Soluble epoxide hydrolase is a therapeutic target for acute inflammation.
As of 2004, >73 million people were prescribed antiinflammatory medication. Despite the extensive number of current products, many people still suffer from their diseases or the pharmacological properties (side effects) of the medications. Therefore, developing therapeutic strategies to treat inflammation remains an important endeavor. Here, we demonstrate that the soluble epoxide hydrolase (sEH) is a key pharmacologic target for treating acute systemic inflammation. Lipopolysaccharide-induced mortality, systemic hypotension, and histologically evaluated tissue injury were substantially diminished by administration of urea-based, small-molecule inhibitors of sEH to C57BL/6 mice. Moreover, sEH inhibitors decreased plasma levels of proinflammatory cytokines and nitric oxide metabolites while promoting the formation of lipoxins, thus supporting inflammatory resolution. These data suggest that sEH inhibitors have therapeutic efficacy in the treatment and management of acute inflammatory diseases.
Schmelzer
Kara R
KR
Department of Entomology, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Kubala
Lukas
L
Newman
John W
JW
Kim
In-Hae
IH
Eiserich
Jason P
JP
Hammock
Bruce D
BD
D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001794:Blood Pressure; D002851:Chromatography, High Pressure Liquid; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D015151:Immunoblotting; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000633:toxicity; D044045:Lipoxins / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
C503560:1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl)urea; C503559:12-(3-adamantan-1-ylureido)dodecanoic acid butyl ester; D001095:Arachidonic Acids; D016207:Cytokines; D008070:Lipopolysaccharides; D044045:Lipoxins; C440499:lipopolysaccharide, Escherichia coli O111 B4; D014508:Urea; D011451:Prostaglandin-Endoperoxide Synthases; D004851:Epoxide Hydrolases; D000218:Adamantane