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

TITLE=Imperatorin ameliorates pulmonary fibrosis via GDF15 expression

JOURNAL=Frontiers in Pharmacology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1292137

DOI=10.3389/fphar.2023.1292137

ISSN=1663-9812

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Hypothesis/purpose:</bold> 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.</p><p><bold>Methods:</bold> In <italic>in vitro</italic>, 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 <italic>in vivo</italic>.</p><p><bold>Results:</bold> 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.</p><p><bold>Conclusion:</bold> Imperatorin reduces fibrotic marker expression in fibroblasts and also increases GDF15 secretion via the LKB1/AMPK/CREB pathway, attenuating pro-fibrotic responses <italic>in vitro</italic>. Imperatorin also alleviates pulmonary fibrosis induced by bleomycin <italic>in vivo</italic>.</p>