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Blockage of soluble epoxide hydrolase (sEH) enhances the anti‐inflammatory effects of aspirin and the 5‐lipoxygenase activation protein (FLAP) inhibitor MK886
Author(s) -
Liu Junyan,
Yang Jun,
Inceoglu Bora,
Ulu Arzu,
Hwang SungHee,
Hammock Bruce D
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.479.25
Subject(s) - aspirin , pharmacology , epoxide hydrolase 2 , celecoxib , chemistry , cyclooxygenase , acetaminophen , lipoxygenase , cox 2 inhibitor , anesthesia , medicine , biochemistry , enzyme
A previous study showed that co‐administration of a sEH inhibitor AUDA‐nBE enhances the antinociception of NSAIDs including indomethacin, celecoxib, or rofecoxib. We here demonstrate that co‐dosing of low dose of a novel potent sEH inhibitor t ‐AUCB with aspirin or FLAP inhibitor MK886 produce significant beneficial effects on reversing hypotension in LPS‐challenged septic shock mouse model, and reducing the expression of inflammatory associated proteins (COX‐2 or 5‐LOX) and/or genes (TNF‐α and IL‐1β), as well as shifting the oxylipin metabolites. When administrated alone, aspirin decreased plasma TXB 2 and PGE 2 levels to 39 ± 14 %, and 47 ± 13 %, respectively, compared with the mice treated with LPS alone. When aspirin was used in a combination of low dose t‐AUCB, plasma TXB 2 and PGE 2 levels were dropped to 15 ± 10 % and 21 ± 5.0 %, respectively, versus LPS control. MK886 decreased plasma 5‐HETE levels to 41 ± 11 % versus LPS control. When MK886 was co‐administrated with low dose t‐AUCB, plasma 5‐HETE levels were dropped to 22 ± 2.7 % versus LPS control. Furthermore, targeted disruption of sEH gene produces the similar significant beneficial effects to pharmacological inhibition of sEH in LPS‐challenged septic shock mouse model. These observations show that blockage of sEH by both pharmacological intervention and gene knockout enhances the anti‐inflammatory effect of aspirin and FLAP inhibitors.