COX‐2/sEH dual inhibitor PTUPB alleviates bleomycin‐induced pulmonary fibrosis in mice via inhibiting senescence

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 (p16 Ink4a and p53-p21 Waf1/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.

Carcinogenesis: Failure of resolution of inflammation?

“…Cancer progression is stimulated by inflammation, fibrosis, and oxidative stress. Dual COX-2/sEH inhibition via PTUPB inhibits allergic airway inflammation, pulmonary fibrosis, kidney injury and sepsis via anti-oxidative stress ( Dileepan et al, 2019 ; Hye Khan et al, 2016 ; Zhang et al, 2020 ; Zhang et al, 2019 ) . Dual COX-2/sEH inhibition inhibits primary tumor growth including glioblastoma growth, metastasis and potentiates the antitumor efficacy of chemotherapeutic agents such as cisplatin ( Li et al, 2017 ; Wang et al, 2018 ; Zhang, Panigrahy, et al, 2014 ).…”

The role of NOX4 in pulmonary diseases

“…The activation and differentiation of fibroblasts are the most critical steps in fibrosis. The expression of α-smooth muscle actin (α-SMA), the proliferation of myofibroblasts, and the production of extracellular matrix are the primary markers of pulmonary fibrosis (C. Y Zhang et al, 2020)…”

Ibuprofen alters epoxide hydrolase activity and epoxy-oxylipin metabolites associated with different metabolic pathways in murine livers

“…Increased sEH activity is associated with inflammation of the kidney and other organs as well as higher blood pressure and greater pain levels. AA metabolites has been linked to pathogenesis of certain types of fibrosis 91 . Interestingly, dual COX2/sEH inhibitor has been shown to alleviate experimentally induced pulmonary fibrosis in mice 91 .…”

“…AA metabolites has been linked to pathogenesis of certain types of fibrosis 91 . Interestingly, dual COX2/sEH inhibitor has been shown to alleviate experimentally induced pulmonary fibrosis in mice 91 . Overall, oxylipins are likely to be an important group of molecules that can be modified by diet to reduce disease and age-related problems.…”