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. 2021 Apr 23;19(5):1327-1359.
doi: 10.5114/aoms/135703. eCollection 2023.

Bioactive lipid-based therapeutic approach to COVID-19 and other similar infections

Undurti N Das  1   2   3   4
Affiliations

Bioactive lipid-based therapeutic approach to COVID-19 and other similar infections

Undurti N Das. Arch Med Sci. .

Abstract

COVID-19 is caused by SARS-CoV-2 infection. Epithelial and T, NK, and other immunocytes release bioactive lipids especially arachidonic acid (AA) in response to microbial infections to inactivate them and upregulate the immune system. COVID-19 (coronavirus) and other enveloped viruses including severe acute respiratory syndrome (SARS-CoV-1 of 2002-2003) and Middle East respiratory syndrome (MERS; 2012-ongoing) and hepatitis B and C (HBV and HCV) can be inactivated by AA, γ-linolenic acid (GLA, dihomo-GLA (DGLA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), which are precursors to several eicosanoids. Prostaglandin E1, lipoxin A4, resolvins, protectins and maresins enhance phagocytosis of macrophages and leukocytes to clear debris from the site(s) of infection and injury, enhance microbial clearance and wound healing to restore homeostasis. Bioactive lipids modulate the generation of M1 and M2 macrophages and the activity of other immunocytes. Mesenchymal and adipose tissue-derived stem cells secrete LXA4 and other bioactive lipids to bring about their beneficial actions in COVID-19. Bioactive lipids regulate vasomotor tone, inflammation, thrombosis, immune response, inactivate enveloped viruses, regulate T cell proliferation and secretion of cytokines, stem cell survival, proliferation and differentiation, and leukocyte and macrophage functions, JAK kinase activity and neutrophil extracellular traps and thus, have a critical role in COVID-19.

Keywords: COVID-19; SARS-CoV-2; bioactive lipids; essential fatty acids; inflammation; lipoxin A4; macrophages; maresins; polyunsaturated fatty acids; prostaglandins; protectins; resolvins.

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Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
A – Structure of SARS-CoV-2 that causes COVID-19. Note the structural similarity with swine flu virus given in Figure 1 B. B – Structure of the swine flu A/Mexico/09 (H1N1) virus. For comparison between influenza virus and coronavirus see Table II
Figure 2
Figure 2
Scheme showing the actions of ACE and ACE2 and their role in the regulation of blood pressure, humoral balance, inflammation, cell proliferation, hypertrophy, and fibrosis. The ACE/Ang /AT1R axis and the ACE2/Ang 1–7/MAS axis balance each other. Ang 1–7 is known to restore polyunsaturated fatty acid content of cells to normal especially in diabetes mellitus. Thus implies that there is a close interaction between Ang 1–7 and BALs and possibly some of the beneficial actions of Ang 1–7 on vascular tissue could be due to its actions on EFA metabolism (see Singh K, Singh T, Sharma PL. J Exp Pharmacol 2010: 2: 163-8. DOI: 10.2147/JEP.S14342)
Figure 3
Figure 3
A – Scheme showing the metabolism of essential fatty acids, their role in inflammation and cytoprotection of endothelial cells. Note that corticosteroids block the activity of PLA2, desaturases, COX-2 and LOX and thus cause EFA/PUFA deficiency and inhibit the formation of PGE2, LTs and of LXA4/resolvins, protectins and maresins. Statins enhance the activities of desaturases and increase the formation of GLA, DGLA, AA and of LXA4/resolvins/protectin/maresins. TNF-α and IL-6 decrease the activity of desaturases and thus decrease the formation of GLA, DGLA and AA but enhance the activity of COX-2 and thus cause EFA/PUFA deficiency but increase the formation of PGE2. TNF-α and IL-6 stimulate PLA2 and thus increase the release of AA from the cell membrane lipid pool. Thus, both corticosteroids and TNF-α and IL-6 cause an EFA/PUFA deficiency state but have opposite actions on PLA2 and PGE2 formation B – Scheme showing the relationship among SARS-CoV-2 and other enveloped virus induced events on EFA metabolism, pro- and anti-inflammatory cytokines and their modulation by steroids and statins. For details see text. Modified from Das UN. J Inflammation Res 3: 143-70
Figure 3
Figure 3
A – Scheme showing the metabolism of essential fatty acids, their role in inflammation and cytoprotection of endothelial cells. Note that corticosteroids block the activity of PLA2, desaturases, COX-2 and LOX and thus cause EFA/PUFA deficiency and inhibit the formation of PGE2, LTs and of LXA4/resolvins, protectins and maresins. Statins enhance the activities of desaturases and increase the formation of GLA, DGLA, AA and of LXA4/resolvins/protectin/maresins. TNF-α and IL-6 decrease the activity of desaturases and thus decrease the formation of GLA, DGLA and AA but enhance the activity of COX-2 and thus cause EFA/PUFA deficiency but increase the formation of PGE2. TNF-α and IL-6 stimulate PLA2 and thus increase the release of AA from the cell membrane lipid pool. Thus, both corticosteroids and TNF-α and IL-6 cause an EFA/PUFA deficiency state but have opposite actions on PLA2 and PGE2 formation B – Scheme showing the relationship among SARS-CoV-2 and other enveloped virus induced events on EFA metabolism, pro- and anti-inflammatory cytokines and their modulation by steroids and statins. For details see text. Modified from Das UN. J Inflammation Res 3: 143-70
Figure 4
Figure 4
A – Scheme showing potential interaction(s) among invading microbes including SARS-CoV-2, host cell (target tissue/cell), immunocytes including macrophages and bioactive lipids including GLA/DGLA/AA/EPA/DHA, LXA4, PGE2, lipid peroxides (LP), activity of PLA2 COX-2 and LOX enzymes, CO, NO, H2S, and soluble epoxide hydrolase (sEH) and their relationship to the ability of microbes to infect the host cell and the response of the host cell to infection. B – Similarly, potential interaction between tumor host cell (refers to surrounding normal cells present in the microenvironment of tumor) and the role of COX-2, LOX enzymes and the formation of PGE2/LXA4 and their effect(s) on tumor cell. Legend to Figure 4: A – When a microbe (including SARS-CoV-2) invades a normal cell (host cell), it may increase the production of PGE2 using its own (or host cell) COX-2. The microbe using its LPS or by activating host cell LOX enzymes leads to the formation of LXA4 that negates the synthesis or action of PGE2. Microbial infection activates immunocytes leading to release of IL-6 and TNF-α that enhance the production of NO, CO, H2S and other ROS that can kill the microbes. Microbes can also activate PLA2 that induces the release from the cell membrane lipid pool of AA/EPA/DHA that are utilized for the formation of PGE2, LXA4 and lipid peroxides. Depending on the stage of the inflammation initially there will be activation of iPLA2 (inducible phospholipase A2) that induces the release of AA that is directed to form PGE2 and activation of M1 resulting in inflammation. Once PGE2 levels reach a peak it triggers the activation of soluble PLA2 (sPLA2) and cytosolic PLA2 (cPLA2) inducing the release of a second wave of AA and simultaneously activation of LOX leading to the formation of LXA4 and M2. This results in suppression of inflammation and restoration of homeostasis. BALS especially AA/EPA/DHA/LXA4 and lipid peroxides kill the microbes including SARS-CoA2. Lipid peroxides, LXA4 and AA/EPA/DHA may inhibit the activity of soluble epoxide hydrolase that leads to suppression of inflammation. Mesenchymal stem cells (MSCs) produce LXA4 to bring about their beneficial actions. B – A similar set of events occurs in the presence of a tumor cell. There is a crosstalk between normal cells surrounding the tumor cell and immunocytes. Tumor cells have high COX-2 activity that may lead to increased formation of PGE2 (COX-2 of tumor cells may act on normal cells or on exposure to tumor cells normal cells may enhance their COX-2 activity). On exposure to the tumor cell, PLA2 of normal cells/immunocytes is activated to induce the release of AA/EPA/DHA to produce PGE2 or LXA4. If the released AA/EPA/DHA are converted to form excess lipid peroxides and/or LXA4, then tumor cell growth is inhibited or it undergoes apoptosis. If the activity of COX-2 dominates then AA is converted to PGE2 that induces immunosuppression and enhances tumor cell growth. IL-6 and TNF-α released by immunocytes induce the release of ROS that can enhance the formation of lipid peroxides to induce apoptosis of tumor cells. But both IL-6 and TNF-α can induce deficiency of AA/EPA/DHA in the tumor cells and surrounding normal cells and immunocytes by inhibiting the activities of desaturases. See text for further details.
Figure 5
Figure 5
Scheme showing M1 and M2 macrophages and various cytokines produced by them and their respective functions. DGLA, AA, EPA and DHA have anti-inflammatory actions and inhibit the production of pro-inflammatory TNF-α, IL-2 and IL-1 and facilitate the generation of M2 macrophages. PGE1 formed from DGLA, LXA4 from LXA4 are anti-inflammatory in nature. Resolvins (R), protectins (P), and maresins (M) formed from EPA and DHA are anti-inflammatory and block the production of TNF, IL-1, IL-2. PGE2, leukotrienes B4, D4 and E4 formed from AA are pro-inflammatory in nature. LXA4, resolvins, protectins and maresins inhibit the production of PGE2 and LTs. Leukotrienes (of 5 series) are also formed from EPA that have pro-inflammatory action but are much less potent compared to LTs formed from AA. EPA and DHA inhibit the production of PGE2
Figure 6
Figure 6
A – 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; the first phase is used for PGE2 synthesis, whereas the second phase is meant for LXA4 synthesis. Once PGE2 concentration reaches a peak, LXA4 synthesis is triggered, which induces resolution of inflammation. AA release is triggered by SARS-CoV-2 and other infections B – Scheme showing potential relationship among AA, PGE2, LXA4 and viral load in a COVID-19 patient who succumbs to the disease. Absence of biphasic nature of AA release and failure of PGE2 to reach a peak to trigger LXA4 synthesis that results in failure of resolution of inflammation (compare with Figure 7 A). DGLA, EPA and DHA (not shown in the figure) may have actions/functions like AA. Desaturases activities fall with age
Figure 6
Figure 6
A – 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; the first phase is used for PGE2 synthesis, whereas the second phase is meant for LXA4 synthesis. Once PGE2 concentration reaches a peak, LXA4 synthesis is triggered, which induces resolution of inflammation. AA release is triggered by SARS-CoV-2 and other infections B – Scheme showing potential relationship among AA, PGE2, LXA4 and viral load in a COVID-19 patient who succumbs to the disease. Absence of biphasic nature of AA release and failure of PGE2 to reach a peak to trigger LXA4 synthesis that results in failure of resolution of inflammation (compare with Figure 7 A). DGLA, EPA and DHA (not shown in the figure) may have actions/functions like AA. Desaturases activities fall with age
Figure 7
Figure 7
Scheme showing the metabolism of AA and how pro-inflammatory LTA4 can be converted to anti-inflammatory LXA4 by the action of PGE2. Similar conversion of pro-inflammatory PGs, TXs and LTs to anti-inflammatory resolvins, protectins and maresins may occur
Figure 8
Figure 8
Scheme of events that are likely to occur in SARS-CoV-2 infection and the two phases of cytokine response in COVID-19. Initially there will be hyperinflammation due to release of excess of pro-inflammatory cytokines. Subsequently there could occur diminished release of cytokines and immunosuppression. During the hyperinflammation phase dexamethasone and anti-TNF or anti-IL-6 and other cytokine antagonists will be helpful. Once immunosuppression sets in dexamethasone is not of significant help and inflammation resolution molecules are needed to enhance the recovery process. In severe COVID-19 there will be persistently elevated PGE2 and LXA4 fails to rise to induce resolution of inflammation. In contrast, in mild COVID-19, initially there will be an elevation in PGE2 that falls to the normal physiological level that is accompanied by increase in LXA4 to induce resolution of inflammation as shown in the figure. Compare this with Figure 9. This figure is modified from Das UN. Arch Med Sci 2014; 10: 325-35
Figure 9
Figure 9
Viral and host factors influence IFN response. When the viral burden is low, IFN production will be adequate to clear the viral infection effectively that is probably accompanied by an initial PGE2 response and timely LXA4 generation to resolve inflammation. When viral load is high, the virus itself may suppress IFN production and stimulate strong PGE2 and weak LXA4 responses, leading to severe COVID-19. The late onset IFN response may aggravate inflammation as seen in severe COVID-19. The PGE2 response may parallel the IFN response. AA release will occur in both mild and severe SARS-CoV-2 infection, but the products formed (PGE2 and LXA4) and their concentrations may differ as shown in the figure. Compare this with Figures 5 and 6
Figure 10
Figure 10
Scheme showing interaction among SARS-CoV-2, host cells, immunocytes, AA and cytokines. Similar interaction may exist among SARS-CoV-2, host cells/immunocytes, EPA/DHA and resolvins, protectins and maresins
Figure 11
Figure 11
Scheme showing potential involvement of bradykinin in severe COVID-19 as proposed by Garvin et al. (263) and how it could be modulated by BALs
See this image and copyright information in PMC

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