Eicosanoids
2020; Elsevier BV; Volume: 190; Issue: 9 Linguagem: Inglês
10.1016/j.ajpath.2020.06.010
ISSN1525-2191
AutoresBruce D. Hammock, Weicang Wang, Molly M. Gilligan, Dipak Panigrahy,
Tópico(s)Diet, Metabolism, and Disease
ResumoSevere coronavirus disease 2019 (COVID-19) symptoms, including systemic inflammatory response and multisystem organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum stress response and subsequent eicosanoid and cytokine storms. Although proinflammatory eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are critical mediators of physiological processes, such as inflammation, fever, allergy, and pain, their roles in COVID-19 are poorly characterized. Arachidonic acid–derived epoxyeicosatrienoic acids could alleviate the systemic hyperinflammatory response in COVID-19 infection by modulating endoplasmic reticulum stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous epoxyeicosatrienoic acid levels, exhibit potent anti-inflammatory activity and inhibit various pathologic processes in preclinical disease models, including pulmonary fibrosis, thrombosis, and acute respiratory distress syndrome. Therefore, targeting eicosanoids and sEH could be a novel therapeutic approach in combating COVID-19. In this review, we discuss the predominant role of eicosanoids in regulating the inflammatory cascade and propose the potential application of sEH inhibitors in alleviating COVID-19 symptoms. The host-protective action of omega-3 fatty acid–derived epoxyeicosanoids and specialized proresolving mediators in regulating anti-inflammation and antiviral response is also discussed. Future studies determining the eicosanoid profile in COVID-19 patients or preclinical models are pivotal in providing novel insights into coronavirus-host interaction and inflammation modulation. Severe coronavirus disease 2019 (COVID-19) symptoms, including systemic inflammatory response and multisystem organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum stress response and subsequent eicosanoid and cytokine storms. Although proinflammatory eicosanoids, including prostaglandins, thromboxanes, and leukotrienes, are critical mediators of physiological processes, such as inflammation, fever, allergy, and pain, their roles in COVID-19 are poorly characterized. Arachidonic acid–derived epoxyeicosatrienoic acids could alleviate the systemic hyperinflammatory response in COVID-19 infection by modulating endoplasmic reticulum stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous epoxyeicosatrienoic acid levels, exhibit potent anti-inflammatory activity and inhibit various pathologic processes in preclinical disease models, including pulmonary fibrosis, thrombosis, and acute respiratory distress syndrome. Therefore, targeting eicosanoids and sEH could be a novel therapeutic approach in combating COVID-19. In this review, we discuss the predominant role of eicosanoids in regulating the inflammatory cascade and propose the potential application of sEH inhibitors in alleviating COVID-19 symptoms. The host-protective action of omega-3 fatty acid–derived epoxyeicosanoids and specialized proresolving mediators in regulating anti-inflammation and antiviral response is also discussed. Future studies determining the eicosanoid profile in COVID-19 patients or preclinical models are pivotal in providing novel insights into coronavirus-host interaction and inflammation modulation. 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Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?.Cancer Metastasis Rev. 2020; 39: 337-340Crossref PubMed Scopus (122) Google Scholar Cell death, including apoptosis, is induced by host defense mechanisms in response to infections.18Jorgensen I. Rayamajhi M. Miao E.A. Programmed cell death as a defence against infection.Nat Rev Immunol. 2017; 17: 151-164Crossref PubMed Scopus (545) Google Scholar However, cell death (debris) can trigger an eicosanoid and cytokine storm in inflammatory diseases.10Gartung A. Yang J. Sukhatme V.P. Bielenberg D.R. Fernandes D. Chang J. Schmidt B.A. Hwang S.H. Zurakowski D. Huang S. Kieran M.W. Hammock B.D. Panigrahy D. 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Arachidonic acid–derived lipid autacoids, including prostaglandins (PGs), thromboxanes, and leukotrienes, generated by cyclooxygenases and lipoxygenases, are collectively termed eicosanoids and are critical mediators of inflammation, resolution, and tissue homeostasis.22Serhan C.N. Pro-resolving lipid mediators are leads for resolution physiology.Nature. 2014; 510: 92-101Crossref PubMed Scopus (1914) Google Scholar Eicosanoids play pivotal roles in a broad range of physiological processes, such as inflammation, fever, allergy, and pain.22Serhan C.N. Pro-resolving lipid mediators are leads for resolution physiology.Nature. 2014; 510: 92-101Crossref PubMed Scopus (1914) Google Scholar,23Wang D. Dubois R.N. 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Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?.Cancer Metastasis Rev. 2020; 39: 337-340Crossref PubMed Scopus (122) Google Scholar,22Serhan C.N. Pro-resolving lipid mediators are leads for resolution physiology.Nature. 2014; 510: 92-101Crossref PubMed Scopus (1914) Google Scholar Although eicosanoids, such as prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway; the cytochrome P450 system. This eicosanoid pathway consists of two main branches: ω-hydroxylases, which convert arachidonic acid to hydroxyeicosatetraenoic acids; and epoxygenases, which convert it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET).36Zeldin D.C. 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Soluble epoxide hydrolase inhibitors, which raise endogenous EET levels, exhibit potent anti-inflammatory activity, including inhibiting proinflammatory cytokines in various pathologic diseases, including inflammatory bowel disease, atherosclerosis, pancreatitis, diabetes, hypertension, stroke, cerebral ischemia, dyslipidemia, pain, immunologic disorders, ocular diseases, neurologic diseases, renal disease (eg, acute kidney injury), organ damage, vascular remodeling, ischemia-reperfusion, lung disease (chronic obstructive pulmonary disease), fibrosis (eg, pulmonary and cardiac fibrosis), graft stenosis, and other medical conditions.37Imig J.D. Hammock B.D. Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases.Nat Rev Drug Discov. 2009; 8: 794-805Crossref PubMed Scopus (487) Google Scholar, 38Shen H.C. Soluble epoxide hydrolase inhibitors: a patent review.Expert Opin Ther Pat. 2010; 20: 941-956Crossref PubMed Scopus (71) Google Scholar, 39Wang W. Zhu J. Lyu F. 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