Inflammation Resolution:
A Dual-Pronged Approach to Averting Cytokine Storms in COVID-19?
Cancer and Metastasis Reviews
May 2020
Dipak Panigrahy, Molly M. Gilligan, Sui Huang, Allison Gartung, Irene Cortés-Puch, Patricia J. Sime, Richard P. Phipps, Charles N. Serhan, Bruce D. Hammock. These authors are from the Harvard Medical School and the University of California, Davis.
SOME BACKGROUND:
In his 2008 book How the Immune System Works, Lauren Sompayrac, PhD, notes that the Innate Immune system (phagocytosis system) “rules” the Adaptive Immune System (antibody producing system); And that the primary cell of the innate immune response is the macrophage (there is a great picture on the cover of his book of a macrophage attacking a bacterium).
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[Eicosa] is the Greek work for 20. Eicosanoids are hormone-like molecules that are synthesized from 20-carbon long polyunsaturated fatty acids. These fatty acids are classified as being either omega-6 or omega-3.
In their 1996 book Protein Power, physicians Michael and Mary Eades (MDs) state:
“Eicosanoids, a gang of at least 100 powerful hormone-like substances that control virtually all physiological actions in your body. The most important thing about eicosanoids is to keep them in balance.”
Eicosanoids “are the most powerful agents known to [hu]man, yet they are totally controlled by the diet.”
“Eicosanoids exert major effects on just about everything that goes on in the body.”
They continue to describe how the definition of health is one’s balance of inflammatory (bad) and anti-inflammatory (good) eicosanoids.
An important aspect of essential fatty acid biology is that the 20-carbon long omega-6 and omega-3 fatty acids are the precursors to a group of powerful but short-lived hormone-like compounds called “eicosanoids.” One category of eicosanoids is referred to as prostaglandins. Another group is referred to as leukotrienes. Clinical applications of this biochemistry are summarized here:
KEY POINTS FROM THIS ARTICLE:
1) “Severe coronavirus disease (COVID-19) caused by the SARS-CoV-2 virus is frequently characterized by pulmonary inflammation.”
2) “Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening ‘cytokine storms’.”
• “Life-threatening ‘cytokine storms’ involving the release of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1, IL-8, and MCP-1) may contribute to the rapid systemic organ failure observed in select critically ill COVID-19 patients.”
• “Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies.” [Important]
3) Eicosanoids play a critical role in the induction of inflammation and proinflammatory cytokine production . [Key Point]
• “SARS-CoV-2 may trigger a cell death (‘debris’)-induced ‘eicosanoid storm’, including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response.”
• “SARS-CoV-2 causes massive cell death and cellular debris that activates inflammasomes, which in turn trigger a macrophage-derived ‘eicosanoid storm’, a surge of pro-inflammatory bioactive lipid mediators, such as prostaglandins and leukotrienes, that fuels local inflammation.” [Key Point]
4) “A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of” resolvins which “resolve” inflammatory eicosanoids. [Key Point]
• Resolvins “counter pro-inflammatory cytokine production, a process called inflammation resolution.” [Key Point]
• Resolvins “and their lipid precursors [omega-3s] exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive.”
• Resolvins “also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19.”
• Other eicosanoid derived molecules stabilize arachidonic acid driven inflammation and activate anti-inflammatory processes “preventing the cytokine storm.”
• Resolvins and other eicosanoid derived molecules “attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection.”
• This resolution of inflammation in COVID-19 may reduce “acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation.”
• These anti-inflammatory strategies (“stimulating inflammation resolution”) may benefit COVID-19 management of “via debris clearance and inflammatory cytokine suppression.”
5) The resolution of inflammation is an active biochemical process, and hyperinflammation may result from a deficit in the active anti-inflammatory biochemical process.
• “Endogenous pro-resolution lipids [omega-3 fatty acids] can terminate the inflammatory response.”
6) Specialized pro-resolving inflammatory mediators including resolvins and other eicosanoid derived molecules “mediate endogenous resolution by stimulating macrophage phagocytosis of cellular debris and countering the release of proinflammatory cytokines/chemokines.”
• Loss of these inflammation resolution mechanisms will sustain pathologic inflammation.
7) Resolvins “promote anti-viral B lymphocytic activity in influenza, suggesting they may be a promising therapy for COVID-19.” [Important]
• Resolvins also “protect against primary influenza infection and promote adaptive immunity.”
8) Resolvins and other eicosanoid derived molecules “downregulate the transcription regulator NF-κB, the center of eicosanoid-induced cytokine storms, which promotes the induction of pro-inflammatory cytokines and prostaglandin synthesis via cyclooxygenase (COX).”
9) Resolvins and other eicosanoid derived molecules “terminate self-sustaining inflammatory processes, such as those induced by COVID-19, by broadly inhibiting proinflammatory cytokine production and promoting a return to tissue homeostasis.”
10) Resolvins and other eicosanoid derived molecules “act at significantly lower doses and are not immunosuppressive.” [Important Point]
• In contrast “conventional anti-inflammatory agents such as NSAIDs and COX-2 inhibitors, while limiting the eicosanoid storm, may be ‘resolution toxic’ as they indiscriminately inhibit eicosanoid pathways that produce resolution mediators and thereby prevent active resolution.”
[meaning they also inhibit the omega-3 eicosanoid pathways]
• Inhibiting the resolution mediator pathway with conventional anti-inflammatory agents such as NSAIDs and COX-2 inhibitors “may potentially facilitate COVID-19-induced tissue injury and progression of infection.” [A critical point: NSAIDs and COX-2 inhibitors may worsen the tissue injury and the progression of infection, which would include risk of death.]
11) “As demonstrated in many inflammatory disease models, selectively promoting endogenous inflammation resolution mechanisms clears inflammatory exudates more effectively and promotes a return to tissue homeostasis compared with classic anti-inflammatory agents [drugs].” [Key Point]
12) “Thus, activating endogenous resolution pathways [with omega-3 fatty acids] may be a novel therapeutic approach to limit severe organ damage and improve outcomes in COVID-19 patients.”
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This article generated this publication (in part) in the lay press:
BREAKING!
COVID-19 Supplements:
US Study Finds That Resolvins From Omega-3 Fatty Acids Could Prevent
COVID-19 Cytokine Storms
Thailand Medical News
May 13, 2020
“Resolvins are specialized pro-resolving mediators (SPMs) derived from omega-3 fatty acids, primarily eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).”
“Medical researchers from the Harvard Medical School, University of California-Davis, Virginia Commonwealth University and Institute for Systems Biology, Seattle have discovered that chemical molecules called resolvins … could help prevent the cytokine storms caused by the COVID-19 disease.”
“The research was published in the journal Cancer & Metastasis Reviews and the study was led by Assistant Professor Dr. Dipak Panigrahy and Dr. Molly Gilligan, both from Harvard Medical School.”
“The researchers studied the human body’s robust inflammatory response to the SARS-CoV-2 virus, which is now recognized as a hallmark symptom and observed that severe COVID-19 illness can result in excessive inflammation throughout the body, including the lungs, heart and brain.”
“Rather than blocking cytokines, medical staff could turn off virus-induced inflammation by broadly activating the body’s natural inflammation-clearing activities.”
“Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19.”
Dr. Gilligan notes, “We are now recognizing the importance of controlling this robust nflammatory response in COVID-19 infection in order to reduce associated organ damage and mortality.
Finding new ways to dampen the body’s inflammatory response to COVID-19 will likely be as important as finding effective antiviral therapies to control COVID-19 infection and reduce life-threatening organ damage. Moreover, these Resolvins have been found to be non-toxic and nonimmunosuppressive in ongoing clinical trials for other inflammatory diseases, making them even more promising candidates for rapid clinical translation.”
Among significant findings from the study are:
• A major effect of SARS-CoV-2 infection is a cytokine storm, which is a drastic increase in immune cell production of cytokines.
• COVID-19 disease can cause unchecked inflammation that can cause extensive organ damage, such as lung failure.
• Present therapeutic strategies in COVID-19 focus on inhibiting a single proinflammatory cytokine [with a drug] rather than broadly inhibiting the body’s inflammatory response.
• Resolvins are lipid mediators derived from omega-3 fatty acids and serve as the body’s natural “stop” signals to inflammation.
•• “The medical researchers found that increasing levels of these resolvins or lipid mediators in the body could be a new therapeutic approach to preventing life-threatening inflammation caused by SARS-CoV-2.”
•• “What is exciting for us is that these lipid mediators that ‘turn off,’ or resolve, inflammation are already in clinical trials for other inflammation-driven diseases, such as eye disease, periodontal disease and pain. The mediators can quickly be applied to turn off inflammation in COVID-19 patients.”
•• “What makes resolvins ideal is that there are basically derived from omega-3 fatty acids that are already proven safe for human consumption, are inexpensive, easily available and consumed.”
The article cautions “that if anyone suspects that they have contracted COVID-19 disease, do no attempt to self-treat but instead immediately report to local health authorities or a nearby hospital and also prior to consuming any supplements, always check first with a doctor.” And as this write-up is in NO WAY medical advice, I too recommend heading in to get checked if you have the symptoms.
COMMENTS FROM Dr. MacDonald:
Over the decades I have reviewed/read dozens of articles showing the health benefits of omega-3 fatty acids. Towards the end of last summer, I increased my intake of Omega-3 from about 3,000 mg daily to closer to 4,000-5,000 mg daily after reading the 2016 book “When Brains Collide: What Every Athlete and Parent Should Know About the Prevention and Treatment of Concussions and Head Injuries”, written by Michael D. Lewis, MD. But the reasons for that require another blog post.
This article adds that adequate levels of omega-3s may reduce the adverseness of the COVID-19 “eicosanoid and cytokine storms,” reducing symptoms, improving clinical outcomes, and possibly reducing deaths.
The bottom line is that this is another reason to take omega-3s, as eicosanoid balance is an important factor in optimizing host health.
My family and practice use the Nutri-West brand: 800-443-3333
See the summary graph below:
