{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:32:50Z","timestamp":1791300770518,"version":"4.1.0"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2014,10,1]],"date-time":"2014-10-01T00:00:00Z","timestamp":1412121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To determine if oxidative stress and soluble epoxide hydrolase (sEH) activity are linked to decreased LX biosynthesis in severe asthma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2013platelet aggregates were monitored by flow cytometry, and bronchial contraction was determined with cytokine-treated human lung sections.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>8-Isoprostane levels in sputum supernatants were inversely related to LXA4 in severe asthma (r = \u22120.55; 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\u2013platelet aggregates was related to asthma severity. In a concentration-dependent manner, LXs significantly inhibited platelet-activating factor\u2013induced increases in leukocyte\u2013platelet aggregates (70.8% inhibition [LXA4 100 nM], 78.3% inhibition [15-epi-LXA4 100 nM]) and 15-epi-LXA4 markedly inhibited tumor necrosis factor-\u03b1\u2013induced increases in bronchial contraction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                    <jats:p>Clinical trial registered with www.clinicaltrials.gov (NCT 00595114).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201403-0544oc","type":"journal-article","created":{"date-parts":[[2014,8,27]],"date-time":"2014-08-27T16:28:08Z","timestamp":1409156888000},"page":"886-897","source":"Crossref","is-referenced-by-count":78,"title":["Lipoxin Generation is Related to Soluble Epoxide Hydrolase Activity in Severe Asthma"],"prefix":"10.1093","volume":"190","author":[{"given":"Emiko","family":"Ono","sequence":"first","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Dutile","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shamsah","family":"Kazani","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Wechsler","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Entomology and Comprehensive Cancer Center, University of California at Davis, Davis, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce D.","family":"Hammock","sequence":"additional","affiliation":[{"name":"Department of Entomology and Comprehensive Cancer Center, University of California at Davis, Davis, California; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David Nobuhiro","family":"Douda","sequence":"additional","affiliation":[{"name":"Pulmonary and Critical Care Medicine, Brigham and Women\u2019s Hospital and Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yacine","family":"Tabet","sequence":"additional","affiliation":[{"name":"Le Bilarium, Department of Physiology and Biophysics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayan","family":"Khaddaj-Mallat","sequence":"additional","affiliation":[{"name":"Le Bilarium, Department of Physiology and Biophysics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Sirois","sequence":"additional","affiliation":[{"name":"Service of Thoracic Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Sirois","sequence":"additional","affiliation":[{"name":"Service of Thoracic Surgery, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edmond","family":"Rizcallah","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c9ric","family":"Rousseau","sequence":"additional","affiliation":[{"name":"Le Bilarium, Department of Physiology and Biophysics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Medicine, National Jewish Health, Denver, Colorado"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. 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