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Anlotinib attenuated bleomycin-induced pulmonary fibrosis via the TGF-β1 signalling pathway.

Authors
  • Ruan, Hao1, 2
  • Lv, Ziwei1, 2
  • Liu, Shuaishuai1, 2
  • Zhang, Liang3
  • Huang, Kai1, 2
  • Gao, Shaoyan1, 2
  • Gan, Wenhua1, 2
  • Liu, Xiaowei1, 2
  • Zhang, Shanshan1, 2
  • Helian, Kaiyue4
  • Li, Xiaohe1, 2
  • Zhou, Honggang1, 2
  • Yang, Cheng1, 2
  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, China. , (China)
  • 2 High-throughput Molecular Drug Screening Centre, Tianjin International Joint Academy of Biomedicine, Tianjin, China. , (China)
  • 3 Department of Thoracic Surgery, Tian Jin First Central Hospital, Tianjin, China. , (China)
  • 4 College of Health and Medicine and College of Science, Australian National University, Canberra, ACT, Australia. , (Australia)
Type
Published Article
Journal
The Journal of pharmacy and pharmacology
Publication Date
Jan 01, 2020
Volume
72
Issue
1
Pages
44–55
Identifiers
DOI: 10.1111/jphp.13183
PMID: 31659758
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Anlotinib hydrochloride (AL3818) is a novel multitarget tyrosine kinase inhibitor which has the same targets as nintedanib, an effective drug has been approved for the treatment of idiopathic pulmonary fibrosis. Here, we examined whether anlotinib could also attenuate bleomycin-induced pulmonary fibrosis in mice and explored the antifibrosis mechanism. We have evaluated the effect of anlotinib on bleomycin-induced pulmonary fibrosis in mice. Inflammatory cytokines in alveolar lavage fluid including IL-1β, IL-4, IL-6 and TNF-α were determined by ELISA. Biomarkers of oxidative stress were measured by corresponding kit. Histopathologic examination was analysed by H&E staining and immunohistochemistry. In vitro, we investigated whether anlotinib inhibited TGFβ/Smad3 and non-Smad pathways by luciferase assay or Western blotting. We also evaluated whether anlotinib inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) and promoted myofibroblast apoptosis in order to explore the possible molecular mechanism. The results indicated that anlotinib treatment remarkably attenuated inflammation, oxidative stress and pulmonary fibrosis in mouse lungs. Anlotinib could inhibit the TGF-β1 signalling pathway. Additionally, anlotinib not only profoundly inhibited TGF-β1-induced EMT in alveolar epithelial cells, but also simultaneously reduced the proliferation and promoted the apoptosis in fibroblasts. In summary, the results suggest that anlotinib-mediated suppression of pulmonary fibrosis is related to the inhibition of TGF-β1 signalling pathway. © 2019 Royal Pharmaceutical Society.

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