title: Soluble epoxide hydrolase inhibitor attenuates inflammation and airway hyperresponsiveness in mice.
abstract: Control of airway inflammation is critical in asthma treatment. Soluble epoxide hydrolase (sEH) has recently been demonstrated as a novel therapeutic target for treating inflammation, including lung inflammation. We hypothesized that pharmacological inhibition of sEH can modulate the inflammatory response in a murine ovalbumin (OVA) model of asthma. BALB/c mice were sensitized and exposed to OVA over 6 weeks. A sEH inhibitor (sEHI) was administered for 2 weeks. Respiratory system compliance, resistance, and forced exhaled nitric oxide were measured. Lung lavage cell counts were performed, and selected cytokines and chemokines in the lung lavage fluid were measured. A LC/MS/MS method was used to measure 87 regulatory lipids mediators in plasma, lung tissue homogenates, and lung lavage fluid. The pharmacological inhibition of sEH increased concentrations of the antiinflammatory epoxy eicosatrienoic acids and simultaneously decreased the concentrations of the proinflammatory dihydroxyeicosatrienoic acids and dihydroxyoctadecenoic acids. All monitored inflammatory markers, including FeNO levels, and total cell and eosinophil numbers in the lung lavage of OVA-exposed mice were reduced by sEHI. The type 2 T helper cell (Th2) cytokines (IL-4, IL-5) and chemokines (Eotaxin and RANTES) were dramatically reduced after sEHI administration. Resistance and dynamic lung compliance were also improved by sEHI. We demonstrated that sEHI administration attenuates allergic airway inflammation and airway responsiveness in a murine model. sEHI may have potential as a novel therapeutic strategy for allergic asthma.
authors.affiliation: 1 Department of Entomology and Nematology and Comprehensive Cancer Center.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bratt
authors.forename: Lisa
authors.initials: L
authors.lastname: Franzi
authors.forename: Jun-Yan
authors.initials: JY
authors.lastname: Liu
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhang
authors.forename: Amir A
authors.initials: AA
authors.lastname: Zeki
authors.forename: Christoph F A
authors.initials: CF
authors.lastname: Vogel
authors.forename: Keisha
authors.initials: K
authors.lastname: Williams
authors.forename: Hua
authors.initials: H
authors.lastname: Dong
authors.forename: Yanping
authors.initials: Y
authors.lastname: Lin
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Kenyon
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
mesh_terms: D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000401:mortality; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004537:Eicosanoic Acids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D051379:Mice; D018418:Th2 Cells / Q000378:metabolism* / Q000473:pathology; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D016207:Cytokines; D004537:Eicosanoic Acids; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse
keywords: asthma; inflammation; lipid mediators; soluble epoxide hydrolase; type 2 T helper cell cytokines