Eicosanoids: The Overlooked Storm in Coronavirus Disease 2019 (COVID-19)?

Abstract

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.

Figure 1

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to severe tissue damage, which releases cell debris. Both primary infection and the accumulation of cell debris initiate the endoplasmic reticulum (ER) stress response and up-regulate inflammatory enzymes, including microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 [cyclooxygenase 2 (COX-2)], which subsequently produce eicosanoids, including prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs). These proinflammatory lipid autacoids induce cytokine storms that mediate widespread inflammatory responses and organ damage in severe coronavirus disease 2019 (COVID-19) patients. By contrast, epoxyeicosatrienoic acids (EETs), which are stabilized by inhibition of their metabolizing enzyme, soluble epoxide hydrolase (sEH), are anti-inflammatory and proresolving mediators that promote the termination (resolution) of inflammation by suppressing the ER stress response, inflammatory enzyme induction, and proinflammatory cytokine production. EETs also shift arachidonic acid metabolism to favor the production of specialized proresolving mediators (SPMs), which initiate downstream anti-inflammatory and proresolving programs. EETs and sEH inhibitors may counterregulate the unabated systemic inflammatory response and organ failure associated with COVID-19 infection. DHET, dihydroxyeicosatrienoic acid; TNF-α, tumor necrosis factor-α.