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

Abstract

OBJECTIVES:

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.

METHODS:

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.

KEY FINDINGS:

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.

CONCLUSIONS:

In summary, the results suggest that anlotinib-mediated suppression of pulmonary fibrosis is related to the inhibition of TGF-β1 signalling pathway.

• Authors: Hao Ruan, Ziwei Lv, Shuaishuai Liu, Liang Zhang, Kai Huang, Shaoyan Gao, Wenhua Gan, Xiaowei Liu, Shanshan Zhang, Kaiyue Helian, Xiaohe Li, Honggang Zhou, Cheng Yang
• Journal: The Journal of pharmacy and pharmacology (J Pharm Pharmacol) Vol. 72 Issue 1 Pg. 44-55 (Jan 2020) ISSN: 2042-7158 [Electronic] England
• PMID: 31659758 (Publication Type: Journal Article)
• Copyright: © 2019 Royal Pharmaceutical Society.

Chemical References

• Indoles
• Protein Kinase Inhibitors
• Quinolines
• Smad3 Protein
• Transforming Growth Factor beta1
• anlotinib
• Bleomycin

Topics

• A549 Cells
• Animals
• Apoptosis (drug effects)
• Bleomycin
• Disease Models, Animal
• Epithelial-Mesenchymal Transition (drug effects)
• Humans
• Indoles (pharmacology)
• Lung (drug effects, enzymology, pathology)
• Male
• Mice
• Mice, Inbred C57BL
• NIH 3T3 Cells
• Oxidative Stress (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Pulmonary Fibrosis (chemically induced, drug therapy, enzymology, pathology)
• Quinolines (pharmacology)
• Signal Transduction
• Smad3 Protein (genetics, metabolism)
• Transforming Growth Factor beta1 (genetics, metabolism)