Hypothesis: mPGES-1-Derived Prostaglandin E2, a So Far Missing Link in COVID-19 Pathophysiology?

Abstract

With frequencies varying up to 20%, treatment resistant pulmonary failure is a major life-threatening complication in COVID-19 (SARS-CoV-2, HCoV19) disease pathology. Both acute respiratory distress syndrome (ARDS), proposed to be caused by an over-reacting immune system which floods the lung with edema, a liquid consisting of inflammatory cells, and diminished lung perfusion, have been postulated to cause this treatment resistant lung failure. Aging, co-morbidities, male gender and obesity are pre-existing factors associated with the more severe outcome. Thrombosis is more frequently observed than usually seen during ICU admission. Different hypotheses explaining the pathophysiological cascade leading to fast progressing severe COVID-19 disease and how to counteract it have been proposed. A variety of intervention studies to control severity are ongoing or planned. Not suggested so far, we here hypothesize that the inflammatory lipid modulator prostaglandin E2 (PGE2) executes a prominent role in COVID-19 pathophysiology. Based on this we suggest measuring PGE2 in patients and evaluating selective inhibition of the human microsomal prostaglandin E synthase-1 (mPGES-1) as a potential innovative therapeutic approach in this devastating condition for which sonlicromanol, a drug currently in phase 2b studies for mitochondrial disease, is a candidate.

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

“…Indeed, elevated levels of PGE 2 were observed in patients infected with SARS-CoV-1 or SARS-CoV-2 (Hong et al, 2020;Lee et al, 2004). Furthermore, Smeitink et al (2020) (Figure 3).…”

What about COVID-19 and arachidonic acid pathway?

“…Following viral infection, an activation of immune response occurs, which includes the release of inflammatory mediators, such as pro-inflammatory cytokines (IL-6, IL-1 β, TNF-α) and eicosanoids (prostaglandins and leukotrienes) [3]. The second isoform of cyclooxygenase (COX-2) is responsible for producing the major part of PGs that are responsible for pain and inflammation [4].…”

“…Analogously, the SARS coronavirus responsible for the 2003 outbreak increased the production of PGs by binding to COX-2 [4]. Different studies have demonstrated that PGE 2 increases the viral pathogenicity in many viral infections such as CMV, RB, RSV, HSV, EV71, and CVB2 by interfering with the viral transcription translation and/or replication [3]. However, we should also consider that in some cases, such as in HBV and PIV3, PGE 2 can either stimulate or inhibit the viral pathogenicity [3].…”

“…Different studies have demonstrated that PGE 2 increases the viral pathogenicity in many viral infections such as CMV, RB, RSV, HSV, EV71, and CVB2 by interfering with the viral transcription translation and/or replication [3]. However, we should also consider that in some cases, such as in HBV and PIV3, PGE 2 can either stimulate or inhibit the viral pathogenicity [3]. Aso et al reported that in human pulmonary microvascular endothelial cells, PGE 2 can play an upstream essential role in inflammation, leading to the increase of COX-2 expression, without affecting the COX-1 isoform, and increasing IL-8 [5].…”

A Rapid Advice Guideline for the Prevention of Novel Coronavirus Through Nutritional Intervention

“…Hence, inculcation of omega-3 and omega-6 PUFAs in diet could serve as a major therapeutic tool for this novel virus, COVID-19. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) possess anti-inflammatory properties, resulting in the lower level of these inflammatory eicosanoids produced from arachidonic acid that inhibits NFκβ (nuclear factor kappa-light-chain-enhancer of activated B cells) signalling, leading to lesser production of inflammatory cytokines [47][48][49]. In a study, animal models with lung injury showed that administration of fish oil lessens pulmonary accumulation of neutrophils with reduced lung permeability, pulmonary oedema, and cardiopulmonary dysfunction [50].…”