It is proposed that the beneficial action of mesenchymal stem cells (MSCs) in COVID-19 and other inflammatory diseases could be attributed to their ability to secrete bioactive lipids (BALs) such as prostaglandin E2 (PGE2) and lipoxin A4 (LXA4) and other similar BALs. This implies that MSCs that have limited or low capacity to secrete BALs may be unable to bring about their beneficial actions. This proposal implies that pretreatment of MSCs with BALs enhance their physiological action or improve their (MSCs) anti-inflammatory and disease resolution capacity to a significant degree. Thus, the beneficial action of MSCs reported in the management of COVID-19 could be attributed to their ability to secrete BALs, especially PGE2 and LXA4. Since PGE2, LXA4 and their precursors AA (arachidonic acid), dihomo-gamma-linolenic acid (DGLA) and gamma-linolenic acid (GLA) inhibit the production of pro-inflammatory IL-6 and TNF-α, they could be employed to treat cytokine storm seen in COVID-19, immune check point inhibitory (ICI) therapy, sepsis and ARDS (acute respiratory disease). This is further supported by the observation that GLA, DGLA and AA inactivate enveloped viruses including COVID-19. Thus, infusions of appropriate amounts of GLA, DGLA, AA, PGE2 and LXA4 are of significant therapeutic benefit in COVID-19, ICI therapy and other inflammatory conditions including but not limited to sepsis. AA is the precursor of both PGE2 and LXA4 suggesting that AA is most suited for such preventive and therapeutic approach.
Figure 1. Scheme showing potential relationship among AA, PGE2, LXA4 and viral load in a COVID-19 patient who recovers. AA is released from the cell membrane in two phases, first phase is used for PGE2 synthesis, whereas the second phase is meant for LXA4 synthesis. Once PGE2 concentration reaches its peak, LXA4 synthesis is triggered that induces resolution of inflammation. AA release is triggered by SARS-CoV-2 and other infections.
Figure 2. Scheme showing potential relationship among AA, PGE2, LXA4 and viral load in a COVID-19 patient who succumbs to the disease. Note the absence of biphasic nature of AA release and failure of PGE2 to reach its peak and as a result deficiency in LXA4 synthesis occurs that results in failure of resolution of inflammation (compare with Fig 1). DGLA, EPA and DHA (not shown in the figure) may have actions/functions like AA.
Figure 3. Scheme showing possible role of MSCs and bioactive lipids in COVID-19. Dietary LA and ALA are converted to AA and EPA and DHA by desaturases. Viruses block the activities of desaturases. PGE2 and LTs derived from AA/EPA/DHA facilitate M1 generation and enhance inflammation. Anti-inflammatory PGE1/PGE2, lipoxins, resolvins, protectins and maresins derived from DGLA, AA, EPA and DHA facilitate M2 generation and suppress inflammation. PLA2 activated by SARS-CoV-2 and other viruses induce the release of DGLA/AA/EPA/DHA that inactivate enveloped viruses by themselves and through their products and regulate inflammatory process. MSCs and other stem cells contain DGLA/AA/EPA/DHA and release PGE2 and LXA4 and other bioactive lipids to resolve inflammation. DGLA/AA/EPA/DHA by their ability to alter cell membrane composition can regulate ACE2 expression. ACE2 is needed for SARS-CoV-2 entry into the cells.
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