title: Lipoxin generation is related to soluble epoxide hydrolase activity in severe asthma.
abstract: BACKGROUND
  Severe asthma is characterized by airway inflammatory responses associated with aberrant metabolism of arachidonic acid. Lipoxins (LX) are arachidonate-derived pro-resolving mediators that are decreased in severe asthma, yet mechanisms for defective LX biosynthesis and a means to increase LXs in severe asthma remain to be established.
  
  
  OBJECTIVE
  To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.
  
  
  METHODS
  Aliquots of blood, sputum, and bronchoalveolar lavage fluid were obtained from asthma subjects for mediator determination. Select samples were exposed to t-butyl-hydroperoxide or sEH inhibitor (sEHI) before activation. Peripheral blood leukocyte-platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections.
  
  
  RESULTS
  8-Isoprostane levels in sputum supernatants were inversely related to LXA4 in severe asthma (r = -0.55; P = 0.03) and t-butyl-hydroperoxide decreased LXA4 and 15-epi-LXA4 biosynthesis by peripheral blood leukocytes. LXA4 and 15-epi-LXA4 levels were inversely related to sEH activity in sputum supernatants and sEHIs significantly increased 14,15-epoxy-eicosatrienoic acid and 15-epi-LXA4 generation by severe asthma whole blood and bronchoalveolar lavage fluid cells. The abundance of peripheral blood leukocyte-platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited platelet-activating factor-induced increases in leukocyte-platelet aggregates (70.8% inhibition [LXA4 100 nM], 78.3% inhibition [15-epi-LXA4 100 nM]) and 15-epi-LXA4 markedly inhibited tumor necrosis factor-α-induced increases in bronchial contraction.
  
  
  CONCLUSIONS
  LX levels were decreased by oxidative stress and sEH activity. Inhibitors of sEH increased LXs that mediated antiphlogistic actions, suggesting a new therapeutic approach for severe asthma. Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).
authors.affiliation: 1 Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Emiko
authors.initials: E
authors.lastname: Ono
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dutile
authors.forename: Shamsah
authors.initials: S
authors.lastname: Kazani
authors.forename: Michael E
authors.initials: ME
authors.lastname: Wechsler
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: David Nobuhiro
authors.initials: DN
authors.lastname: Douda
authors.forename: Yacine
authors.initials: Y
authors.lastname: Tabet
authors.forename: Rayan
authors.initials: R
authors.lastname: Khaddaj-Mallat
authors.forename: Marco
authors.initials: M
authors.lastname: Sirois
authors.forename: Chantal
authors.initials: C
authors.lastname: Sirois
authors.forename: Edmond
authors.initials: E
authors.lastname: Rizcallah
authors.forename: Eric
authors.initials: E
authors.lastname: Rousseau
authors.forename: Richard
authors.initials: R
authors.lastname: Martin
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
authors.forename: Mario
authors.initials: M
authors.lastname: Castro
authors.forename: Nizar N
authors.initials: NN
authors.lastname: Jarjour
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Levy
mesh_terms: D000328:Adult; D001249:Asthma / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D044045:Lipoxins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D012720:Severity of Illness Index; D013183:Sputum / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015415:Biomarkers; D044045:Lipoxins; D014409:Tumor Necrosis Factor-alpha; C040527:lipoxin A4; D004851:Epoxide Hydrolases
keywords: asthma; inflammation; pro-resolving mediators; resolution