key: cord-0926311-glv6870o
authors: Hammock, Bruce D.; Wang, Weicang; Gilligan, Molly M.; Panigrahy, Dipak
title: Eicosanoids: the Overlooked Storm in COVID-19?
date: 2020-07-08
journal: Am J Pathol
DOI: 10.1016/j.ajpath.2020.06.010
sha: 4963e17b14e685b4d74f343ed1f21f1f42c11282
doc_id: 926311
cord_uid: glv6870o

Severe coronavirus-19 (COVID-19) symptoms, including systemic inflammatory response and multi-system organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum (ER) stress response and subsequent eicosanoid and cytokine storms. While pro-inflammatory eicosanoids including prostaglandins, thromboxanes, and leukotrienes are critical mediators of physiological processes such as inflammation, fever, allergy, and pain, their role in COVID-19 are poorly characterized. Arachidonic acid derived epoxyeicosatrienoic acids (EETs) could alleviate the systemic hyper-inflammatory response in COVID-19 infection by modulating ER stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous EET 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. We also discuss the host-protective action of omega-3 fatty acid-derived epoxyeicosanoids and specialized pro-resolving mediators (SPMs) in regulating anti-inflammation and anti-viral response. Future studies determining the eicosanoid profile in COVID-19 patient or preclinical model are pivotal in providing the novel insight of coronavirus-host interaction and inflammation modulation.

Severe coronavirus-19 symptoms, including systemic inflammatory response and multi-system organ failure, are now affecting thousands of infected patients and causing widespread mortality. Coronavirus infection causes tissue damage, which triggers the endoplasmic reticulum (ER) stress response and subsequent eicosanoid and cytokine storms.

While pro-inflammatory eicosanoids including prostaglandins, thromboxanes, and leukotrienes are critical mediators of physiological processes such as inflammation, fever, allergy, and pain, their role in COVID-19 are poorly characterized. Arachidonic acid derived epoxyeicosatrienoic acids (EETs) could alleviate the systemic hyper-inflammatory response in COVID-19 infection by modulating ER stress and stimulating the resolution of inflammation. Soluble epoxide hydrolase (sEH) inhibitors, which increase endogenous EET levels, exhibit potent antiinflammatory 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. We also discuss the host-protective action of omega-3 fatty acid-derived epoxyeicosanoids and specialized pro-resolving mediators (SPMs) in regulating antiinflammation and anti-viral response. Future studies determining the eicosanoid profile in COVID-19 patient or preclinical model are pivotal in providing the novel insight of coronavirushost interaction and inflammation modulation.

Quite early in the coronavirus disease (COVID-19) pandemic, it was observed that morbidity and mortality were associated with a drastic systemic inflammatory response caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. [1] [2] [3] This was initially observed in the lung, with many patients experiencing respiratory distress, pneumonia, fever, and multi-organ failure. Severe pathologies are now widely appreciated in many organs throughout the human body including the lung, heart, spleen, lymph nodes, brain, liver, kidneys, eyes, and vasculature due to widespread inflammatory responses. 1, 4, 5 The pro-inflammatory cytokine storm is a critical driving force in severe COVID-19 infection and may lead to multisystem organ failure. 2, 3, 5, 6 One of the first descriptions of the "cytokine storm" was detailed on graft-versus-host disease in 1993. 7 Since then, cytokine storms and associated hyperinflammatory mechanisms have been characterized in studies of viral infection (influenza, SARS-CoV, SARS-CoV-2), macrophage activation syndrome, immunotherapy, chemotherapy, rheumatic diseases, traumatic injury and acute respiratory disease and may thus be utilized as potential diagnostic markers of inflammatory disease progression. [8] [9] [10] [11] [12] Both SARS-CoV and the influenza virus induce apoptosis and necrosis of various cell types, including T cells, endothelial cells, and epithelial cells, through pro-inflammatory cytokine and chemokine mediated vascular leakage and suboptimal T cell responses. 6, [13] [14] [15] [16] Moreover, viral clearance may be impaired by a macrophage-derived pro-inflammatory cytokine storm and thus targeting viral replication may not be sufficient to promote host survival. 16 Locally and systemically elevated pro-inflammatory cytokines, including IL-1β, IFN-γ, IP-10, IL-1, IL-6 and MCP-1, have been detected in select critically ill patients with COVID-19 and found to correlate with disease severity. 2, 6 Interestingly, this hyper-inflammatory innate host response to SARS-CoV may additionally correlate with death in large animal models (e.g. primates) more directly than virus titers. 17 Thus, a therapeutic approach to stimulating the resolution of the host inflammatory response including the cytokine storm may be as critical as preventing viral replication for patient survival. 3 Cell death, including apoptosis, is induced by host defense mechanisms in response to infections. 18 However, cell death ("debris") can trigger an eicosanoid and cytokine storm in inflammatory diseases. 10 Virus-induced inflammatory proteins and cell debris trigger a cellular endoplasmic reticulum (ER) stress response, which mediates the virus-host interaction in infected cells. 19 Normally, an ER stress response down-regulates global protein synthesis to diminish further viral replication in infected cells. However, prolonged responses initiate proinflammatory and later pro-apoptotic programs of ER stress in host cells, which give rise to elevated cytokine production during infection. The spike protein, which mediates SARS-CoV binding to angiotensin-converting enzyme 2 (ACE2) for cellular entry, has been shown to activate ER stress transducer X-box binding protein 1 (XBP1) and up-regulate ER-resident protein Herpud1 and chemokine Cxcl2 in infected murine fibroblast L cells. 20 Additionally, overexpression of SARS-CoV ORF8b protein elevates ER stress effector CHOP, which leads to cell apoptosis in HeLa cells. 21 Coronavirus-induced tissue damage and accumulation of cellular debris (i.e. cell fragments and proteins) has further been implicated in stimulating cell apoptosis and boosting inflammation by regulating other cellular pathways (JNK/p38, Bcl2/Bax, inflammasome and NF-κB) with specific ER stress sensor arms. 19 Manipulations of the coronavirus-induced ER stress response upstream of the devastating cytokine storm could be a powerful approach in combating COVID-19 pathogenesis in patients with severe pneumonia or multi-organ failure (Figure 1 ).

Arachidonic acid-derived lipid autacoids, including prostaglandins, thromboxanes, and leukotrienes generated by cyclooxygenases and lipoxygenases are collectively termed eicosanoids and are critical mediators of inflammation, resolution, and tissue homeostasis 22 .

Eicosanoids play pivotal roles in a broad range of physiological processes such as inflammation, fever, allergy, and pain. 22, 23 Upon activation by cell debris or infection, the inositolrequiring enzyme 1α (IRE1α)-XBP1 branch of the ER stress pathway up-regulates expression of microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 (COX-2), and accelerates the biosynthesis of prostaglandins (PGE 2 , PGD 2 , and PGF 2α ) and thromboxane B 2 (TBX 2 ) from arachidonic acid. 24, 25 This ensuing "eicosanoid storm" may be associated with production of a cytokine storm. 10, 26 Indeed, activated ER stress signaling alone only slightly increases the level of IL-6, while the presence of PGE 2 and/or other cytokines (IFNγ) with an activated ER stress response greatly enhances IL-6 production in glial cells. 27 Importantly, this eicosanoid surge has not been adequately evaluated in the setting of COVID-19 infection.

While elevated cytokine levels in COVID-19 have been identified as a major factor contributing morbidity and mortality, the role of eicosanoids in COVID-19 as key mediators of both inflammation and its active resolution remains poorly characterized. 3, 28-30 Importantly, not all eicosanoids are pro-inflammatory as arachidonic acid and related fatty acids are also metabolized into anti-inflammatory and pro-resolution docosanoids in certain temporal situations. 22, [31] [32] [33] Infectious processes often activate inflammasome formation and the subsequent formation of an eicosanoid storm consisting of both pro-inflammatory and antiinflammatory mediators, thereby disrupting the temporal progression of inflammation and its resolution. 34 Namely, phospholipase A 2 regulates eicosanoid class switching during inflammasome and caspase activation, triggering arachidonic acid to generate pro-resolution mediators such as lipoxins. 34, 35 As increased pro-inflammatory cytokines may be a driving force in severe COVID-19, the balance of pro-inflammatory/anti-inflammatory eicosanoids and proresolution lipid mediators during the initiation and resolution of infection can regulate the cytokine storm. 34 Thus, we hypothesize that SARS-CoV-2 may trigger a temporal production of an eicosanoid storm, including an imbalance of both pro-inflammatory and pro-resolution mediators. 3, 22 While eicosanoids such as prostaglandins and leukotrienes are the 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 (CYP) system. This eicosanoid pathway consists of two main branches: ω-hydroxylases which convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which convert it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). 36 EETs regulate inflammation and vascular tone and are produced predominantly in the endothelium. 36 Importantly, the epoxides of EETs are rapidly converted into dihydroxyeicosatrienoic acids (DHETs) by the soluble epoxide hydrolase (sEH) enzyme ( Figure   1 ). Soluble epoxide hydrolase inhibitors, which raise endogenous EET levels, exhibit potent anti-inflammatory activity including inhibiting pro-inflammatory cytokines in various pathologic diseases including inflammatory bowel disease, atherosclerosis, pancreatitis, diabetes, hypertension, stroke, cerebral ischemia, dyslipidemia, pain, immunological disorders, ocular diseases, neurological diseases, renal disease (e.g. acute kidney injury), organ damage, vascular remodeling, ischemia-reperfusion, lung disease (chronic obstructive pulmonary disease [COPD]), fibrosis (e.g. pulmonary and cardiac fibrosis), graft stenosis, and other medical conditions. 37-39 While EETs and sEH signaling play a key role in hyper-inflammatory diseases, their role in COVID-19 should be explored.

EETs, which are generated from arachidonic acid by CYP enzymes, promote the active termination ('resolution') of inflammation through mediating a broad array of anti-inflammatory and pro-resolving mechanisms, including mitigation of the cytokine storm. 3, 40, 41 In an endotoxemia mouse model, increased EET biosynthesis suppresses the endotoxin-induced surge of pro-inflammatory cytokines (IL-6, IL-1β), chemokines (MCP-1, ENA-78), adhesion molecules (E-selectin), and NF-κB activation in lung. 42 Similarly, treatment with 14,15-EET inhibits activation of ER stress effectors (p-elF2α, CHOP and GRP78) by cigarette smoke and suppresses injury-induced oxidative stress and cell apoptosis in human bronchial epithelial cells. 43 Reduction of the ER stress response by EETs and promoting the activity of antiinflammatory, pro-resolving mediators may represent a promising new therapeutic avenue in COVID-19 treatment.

While inflammation can induce sEH expression 36, 37 , COVID-19 infection may further stimulate sEH levels throughout the body in various tissues. Stabilizing the anti-inflammatory, pro-resolving EETs by using sEH inhibitors (sEHIs) has been shown to have a valuable therapeutic application in various preclinical models and human trials, including sepsis, cardiovascular disease, neuroinflammatory disease, and cancer. [44] [45] [46] More importantly, administration of sEHIs suppresses pulmonary cytokine expression and neutrophil infiltration, thereby alleviating pulmonary inflammation and edema and decreasing mortality in murine models of endotoxin-induced acute respiratory distress syndrome (ARDS). 47 Similar antiinflammatory activity has been observed in other models of COPD, asthma, and pulmonary fibrosis. 48 Additionally, sEHIs dramatically reduce NF-κB induction of inflammatory enzymes (i.e. cyclooxygenase (COX-2)), as well as the downstream production of pro-inflammatory mediators such as PGE 2 . 24 These omega-3 fatty acid-derived epoxyeicosanoids exhibit anti-inflammatory activity in various inflammatory diseases including in the lung, heart, ocular angiogenesis, and pain. 49 Omega-3 supplementation may also synergize with sEH inhibition to suppress inflammation. 50 Omega-3 epoxides, stabilized via inhibition of sEH, are important regulators of inflammation and autophagy in metabolic diseases. 51 Dietary EPA/DHA supplementation causes a profound shift of the endogenous CYP-eicosanoid profile from arachidonic acid (AA)-to EPA-and DHAderived metabolites, increasing, in particular, the plasma and tissue levels of 17,18epoxyeicosatetraenoic acid (17, and 19,20-epoxydocosapentaenoic acid (19, . COVID-19 is characterized by increased angiogenesis demonstrated in autopsy samples of lungs from patients who died from COVID-19 compared to influenza patients. 52 Inhibition of sEH prevents angiogenic diseases such as diabetic retinopathy. 53 

EDPs and EEQs also dampen choroidal angiogenesis. 54 Moreover, EETs shift arachidonic acid metabolism to stimulate the production of specialized pro-resolving mediators (SPMs) such as lipoxins, which stimulate clearance of inflammatory cellular debris and counter pro-inflammatory cytokine production without being immunosuppressive. 24, 48 Pharmacological enhancement of resolution via resolvins at nanogram doses per day or omega-3 fatty acid supplementation restores endogenous SPMs. [55] [56] [57] Stimulation of resolution of inflammation by immunoresolvent agonists including resolvins is host-protective during infection and sepsis. [58] [59] [60] [61] The anti-inflammatory agent dexamethasone may have activity in COVID-19 patients 62 . Dexamethasone stimulates SPMs to stimulate resolution of airway inflammation. 63 The ER stress response can be reduced by dexamethasone by promoting protein folding and degradation of misfolded proteins from the ER. 64 Targeting eicosanoid metabolism could be a promising new approach in COVID-19 infection given the critical role that eicosanoids play in both the initiation and resolution of inflammation. 22 While current therapeutic strategies are aimed at inhibiting individual inflammatory cytokines (i.e. IL-1 and/or IL-6) or viral cell entry and intracellular processing, these strategies neglect the critical upstream role that ER stress and eicosanoids play between generation of cell fragments and proteins released during viral-induced death ("debris") and the downstream cytokine production in coronavirus infection (Figure 1) . Nonsteroidal antiinflammatory drugs (NSAIDs), the pan-COX inhibitors which block prostaglandin biosynthesis, are a routine and effective choice for the relief of influenza-caused fever and pain. 23, 37 There may be minimal to no benefit for severe SARS-CoV-2 infections with NSAIDs, which also increase the risk of gastrointestinal and cardiovascular complications. 65 Initially during infection the classic mediators of inflammation including prostaglandins and leukotrienes are produced leading to the initiation of inflammation. 66 Subsequently, prostaglandin E 2 and prostaglandin D 2 induce a lipid mediator class switching of eicosanoid production by neutrophils from leukotriene B 4 and 5-lipoxygenase (5-LO) pathways to lipoxins, resolvins, and protectins to promote resolution. 33, [66] [67] [68] [69] Thus, NSAIDs should be used with caution as they may block subsequent activity of prostaglandins, which are essential for the resolution of inflammation. 22 NSAIDs are currently recommended to be on an individual basis due to the insufficient evidence in clinical trials and their well-known gastrointestinal and cardiovascular toxicities. 70 Interestingly, sEH inhibitors synergize with COX inhibitors in reducing inflammation and blocking the gastrointestinal erosion and cardiovascular events associated with these drugs. 40, 71, 72 Shifting arachidonic acid metabolism via sEH inhibition also alters the ER stress response towards a more homeostatic role in cell maintenance and promotes the production of antiinflammatory, pro-resolving lipids, thus representing an attractive new approach to controlling inflammation in COVID-19. Indeed, sEH inhibitors have been demonstrated to suppress the inflammatory response and inflammation-driven diseases in lung, heart, liver, kidney and vasculature in numerous preclinical models. 37, 40 Recently, sEH inhibitors have proven non-toxic at high doses in clinical development (phase 2A trials) and synergistic with other wellestablished anti-inflammatory medications, such as NSAIDs, to promote anti-inflammatory programs and reduce the gastrointestinal side-effects. 71 Interestingly, risk factors for COVID-19 are similar to idiopathic pulmonary fibrosis and previous coronavirus outbreaks have been characterized by fibrosis. 73 Pharmacologic or genetic inhibition of soluble epoxide hydrolase prevents inflammation and liver fibrosis in various tissues including lung, heart, liver and kidney. [74] [75] [76] [77] [78] [79] [80] Thus, the anti-fibrotic activity of sEH inhibitors may additionally be useful in speeding recovery post COVID-19 infection. 40 Temporal data on eicosanoid levels in patients is critical to further establish the role of a putative eicosanoid storm in COVID-19, and additional preclinical and clinical studies are needed to test the safety and efficacy of sEH inhibitors in COVID-19

patients. Here we propose sEH inhibitors alone or in combination with other agents such as COX inhibitors or omega-3 lipids are envisioned to be of benefit in blocking or moderating the inflammatory cascade when the patient's condition first appears to be deteriorating in COVID- stress response and upregulate inflammatory enzymes, including microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 (COX-2), which subsequently produce eicosanoids including prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs). These pro-inflammatory lipid autacoids induce cytokine storms which mediate widespread inflammatory responses and organ damage in severe COVID-19 patients.

By contrast, epoxyeicosatrienoic acids (EETs), which are stabilized by inhibition of its metabolizing enzyme soluble epoxide hydrolase (sEH), are anti-inflammatory and pro-resolving mediators that promote the termination ('resolution') of inflammation by suppressing the ER stress response, inflammatory enzyme induction and suppressing pro-inflammatory cytokine production. EETs also shift arachidonic acid metabolism to favor the production of SPMs, which initiate downstream anti-inflammatory and pro-resolving programs. EETs and sEH inhibitors may counterregulate the unabated systemic inflammatory response and organ failure associated with COVID-19 infection.

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