A COX-2/sEH dual inhibitor PTUPB ameliorates cecal ligation and puncture-induced sepsis in mice via anti-inflammation and anti-oxidative stress

• Published in: Biomedicine & pharmacotherapy Vol. 126; p. 109907
• Main Authors: Zhang, Yan-Feng, Sun, Chen-Chen, Duan, Jia-Xi, Yang, Hui-Hui, Zhang, Chen-Yu, Xiong, Jian-Bing, Zhong, Wen-Jing, Zu, Cheng, Guan, Xin-Xin, Jiang, Hui-Ling, Hammock, Bruce D., Hwang, Sung Hee, Zhou, Yong, Guan, Cha-Xiang
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 01-06-2020; Elsevier
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - pharmacology; Dual COX-2 and sEH inhibitor; Epoxide Hydrolases - antagonists & inhibitors; Inflammasomes - antagonists & inhibitors; Male; Malondialdehyde; Mice; Mice, Inbred C57BL; Multiple organ dysfunction; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; NLRP3 inflamma some; Oxidative stress; Oxidative Stress - drug effects; Pyrazoles - therapeutic use; Real-Time Polymerase Chain Reaction; Sepsis; Sepsis - drug therapy; Sulfonamides - therapeutic use; Superoxide Dismutase; Dual COX-2 and sEH inhibitor; NLRP3 inflamma some; Oxidative stress; Sepsis; Multiple organ dysfunction
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2020.109907

This article reports that the cyclooxygenase-2 (COX-2) and cytochrome P450 (CYP) pathways of arachidonic acid metabolism were dysregulated in mice of cecal ligation and puncture (CLP)-induced sepsis. Restoring the dysregulation of COX-2 and CYP pathways with PTUPB ameliorates multiple-organ dysfunction in septic mice via anti-inflammation and anti-oxidative stress.
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•The COX-2 and CYP pathways of arachidonic acid metabolism were dysregulated in mice of CLP-induced sepsis.•Inhibition of COX-2 and sEH effectively attenuated sepsis-induced multiple organ dysfunction in mice.•The dual inhibitor of COX-2 and sEH (PTUPB) may be a therapeutic candidate for the treatment of sepsis.
Arachidonic acid can be metabolized to prostaglandins and epoxyeicosatrienoic acids (EETs) by cyclooxygenase-2 (COX-2) and cytochrome P450 (CYP), respectively. While protective EETs are degraded by soluble epoxide hydrolase (sEH) very fast. We have reported that dual inhibition of COX-2 and sEH with specific inhibitor PTUPB shows anti-pulmonary fibrosis and renal protection. However, the effect of PTUPB on cecal ligation and puncture (CLP)-induced sepsis remains unclear. The current study aimed to investigate the protective effects of PTUPB against CLP-induced sepsis in mice and the underlying mechanisms. We found that COX-2 expressions were increased, while CYPs expressions were decreased in the liver, lung, and kidney of mice undergone CLP. PTUPB treatment significantly improved the survival rate, reduced the clinical scores and systemic inflammatory response, alleviated liver and kidney dysfunction, and ameliorated the multiple-organ injury of the mice with sepsis. Besides, PTUPB treatment reduced the expression of hypoxia-inducible factor-1α in the liver, lung, and kidney of septic mice. Importantly, we found that PTUPB treatment suppressed the activation of NLRP3 inflammasome in the liver and lung of septic mice. Meanwhile, we found that PTUPB attenuated the oxidative stress, which contributed to the activation of NLRP3 inflammasome. Altogether, our data, for the first time, demonstrate that dual inhibition of COX-2 and sEH with PTUPB ameliorates the multiple organ dysfunction in septic mice.