Imperatorin ameliorates pulmonary fibrosis via GDF15 expression

Cheng-Fang Tsai; Yen-Chang Chen; Ya-Zhen Li; Chen-Teng Wu; Pei-Chun Chang; Wei-Lan Yeh

doi:10.3389/fphar.2023.1292137

Imperatorin ameliorates pulmonary fibrosis via GDF15 expression

Front Pharmacol. 2023 Dec 4:14:1292137. doi: 10.3389/fphar.2023.1292137. eCollection 2023.

Authors

Cheng-Fang Tsai¹, Yen-Chang Chen², Ya-Zhen Li², Chen-Teng Wu³, Pei-Chun Chang⁴, Wei-Lan Yeh^{2

5}

Affiliations

¹ Department of Medical Laboratory Science and Biotechnology, Asia University, Taichung, Taiwan.
² Institute of New Drug Development, China Medical University, Taichung, Taiwan.
³ Department of Surgery, China Medical University Hospital, Taichung, Taiwan.
⁴ Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
⁵ Department of Biochemistry, School of Medicine, China Medical University, Taichung, Taiwan.

Abstract

Background: Pulmonary fibrosis features in damaged pulmonary structure or over-produced extracellular matrix and impaired lung function, leading to respiratory failure and eventually death. Fibrotic lungs are characterized by the secretion of pro-fibrotic factors, transformation of fibroblasts to myofibroblasts, and accumulation of matrix proteins. Hypothesis/purpose: Imperatorin shows anti-inflammatory effects on alveolar macrophages against acute lung injury. We attempt to evaluate the properties of imperatorin on the basis of fibroblasts. Methods: In in vitro, zymosan was introduced to provoke pro-fibrotic responses in NIH/3T3 or MRC-5 pulmonary fibroblasts. Imperatorin was given for examining its effects against fibrosis. The mice were stimulated by bleomycin, and imperatorin was administered to evaluate the prophylactic potential in vivo. Results: The upregulated expression of connective tissue growth factor (CTGF), α-smooth muscle actin (α-SMA), and collagen protein due to zymosan introduction was decreased by imperatorin in fibroblasts. Zymosan induced the activity of transglutaminase 2 (TGase2) and lysyl oxidase (LOX), which was also inhibited by the administration of imperatorin. Imperatorin alone enhanced sirtuin 1 (SIRT1) activity and growth differentiation factor 15 (GDF15) secretion in fibroblasts via LKB1/AMPK/CREB pathways. In addition, GDF15 exerted a beneficial effect by reducing the protein expression of CTGF, α-SMA, and collagen and the activities of TGase and LOX. Moreover, orally administered imperatorin showed prophylactic effects on bleomycin-induced pulmonary fibrosis in mice. Conclusion: Imperatorin reduces fibrotic marker expression in fibroblasts and also increases GDF15 secretion via the LKB1/AMPK/CREB pathway, attenuating pro-fibrotic responses in vitro. Imperatorin also alleviates pulmonary fibrosis induced by bleomycin in vivo.

Keywords: fibroblasts; fibrosis; growth differentiation factor 15; imperatorin; lung.

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was financially supported by the Ministry of Science and Technology (MOST 110-2320-B-039-030-MY3), China Medical University (CMU110-MF-51), and China Medical University Hospital (DMR-109-036, DMR-110-047, and DMR-111-051).