Soluble epoxide hydrolase inhibitor attenuates inflammation and airway hyperresponsiveness in mice

Am J Respir Cell Mol Biol. 2015 Jan;52(1):46-55. doi: 10.1165/rcmb.2013-0440OC.

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.

Keywords: asthma; inflammation; lipid mediators; soluble epoxide hydrolase; type 2 T helper cell cytokines.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Asthma / enzymology*
  • Asthma / genetics
  • Asthma / mortality
  • Cytokines / genetics
  • Cytokines / metabolism
  • Disease Models, Animal
  • Eicosanoic Acids / metabolism
  • Enzyme Inhibitors / pharmacology
  • Epoxide Hydrolases / antagonists & inhibitors
  • Epoxide Hydrolases / genetics
  • Epoxide Hydrolases / metabolism*
  • Inflammation / enzymology
  • Inflammation / genetics
  • Inflammation / pathology
  • Inflammation Mediators / metabolism*
  • Male
  • Mice
  • Th2 Cells / metabolism*
  • Th2 Cells / pathology
  • Vascular Resistance / drug effects

Substances

  • Cytokines
  • Eicosanoic Acids
  • Enzyme Inhibitors
  • Inflammation Mediators
  • Epoxide Hydrolases
  • Ephx2 protein, mouse