Effect of FTY-720 on Pulmonary Fibrosis in Mice via the TGF-β1 Signaling Pathway and Autophagy

Yuying Jin; Weidong Liu; Ge Gao; Yilan Song; Hanye Liu; Liangchang Li; Jiaxu Zhou; Guanghai Yan; Hong Cui

doi:10.4062/biomolther.2022.123

Effect of FTY-720 on Pulmonary Fibrosis in Mice via the TGF-β1 Signaling Pathway and Autophagy

Biomol Ther (Seoul). 2023 Jul 1;31(4):434-445. doi: 10.4062/biomolther.2022.123. Epub 2023 Apr 6.

Authors

Yuying Jin^{1

2}, Weidong Liu^{1

2}, Ge Gao³, Yilan Song^{1

4}, Hanye Liu^{1

4}, Liangchang Li^{1

4}, Jiaxu Zhou^{1

2}, Guanghai Yan^{1

4}, Hong Cui^{1

2}

Affiliations

¹ Jilin Key Laboratory for Immune and Targeting Research on Common Allergic Diseases, Yanbian University, Jilin 133002, China.
² Center of Medical Functional Experiment, Yanbian University Medical College, Jilin 133002, China.
³ Department of Life Sciences, Hainan University of Biology, Hainan 570228, China.
⁴ Department of Anatomy, Histology and Embryology, Yanbian University Medical College, Jilin 133002, China.

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: Autophagy; FTY-720; Lung epithelial cells; Pulmonary fibrosis; TGF-β1 signaling pathway.

Grants and funding

ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (grant number 82260002 & 81460001), the Natural Science Research Foundation of Jilin Province for Sciences and Technology (grant number 20220101353JC), and the Education Department Project of Jilin (grant number JJKH20220546KJ).