Figure 3
From: The severity of COVID-19 upon hospital admission is associated with plasma omega-3 fatty acids
Summary of the main hypothesis of this study. The SARS-CoV-2 virus present in the airway infects cells that express the surface receptors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), such as alveolar epithelial cells. The virus’s surface spike protein (S) binds to ACE2, initiating endocytosis mediated by TMPRSS2. Acidification of the endosome triggers viral and cellular membrane fusion, allowing the release of viral single-stranded RNA (ssRNA) into the cytosol. Subsequently, the virus undergoes replication and is released back into the airway. Within the endosomes, viral RNA activates Toll-like receptors (TLR3, TLR7/8), inducing endoplasmic reticulum (ER) stress. This stress leads to the release of NFκB, which translocates to the nucleus, initiating the transcription of genes for inflammatory cytokines, chemokines, adhesion molecules, and growth factors. These proteins attract monocytes and T cells to the infection site, establishing a pro-inflammatory feedback loop. In the macrophages, in response to ER stress, phospholipase A2 (PLA2) hydrolyzes fatty acids esterifying phospholipids in the membranes, serving as substrates for oxidative enzymes, producing various oxylipins. Arachidonic acid (AA) is converted by cyclooxygenase (COX) into PGH2, further transformed into PGE2, binding to EP2/EP4 receptors on macrophage membranes. This activation of cAMP intensifies inflammation, causing pain, immunoregulation, mitogenesis, and cell injury. Conversely, if eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are released, PGH3 is synthesized. This mechanism explains the use of NSAIDs in reducing COVID-19 symptoms. Excessive reactive oxygen species (ROS) generated by macrophages can oxidize AA within phospholipids, increasing F2-IsoPs concentration. It is possible that EPA and DHA might reduce pro-inflammatory molecules by activating peroxisome proliferator-activated receptor gamma (PPARγ), consequently inhibiting NFκB translocation to the nucleus. Additionally, EPA and DHA may inhibit the NLRP3 inflammasome, impeding interleukin-1β maturation, and induce specialized pro-resolving mediators (SPMs) to alter macrophage phenotypes, facilitating inflammation resolution2,4,25,34,43,48. ACE2 angiotensin-converting enzyme 2, TMPRSS2 transmembrane serine protease 2, TLR3, TLR7/8 toll-like receptors, ER endoplasmic reticulum, NFκB nuclear factor-kappa B, PLA2 phospholipase A2, AA arachidonic acid, PGE2 prostaglandin E2, COX cyclooxygenase, LOX lipoxygenase, cAMP cyclic adenosin monophopshate, NSAIDs non-steroidal anti-inflammatory drugs, F2-IsoPs F2-isoprostanes, PPARγ peroxissome proliferator-activated receptor gamma, NLRP3 NLR family pyrin domain containing 3, IL-1β inteleukin 1β, SPMs specialized pro-resolving mediators, EPA eicosapentaenoic acid, DHA docosahexaenoic acid.
