term treatment with high concentrations of derrone increased the cytotoxicity of MRC-5 cells; however, substantial cell death was not observed at low concentrations of derrone (below 0.05 μg/mL) during a three-day treatment. In addition, derrone significantly decreased the expressions of TGF-β1, fibronectin, elastin, and collagen1α1, and these decreases were accompanied by downregulation of α-SMA expression in TGF-β1-stimulated MRC-5 cells. Severe fibrotic histopathological changes in infiltration, alveolar congestion, and alveolar wall thickness were observed in bleomycin-treated mice; however, derrone supplementation significantly reduced these histological deformations. In addition, intratracheal administration of bleomycin resulted in lung collagen accumulation and high expression of α-SMA and fibrotic genes—including TGF-β1, fibronectin, elastin, and collagen1α1—in the lungs. However, fibrotic severity in intranasal derrone-administrated mice was significantly less than that of bleomycin-administered mice. Molecular docking predicted that derrone potently fits into the ATP-binding pocket of the TGF-β receptor type 1 kinase domain with stronger binding scores than ATP. Additionally, derrone inhibited TGF-β1-induced phosphorylation and nuclear translocations of Smad2/3. Overall, derrone significantly attenuated TGF-β1-stimulated lung inflammation in vitro and bleomycin-induced lung fibrosis in a murine model, indicating that derrone may be a promising candidate for preventing pulmonary fibrosis.

Funder

National Research Foundation of Korea

Korea Environment Industry & Technology Institute

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference42 articles.

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