{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:36:22Z","timestamp":1787726182686,"version":"build-2784847793"},"reference-count":77,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T00:00:00Z","timestamp":1716508800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["Z01 ES025034"],"award-info":[{"award-number":["Z01 ES025034"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI001281\u201004"],"award-info":[{"award-number":["AI001281\u201004"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2024,5,31]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Severe acute respiratory syndrome coronavirus 2 (SARS\u2010CoV\u20102) infection involves an initial viral infection phase followed by a host\u2010response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti\u2010viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti\u2010inflammatory molecules called epoxyeicosatrienoic acids (EETs). This study aimed to investigate the impact of sEH inhibition on the host response to SARS\u2010CoV\u20102 infection in a mouse model with human angiotensin\u2010converting enzyme 2 (ACE2) expression. Mice were infected with SARS\u2010CoV\u20102 and treated with either vehicle or the sEH inhibitor 1\u2010trifluoromethoxyphenyl\u20103\u2010(1\u2010propionylpiperidin\u20104\u2010yl) urea (TPPU). At day 5 post\u2010infection, SARS\u2010CoV\u20102 induced weight loss, clinical signs, a cytokine storm, an eicosanoid storm, and severe lung inflammation with ~50% mortality on days 6\u20138 post\u2010infection. SARS\u2010CoV\u20102 infection induced lung expression of phospholipase A\n                    <jats:sub>2<\/jats:sub>\n                    (PLA\n                    <jats:sub>2<\/jats:sub>\n                    ), cyclooxygenase (COX) and lipoxygenase (LOX) pathway genes, while suppressing expression of most cytochrome P450 genes. Treatment with the sEH inhibitor TPPU delayed weight loss but did not alter clinical signs, lung cytokine expression or overall survival of infected mice. Interestingly, TPPU treatment significantly reversed the eicosanoid storm and attenuated viral\u2010induced elevation of 39 fatty acids and oxylipins from COX, LOX and P450 pathways, which suggests the effects at the level of PLA\n                    <jats:sub>2<\/jats:sub>\n                    activation. The suppression of the eicosanoid storm by TPPU without corresponding changes in lung cytokines, lung inflammation or mortality reveals a surprising dissociation between systemic oxylipin and cytokine signaling pathways during SARS\u2010CoV\u20102 infection and suggests that the cytokine storm is primarily responsible for morbidity and mortality in this animal model.\n                  <\/jats:p>","DOI":"10.1096\/fj.202302202rr","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T09:10:24Z","timestamp":1716541824000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Effects of\n                    <scp>sEH<\/scp>\n                    inhibition on the eicosanoid and cytokine storms in\n                    <scp>SARS\u2010CoV<\/scp>\n                    \u20102\u2010infected mice"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7042-500X","authenticated-orcid":false,"given":"Matthew L.","family":"Edin","sequence":"first","affiliation":[{"name":"Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1698-7159","authenticated-orcid":false,"given":"Artiom","family":"Gruzdev","sequence":"additional","affiliation":[{"name":"Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan P.","family":"Graves","sequence":"additional","affiliation":[{"name":"Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2260-816X","authenticated-orcid":false,"given":"Fred B.","family":"Lih","sequence":"additional","affiliation":[{"name":"Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5672-6631","authenticated-orcid":false,"given":"Christophe","family":"Morisseau","sequence":"additional","affiliation":[{"name":"Department of Entomology and Nematology and UCD Comprehensive Cancer Center University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9510-2848","authenticated-orcid":false,"given":"James M.","family":"Ward","sequence":"additional","affiliation":[{"name":"Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1408-8317","authenticated-orcid":false,"given":"Bruce D.","family":"Hammock","sequence":"additional","affiliation":[{"name":"Department of Entomology and Nematology and UCD Comprehensive Cancer Center University of California Davis  Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9039-6341","authenticated-orcid":false,"given":"Catharine M.","family":"Bosio","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, Rocky Mountain Laboratories National Institute of Allergy and Infectious Diseases, NIH  Hamilton Montana USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-7307","authenticated-orcid":false,"given":"Darryl C.","family":"Zeldin","sequence":"additional","affiliation":[{"name":"Division of Intramural Research National Institute of Environmental Health Sciences, National Institutes of Health  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,24]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.m3862"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-022-00713-0"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/v13071362"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/092986712799828346"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-20568-4"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-020-09889-4"},{"key":"e_1_2_9_8_1","volume-title":"Coronavirus Disease 2019 (COVID\u201019) Treatment Guidelines","author":"COVID\u201019 Treatment Guidelines Panel","year":"2023"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13613-021-00941-2"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2001025"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3859"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.10.016"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.207449"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04630-3"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202108-1855OC"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-021-01473-y"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-011112-140244"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-171488"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.285.5431.1276"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00533.2009"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00427.2005"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00242"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1521453113"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000298"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00161.2016"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0000000000000767"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-188300"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx990162c"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1006\/taap.1997.8197"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2120691119"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2020.06.010"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.663869"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.0c01886"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.12855"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.00464"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.35073"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA120.016570"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-018-1367-3"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02012-06"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00014-21"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-0778-2"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2010.12.042"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00402.2006"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.067819"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.5b00873"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.112.049429"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2020.12.005"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2020.04.003"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1093\/nsr\/nwaa037"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s40246-020-00272-6"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1195299"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2101555118"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejps.2023.106489"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1055811"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2200162"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.C300033200"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.000405"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901872R"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.035287"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.14-268458"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.893792"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.08.006"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M049718"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.15-275065"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2015.06.005"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2017.06.006"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0409591102"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22094993"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI129679"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14530"},{"key":"e_1_2_9_71_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830271254"},{"key":"e_1_2_9_72_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11050717"},{"key":"e_1_2_9_73_1","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/926968"},{"key":"e_1_2_9_74_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-021-00618-7"},{"key":"e_1_2_9_75_1","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2022.2076901"},{"key":"e_1_2_9_76_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2021436"},{"key":"e_1_2_9_77_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-17993-9"},{"key":"e_1_2_9_78_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2010.12.021"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202302202RR","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,29]],"date-time":"2025-10-29T01:18:29Z","timestamp":1761700709000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202302202RR"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,24]]},"references-count":77,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,5,31]]}},"alternative-id":["10.1096\/fj.202302202RR"],"URL":"https:\/\/doi.org\/10.1096\/fj.202302202rr","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,24]]},"assertion":[{"value":"2023-10-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e23692"}}