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Title: COX-2/sEH dual inhibitor PTUPB alleviates bleomycin-induced pulmonary fibrosis in mice via inhibiting senescence.

Authors: Zhang, Chen-Yu; Duan, Jia-Xi; Yang, Hui-Hui; Sun, Chen-Chen; Zhong, Wen-Jing; Tao, Jia-Hao; Guan, Xin-Xin; Jiang, Hui-Ling; Hammock, Bruce D; Hwang, Sung Hee; Zhou, Yong; Guan, Cha-Xiang

Published In FEBS J, (2020 04)

Abstract: Pulmonary fibrosis (PF) is a senescence-associated disease with poor prognosis. Currently, there is no effective therapeutic strategy for preventing and treating the disease process. Mounting evidence suggests that arachidonic acid (ARA) metabolites are involved in the pathogenesis of various fibrosis. However, the relationship between the metabolism of ARA and PF is still elusive. In this study, we observed a disorder in the cyclooxygenase-2/cytochrome P450 (COX-2/CYP) metabolism of ARA in the lungs of PF mice induced by bleomycin (BLM). Therefore, we aimed to explore the role of COX-2/CYP-derived ARA metabolic disorders in PF. PTUPB, a dual COX-2 and soluble epoxide hydrolase (sEH) inhibitor, was used to restore the balance of COX-2/CYP metabolism. sEH is an enzyme hydrolyzing epoxyeicosatrienoic acids derived from ARA by CYP. We found that PTUPB alleviated the pathological changes in lung tissue and collagen deposition, as well as reduced senescence marker molecules (p16Ink4a and p53-p21Waf1/Cip1 ) in the lungs of mice treated by BLM. In vitro, we found that PTUPB pretreatment remarkably reduced the expression of senescence-related molecules in the alveolar epithelial cells (AECs) induced by BLM. In conclusion, our study supports the notion that the COX-2/CYP-derived ARA metabolic disorders may be a potential therapeutic target for PF via inhibiting the cellular senescence in AECs.

PubMed ID: 31646730 Exiting the NIEHS site

MeSH Terms: A549 Cells; Aging/drug effects*; Animals; Arachidonic Acid/metabolism; Bleomycin; Cellular Senescence/drug effects; Cyclooxygenase 2/metabolism*; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors/administration & dosage; Enzyme Inhibitors/pharmacology*; Epithelial Cells/drug effects; Epithelial Cells/metabolism; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Humans; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis/chemically induced; Pulmonary Fibrosis/drug therapy*; Pulmonary Fibrosis/metabolism; Structure-Activity Relationship; Tumor Cells, Cultured

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