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

Abstract

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.

• Authors: Yan-Feng Zhang, Chen-Chen Sun, Jia-Xi Duan, Hui-Hui Yang, Chen-Yu Zhang, Jian-Bing Xiong, Wen-Jing Zhong, Cheng Zu, Xin-Xin Guan, Hui-Ling Jiang, Bruce D Hammock, Sung Hee Hwang, Yong Zhou, Cha-Xiang Guan
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 126 Pg. 109907 (Jun 2020) ISSN: 1950-6007 [Electronic] France
• PMID: 32114358 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Cyclooxygenase Inhibitors
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Pyrazoles
• Sulfonamides
• dual inhibitor PTUPB
• Malondialdehyde
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Superoxide Dismutase
• Epoxide Hydrolases
• Ephx2 protein, mouse

Topics

• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Cyclooxygenase 2 (genetics, metabolism)
• Cyclooxygenase Inhibitors (chemistry, pharmacology)
• Epoxide Hydrolases (antagonists & inhibitors)
• Inflammasomes (antagonists & inhibitors)
• Male
• Malondialdehyde
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics, metabolism)
• Oxidative Stress (drug effects)
• Pyrazoles (therapeutic use)
• Real-Time Polymerase Chain Reaction
• Sepsis (drug therapy)
• Sulfonamides (therapeutic use)
• Superoxide Dismutase