key: cord-1019418-pa6uecks
authors: Das, Undurti N.
title: Bioactive Lipids in COVID-19-Further Evidence
date: 2020-09-09
journal: Arch Med Res
DOI: 10.1016/j.arcmed.2020.09.006
sha: ef0e64ff6879f3c9025a146b551fc4a97bd06796
doc_id: 1019418
cord_uid: pa6uecks

Previously, I suggested that arachidonic acid (AA, 20:4 n-6) and similar bioactive lipids (BALs) inactivate SARS-CoV-2 and thus, may be of benefit in the prevention and treatment of COVID-19. This proposal is supported by the observation that (i) macrophages and T cells (including NK cells, cytotoxic killer cells and other immunocytes) release AA and other BALs especially in the lungs to inactivate various microbes; (ii) pro-inflammatory metabolites prostaglandin E2 (PGE2) and leukotrienes (LTs) and anti-inflammatory lipoxin A4 (LXA4) derived from AA (similarly, resolvins, protectins and maresins derived from eicosapentaenoic acid: EPA and docosahexaenoic acid :DHA) facilitate the generation of M1 (pro-inflammatory) and M2 (anti-inflammatory) macrophages respectively; (iii) AA, PGE2, LXA4 and other BALs inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) synthesis; (iv) mesenchymal stem cells (MSCs) that are of benefit in COVID-19 elaborate LXA4 to bring about their beneficial actions and (v) subjects with insulin resistance, obesity, type 2 diabetes mellitus, hypertension, coronary heart disease and the elderly have significantly low plasma concentrations of AA and LXA4 that may render them more susceptible to SARS-CoV-2 infection and cytokine storm that is associated with increased mortality seen in COVID-19. Statins, colchicine, and corticosteroids that appear to be of benefit in COVID-19 can influence BALs metabolism. AA, and other BALs influence cell membrane fluidity and thus, regulate ACE-2 (angiotensin converting enzyme-2) receptors (the ligand through which SARS-CoV2 enters the cell) receptors. These observations lend support to the contention that administration of BALs especially, AA could be of significant benefit in prevention and management of COVI-19 and other enveloped viruses.

systemic hyperinflammation (25,26) can also be attributed to their ability to block the formation of excess of pro-inflammatory PGE2 and leukotriene B4 (LTB4) from AA and cytokines.

Corticosteroids inhibit the activity of phospholipase A2 (PLA2) (thus, inhibit the release of AA and other PUFAs from the cell membrane), desaturases (that are needed for the conversion of dietary LA and ALA-AA and EPA and DHA respectively), and COX-2 and LOX enzymes leading to decreased formation of prostaglandins, leukotrienes and thromboxanes and thus, ameliorate inflammation. Thus, corticosteroids induce AA, EPA and DHA deficiency state due to their inhibitory action on desaturases. Corticosteroids also inhibit LXA4 synthesis (from AA) and possibly, resolvins, protectins and maresins (from EPA and DHA) due to their inhibitory action on CX-2 and LOX enzymes. The inhibitory action of corticosteroids on LXA4 is much stronger compared to its action on PGE2 and LTB4 synthesis (27). This results in suppression of inflammation but at the same time corticosteroids interfere with resolution of inflammation and wound healing process for which LXA4, resolvins, protectins and maresins are needed. Thus, corticosteroids have both beneficial and harmful actions: suppress acute inflammation and interfere with wound healing process. In the initial stages, corticosteroids suppress inflammation but as a result of AA/EPA/DHA deficiency and an imbalance between LTB4 vs. LXA4 can lead to impaired wound healing (12, (27) (28) (29) (30) . In addition, enhanced production of TNF-α and IL-6 seen during active COVID-19 also causes an EFA (PUFAs) deficiency state due to their inhibitory action on desaturases (14) . Hence, in order to bypass this block in the activity of desaturases and augment LXA4 formation supplementation of AA is needed that is known to enhance LXA4 little or no change in PGE2 formation (31) (32) (33) (34) . In such an EFA (PUFAs) deficiency state, AA supplementation results in inhibition of IL-6 and TNF-α synthesis, enhances the formation of LXA4ad suppresses PGE2 production and initiates the much-needed anti-inflammatory events and appropriate wound healing. This may explain why only 1/3 rd of those with COVID-19 showed J o u r n a l P r e -p r o o f response to dexamethasone since the other 2/3 rd might have had significant EFA (PUFAs) deficiency state, especially when they are sicker than those who responded to dexamethasone. Hence, it is suggested that a combined administration of dexamethasone + AA/EPA/DHA will be highly beneficial and more patients are likely to respond compared to dexamethasone alone. This argument is in tune with the recent observation that those with high plasma cortisol concentrations have increased mortality and a reduced median survival (35) , probably not only because of the severity of illness but also since they are likely to have significant reduction in the activity of desaturases, COX-2, LOX and PLA2 resulting in significant EFA (PUFAs) deficiency. This implies that these patients with high plasma cortisol levels may benefit from supplementation of AA and other PUFAs. This suggestion can be verified by measuring plasma concentrations of various PUFAs, PGs, LTs, LXA4, resolvins, protectins and maresins and various cytokines and correlating the same to plasma cortisol levels and the severity of the illness and their survival 5.

In addition to their inhibitory action on the expression of PLA2, COX-2, LOX, and desaturases glucocorticoids enhance the expression of annexin-1 (also called as lipocortin 1). Annexin-1 shows all the actions of glucocorticoids and induces the production of anti-inflammatory cytokine IL-10.

Annexin-1 suppresses the expression of TNF-α, IL-6, and other cytokines (36) . For the antiinflammatory action of annexin-1, there is an essential role for LXA4. Both LXA4 and/or annexin-1 seem to enhance the production of IL-10, which suppresses TNF-α action and the consequent tissue injury and lethality (37) . Thus, there is a complex and inter-dependent interaction among PLA2, COX-2, desaturases, annexin-1 and LXA4 in the anti-inflammatory action of corticosteroids ( Figure   3 ).

J o u r n a l P r e -p r o o f In general, it is believed that AA is pro-inflammatory in nature since it forms the precursor to PGE2, LTB4 and TXB2 which are pro-inflammatory molecules. Interestingly, LXA4, a potent antiinflammatory molecule, is also derived from AA. This implies that AA can have both pro-and antiinflammatory actions depending on the products that are formed from it in a given situation. In a systematic review of randomised controlled trials (RCT) of increased intake of AA by adults revealed that 80 and 2000 mg AA per day for 1-12 weeks did increase the AA content in different blood fractions with no adverse effects on blood lipids, platelet aggregation and blood clotting, immune function, inflammation or urinary excretion of AA metabolites (38) . These result are supported by other studies which showed that dietary supplementation with 1.5 g/d AA (n = 9, 24 ± 1.5 years) or placebo (n = 10, 26 ± 1.3 years) for 4 weeks did increase plasma content of AA and GLA accompanied by a decrease in LA, EPA and DGLA content in plasma compared to placebo.

Surprisingly, AA supplementation decreased the mRNA expression of the immune cell surface markers; neutrophil elastase/CD66b and IL-1β in peripheral blood mononuclear cells with no effect on immune cell markers or inflammatory cytokines, suggesting that AA supplementation is safe and does not increase basal systemic or intramuscular inflammation (39) .

Our studies revealed that alloxan and other chemicals-induced apoptosis of pancreatic β cells and type 1 diabetes mellitus can be prevented by various BALs, especially AA and is not dependent on its (AA) metabolism to PGs (prostaglandins), LTs (leukotrienes) or TXs (thromboxanes) suggesting that the fatty acid by itself is active. Of all the fatty acids tested, AA was found to be the best. In vivo studies showed that alloxan-induced type 1 diabetes mellitus can be prevented to some extent by all the fatty acids (especially GLA, DGLA, AA, EPA and DHA) but again of all, AA was found to be the most effective (Table 1) . It is noteworthy, alloxan-induced a significant decrease in the GLA, J o u r n a l P r e -p r o o f DGLA, and AA of n-6 series with inconsistence changes in EPA and DHA of n-3 series in the plasma, hepatic, and muscle tissues ( Table 2, and Supplementary Tables 1-3) . These changes reverted to normal in AA-treated animals in addition to amelioration of alloxan-induced type 1 diabetes mellitus (40) (41) (42) (43) (44) . In a further extension of these studies, it was noted that both alloxan and streptozotocin-induced apoptosis of RIN (rat insulinoma pancreatic β) cells and alloxan and streptozotocin (STZ)-induced type 1 and type 1 and type 2 diabetes mellitus respectively in Wistar rats could be completely prevented by AA and its anti-inflammatory metabolite lipoxin A4 (LXA4) (45) (46) (47) (48) . It was noted that STZ-induced increase in plasma pro-inflammatory cytokines IL-6 and TNF-α levels and enhanced expression of pro-inflammatory genes NF-kB and COX-2 and iNOS can be suppressed by AA and LXA4 ( Supplementary Figures 1-4 ) in addition to their (AA and LXA4) ability to prevent development of diabetes mellitus (45) (46) (47) (48) . It is noteworthy that both COX-2 (cyclioxygenase-2) and LOX (lipoxygenase) inhibitors did not block the beneficial actions of AA against STZ-induce type 1 and type 2 diabetes mellitus. This suggests that PGs LTs and TXs are not involved in the beneficial actions of AA (41) (42) (43) (44) . These results also indicate that the COX and LOX inhibitors used in our study cannot block the activity of these enzymes completely and minimal activity of these enzymes is sufficient to augment LXA4 formation from AA used these studies (41) (42) (43) (44) (45) . In addition, it was also noted that resolvins and protectins, anti-inflammatory metabolites of EPA and DHA, though were effective in preventing cytotoxic action of alloxan and STZ in vitro and type 1 and type 2 diabetes mellitus in vivo, were still much less effective compared to AA and LXA4 (45, and unpublished data). These results emphasize the anti-inflammatory actions of AA and LXA4 compared to received anti-inflammatory BALs such as EPA and DHA, resolvins and protectins. It is noteworthy that oral AA supplementation is as effective as that of i.p. method of delivery in preventing the development of both type 1 and type 2 diabetes mellitus in experimental animals that J o u r n a l P r e -p r o o f was accompanied by restoration of decreased LXA4 to normal (46) (47) (48) . These results suggest that oral supplementation of AA is adequate to prevent chemical-induced diabetes mellitus that was accompanied by formation of LXA4 in adequate amounts (45) . Based on these results, it can be proposed that pro-inflammatory stimuli induced increase in the formation of PGE2 and decreased levels of LXA4 (as revealed by our studies with alloxan and STZ-induced diabetes studies) and increased expression of NF-kB, COX-2, iNOS and plasma and tissue levels of IL-6 and TNF-α can be suppressed and restored to normal by AA (40) (41) (42) (43) (44) (45) (46) (47) (48) (49) . Thus, AA need to be considered as a potent endogenous anti-inflammatory and cytoprotective molecule, at least in part, due to its ability to give rise to LXA4.

It has been suggested that increased consumption of dietary LA and ALA (that are essential fatty acids) might increase the formation of their long-chain metabolites such as AA (from LA) and EPA and DHA (from ALA) respectively. This is unlikely to happen since only a small percentage of dietary LA and ALA are converted to AA and EPA and DHA due to low activity of desaturase enzymes. It is known that no more than 5% of consumed ALA is converted to EPA and approximately <0.5% to DHA, whereas the formation of AA in many tissues is no more than 0.5% of the total consumed LA (50) . In view of this, it is imperative that to overcome the deficiency of GLA, DGLA, AA, EPA and DHA in many diseases it is necessary to provide GLA/DGLA/AA/EPA/DHA directly.

There is evidence to suggest that COVID-19 is associated with exacerbated oxidative stress (51-56).

Nox2 is activated whenever there is excess production of reactive oxidant species that leads to J o u r n a l P r e -p r o o f enhanced oxidative stress. Several RNA viruses are known to activate Nox2. In patients with COVID-19, Nox2 activation has been reported with much higher Nox2 activation in those with thrombotic events compared to those who did not have thrombotic events suggesting that oxidative stress is present in those with severe disease and thrombotic events. The high neutrophil to lymphocyte ratio observed in critically ill patients with COVID-19 is likely to be another reason for excessive levels of reactive oxygen species (ROS) in them. It is possible that enhanced ROS generation may promote a cascade of biological events that could induce tissue damage, thrombosis and red blood cell dysfunction seen in COVID-19. These results are supported by the finding that activation of Nrf2, a transcription factor that regulates cellular redox balance and the expression of genes involved in immunity and inflammation, downregulates ACE2 and TMPRSS2 mRNA expression, including IL-1-beta, IL-6, TNF-α, the cell adhesion molecules ICAM-1, VCAM-1, and Eselectin, and a group of IFN-γ-induced genes. Many of these cytokines are involved in the development of "cytokine storm" that is responsible for increased fatality in COVID- 19 . This suggests that in fatal cases of COVID-19 Nrf2 activation is impaired and its activation may be of significant benefit in this condition (55). In fact, the potential involvement of ROS and oxidative stress in COVID-19 led to the suggestion that elderly age subjects, and patients with diabetes mellitus, hypertension, cardiovascular disease, and autoimmune diseases such as lupus and rheumatoid arthritis (RA) are at higher risk of mortality since they already have increased oxidative stress (57) ( Table 3 ). Based on the results presented in Supplementary Figures 1-4 , it is evident that both AA and LXA4 have potent anti-inflammatory actions by virtue of their ability to inhibit the production of IL-6 and TNF-α; inhibit iNOS, NF-kB, and COX-2 and enhance NRF2 genes expression and thus, suppress oxidative stress that may account for their (AA and LXA4) potential beneficial action in COVID-19 as suggested previously (1, 2) . Our earlier studies showed that AA and J o u r n a l P r e -p r o o f LXA4 can restore altered antioxidant enzymes due to alloxan and STZ to normal (40) (41) (42) (43) (44) (45) (46) (47) (48) lending further support to the suggestion that these two BALs (AA and LXA4) and possibly, other BALs have potent antioxidant actions as well (40) (41) (42) (43) (44) (45) (46) (47) (48) 58) .

In this context, it is noteworthy that both innate immunity and adaptive immunity are modulated by BALs. Innate immunity (also called natural or native immunity) is responsible for the early line of defense against microbes. It consists of cellular and biochemical defense mechanisms and responds rapidly to infections. Some of the principal components of innate immunity include: (i) physical and chemical barriers, such as epithelia and antimicrobial chemicals produced at epithelial surfaces. As already discussed above (7-13), BALs could be secreted by epithelial cells to inactivate SARS-CoV-2; (ii) neutrophils, macrophages, dendritic cells, and natural killer (NK) cells and other innate lymphoid cells phagocyte microbes (including SARS-CoV-2); (iii) members of the complement system and other mediators of inflammation.

In contrast to this, adaptive immunity (also called specific or acquired immunity) system recognizes and reacts to microbial and nonmicrobial substances. Adaptive immunity distinguishes different substances and responds more vigorously to repeated exposures to the same microbe, known as memory. The major components of adaptive immunity are lymphocytes and antibodies. Innate immunity is activated when pattern recognition receptor(s) (PRR) are activated that recognize different types of microbes including viruses that leads to their phagocytosis and release of interferons (IFNs). Adaptive immunity is based on the special properties of lymphocytes (T and B cells) that respond selectively to non-self-antigens resulting in the development of specific memory. 

The recent report (66) that GM-CSF (granulocyte-macrophage-colony stimulating factor) blockade with mavrilimumab in severe COVID-19 pneumonia and systemic hyperinflammation is beneficial can also be explained in terms of their action on BALs. GM-CSF is a potent stimulant of LTB4 J o u r n a l P r e -p r o o f production and inducer of AA release (67, 68) . Hence, when GM-CSF action is blocked by mavrilimumab, the induced release of AA is utilized for the production of LXA4 that, in turn, induces its (mavrilimumab) ant-inflammatory action (68) . Similarly, the beneficial action of colchicine reported in COVID-19 (69) can also be explained in terms of its action on BALs. Colchicine is known to modulate the metabolism of BALs such as enhancement in the action of PGE1 (70, 71) . The property of colchicine to potentiate the actions of PGE1 is especially interesting since both PGE1 and LXA4 have similar actions (Table 6) .

A recent report indicated that circulating levels of IL-2, IL-4, TNF-α, IFN-γ and C-reactive protein may not be associated with severity of COVID-19 symptoms. This implies that there are two phases in the pathobiology of COVID-19, the first one is characterized by hyperinflammation that may happen in the beginning of COVID-19 and the second phase could result in immunosuppression with little or no change in the levels of pro-inflammatory cytokines as n in sepsis (72, 73) . This suggests that one need to measure plasma levels of various cytokines in order to establish whether COVID-19 is in the first or the second phase and accordingly tailor the administer dexamethasone, anti-cytokine, and other therapies. Hence, one need to exercise caution in rushing to administer immunosuppressive therapies without measuring plasma cytokines levels ( Figure 6 ).

It is evident from the preceding discussion that BALs (Tables 3 and 4 ). The higher degree of morality due to COVID-19 seen in those with diabetes mellitus, hypertension and coronary heart disease can also be attributed to their deficiency of GLA, DGLA, AA, ALA, EPA and DHA ( Table 5 ).

The less frequent and mild disease seen in children and decreased incidence of COVID-19 in women can be ascribed to relatively higher amounts of BALs in them, especially of AA and LXA4. For instance, the activity of desaturases decreases with age whereas children have a relatively higher activity of desaturases ( Figure 6 ), whereas estrogen stimulates LXA4 synthesis (74) (75) (76) (77) . Thus, it is anticipated that children have a higher capacity to generate GLA, DGLA, AA, EPA and DHA that can be converted to form beneficial LXA4, resolvins, protectins and maresins to fight SARS-CoV-2.

On the other hand, pre-menopausal women generate significantly higher amounts of LXA4 due to the stimulatory action of estrogen and thus, are resistant and less likely to develop severe COVID-19.

The observation that when human cells are exposed to SARS-Co-V-2 and/or human coronavirus 229E (HCoV-229E), they release large amounts of AA and LA and both these fatty acids inactivate J o u r n a l P r e -p r o o f the viruses (Figures 1, and 2) (21,22) implies that activation of PLA2 in order to release sufficient amounts of AA and LA is of paramount importance. Adequate activity of PLA2 is needed not only to release appropriate amounts of DGLA/AA/EPA/DHA to inactivate SARS-CoV-2 but also to trigger formation of PGE2 for the initial inflammation and LXA4 for subsequent resolution of inflammation.

In the event the cells are deficient in these fatty acids, the virus replicates and produces COVID-19 lending direct support to the proposal that BALs have a significant role in the pathobiology of SARS-CoV-2 and other corona virus-induced diseases (1, 2) . It is known that deficiency of AA/EPA/DHA (especially that of ALA, the precursor of EPA and DHA) enhances the expression of angiotensin-II receptors (78, 79) , which serves as a receptor for SARS-CoV-2 (80). It is evident from the data presented in Supplementary Figures 1-4 It is evident from these results that though all fatty acid effective to some extent in preventing alloxan-induced type 1 diabetes mellitus, AA is the most effective. This data is taken from ref. 45. J o u r n a l P r e -p r o o f All values are expressed as mean ±SE (n = 10). a p <0.05 compared to untreated control; b p <0.05 compared to alloxan group.

It is evident from this data that in alloxan treated Wistar animals there is a significant decrease in the plasma levels of LA, GLA, DGLA and AA that were restored to normal in alloxan + AA treated animals. There were no significant alterations in n-3 fatty acids (ALA, EPA) except that DHA was significantly increased in alloxan treated animals that was restored to normal in alloxan + AA treated animals. This data is taken from ref. 44. J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f is suboptimal and hence, the recovery process is delayed or not seen. Due to the absence of negative feedback control exerted by AA (due to the absence of second phase of release of AA), IL-6 and TNF levels continue to remain high and usher in cytokine storm and consequent mortality. It is predicted that as the viral load increases so also the plasma levels of PGE2. But, once PGE2 reaches its peak, it triggers the generation of LXA4 to initiate the resolution of inflammation simultaneously with a decrease in pro-inflammatory cytokines. To achieve this aim of initial increase in PGE2 levels and subsequent enhancement of LXA4 production, there could occur two phases of release of DGLA/AA/EPA/DHA from the cell membrane lipid pool (as shown in Figure 6A ) that is not seen in those with severe COVID-19. This failure of biphasic phase of release of DGLA/AA/EPA/DHA leads to heightened mortality. As a result, PGE2 fails to reach its peak to trigger LXA4 synthesis it leads to failure of resolution of inflammation. Plasma IL-6 and TNF levels increase in parallel with J o u r n a l P r e -p r o o f

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