Inhibition of soluble epoxide hydrolase enhances the anti-inflammatory effects of aspirin and 5-lipoxygenase activation protein inhibitor in a murine model.

Abstract

Inflammation is a multi-staged process whose expansive phase is thought to be driven by acutely released arachidonic acid (AA) and its metabolites. Inhibition of cyclooxygenase (COX), lipoxygenase (LOX), or soluble epoxide hydrolase (sEH) is known to be anti-inflammatory. Inhibition of sEH stabilizes the cytochrome P450 (CYP450) products epoxyeicosatrienoic acids (EETs). Here we used a non-selective COX inhibitor aspirin, a 5-lipoxygenase activation protein (FLAP) inhibitor MK886, and a sEH inhibitor t-AUCB to selectively modulate the branches of AA metabolism in a lipopolysaccharide (LPS)-challenged murine model. We used metabolomic profiling to simultaneously monitor representative AA metabolites of each branch. In addition to the significant crosstalk among branches of the AA cascade during selective modulation of COX, LOX, or sEH, we demonstrated that co-administration of t-AUCB enhanced the anti-inflammatory effects of aspirin or MK886, which was evidenced by the observations that co-administration resulted in favorable eicosanoid profiles and better control of LPS-mediated hypotension as well as hepatic protein expression of COX-2 and 5-LOX. Targeted disruption of the sEH gene displayed a parallel profile to that produced by t-AUCB. These observations demonstrate a significant level of crosstalk among the three major branches of the AA cascade and that they are not simply parallel pathways. These data illustrate that inhibition of sEH by both pharmacological intervention and gene knockout enhances the anti-inflammatory effects of aspirin and MK886, suggesting the possibility of modulating multiple branches to achieve better therapeutic effects.

• Authors: Jun-Yan Liu, Jun Yang, Bora Inceoglu, Hong Qiu, Arzu Ulu, Sung-Hee Hwang, Nipavan Chiamvimonvat, Bruce D Hammock
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 79 Issue 6 Pg. 880-7 (Mar 15 2010) ISSN: 1873-2968 [Electronic] England
• PMID: 19896470 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published by Elsevier Inc.

Chemical References

• 4-(4-(3-adamantan-1-ylureido)cyclohexyloxy)benzoic acid
• Anti-Inflammatory Agents, Non-Steroidal
• Benzoates
• Hydroxyeicosatetraenoic Acids
• Indoles
• Lipopolysaccharides
• Lipoxygenase Inhibitors
• MK-886
• Arachidonic Acid
• 5-hydroxy-6,8,11,14-eicosatetraenoic acid
• 15-hydroxy-5,8,11,13-eicosatetraenoic acid
• Urea
• Arachidonate 5-Lipoxygenase
• Prostaglandin-Endoperoxide Synthases
• Epoxide Hydrolases
• Aspirin

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arachidonate 5-Lipoxygenase
• Arachidonic Acid (metabolism)
• Aspirin (pharmacology)
• Benzoates (pharmacology)
• Blood Pressure (drug effects)
• Dose-Response Relationship, Drug
• Enzyme Activation
• Epoxide Hydrolases (antagonists & inhibitors)
• Gene Expression Regulation, Enzymologic
• Hydroxyeicosatetraenoic Acids (blood)
• Indoles (pharmacology)
• Inflammation (drug therapy)
• Lipopolysaccharides (toxicity)
• Lipoxygenase Inhibitors (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Urea (analogs & derivatives, pharmacology)