Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2022.123
Effect of FTY-720 on Pulmonary Fibrosis in Mice via the TGF-β1 Signaling Pathway and Autophagy
Yuying Jin1,2,†, Weidong Liu1,2,†, Ge Gao3, Yilan Song1,4, Hanye Liu1,4, Liangchang Li1,4, Jiaxu Zhou1,2, Guanghai Yan1,4,* and Hong Cui1,2,*
1Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Jilin 133002,
2Center of Medical Functional Experiment, Yanbian University Medical College, Jilin 133002,
3Department of Life Sciences, Hainan University of Biology, Hainan 570228,
4Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Jilin 133002, China
*E-mail: ghyan2015@sina.com (Yan G), cuihong@ybu.edu.cn (Cui H)
Tel: +86-0433-2435137 (Yan G), +86-0433-2435135 (Cui H)
Fax: +86-0433-2435137 (Yan G), +86-0433-2435135 (Cui H)
†The first two authors contributed equally to this work.
Received: September 22, 2022; Revised: December 20, 2022; Accepted: January 11, 2023; Published online: April 6, 2023.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
We investigated whether FTY-720 might have an effect on bleomycin-induced pulmonary fibrosis through inhibiting TGF-β1 pathway, and up-regulating autophagy. The pulmonary fibrosis was induced by bleomycin. FTY-720 (1 mg/kg) drug was intraperitoneally injected into mice. Histological changes and inflammatory factors were observed, and EMT and autophagy protein markers were studied by immunohistochemistry and immunofluorescence. The effects of bleomycin on MLE-12 cells were detected by MTT assay and flow cytometry, and the related molecular mechanisms were studied by Western Blot. FTY-720 considerably attenuated bleomycin-induced disorganization of alveolar tissue, extracellular collagen deposition, and α-SMA and E-cadherin levels in mice. The levels of IL-1β, TNF-α, and IL-6 cytokines were attenuated in bronchoalveolar lavage fluid, as well as protein content and leukocyte count. COL1A1 and MMP9 protein expressions in lung tissue were significantly reduced. Additionally, FTY- 720 treatment effectively inhibited the expressions of key proteins in TGF-β1/TAK1/P38MAPK pathway and regulated autophagy proteins. Similar results were additionally found in cellular assays with mouse alveolar epithelial cells. Our study provides proof for a new mechanism for FTY-720 to suppress pulmonary fibrosis. FTY-720 is also a target for treating pulmonary fibrosis.
Keywords: Pulmonary fibrosis, FTY-720, Lung epithelial cells, TGF-β1 signaling pathway, Autophagy

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