Stimulation of Inflammation Resolution May Avert Cytokine Storm and Improve Clinical Outcomes Associated with Current Pandemic, Prominent Researchers Proposed

As the current pandemic rages on, several hundred clinical trials are recruiting and ongoing hoping to identify efficacious antiviral and anti-inflammatory strategies. In a new commentary published in the journal Cancer Metastasis and Reviews (Springer Nature publishing group),¹ a group of prominent researchers proposed a promising, complementary direction worthy of consideration: targeting inflammation resolution.

Who contributed to this commentary?

The article was led by Dipak Panigrahy, MD, at Beth Israel Deaconess Medical Center of Harvard Medical School, who has had close collaboration with Professor Charles N. Serhan, PhD, DSc, (box below) from Brigham and Women’s Hospital at Harvard Medical School, Professor Sui Huang, MD, PhD, from Institute of Systems Biology, and Professor Bruce Hammock, PhD, of UCD Comprehensive Cancer Center at University of California, Davis, all of whom contributed to the commentary. Other authors included Molly M. Gilligan and Allison Gartung, PhD, from Beth Israel Deaconess Medical Center; Irene Cortés-Puch, MD, project scientist at Division of Pulmonary at UC Davis Medical Center; Richard P. Phipps, PhD, independent scholar; and Patricia J Sime, MD, Chair of the Department of Internal Medicine at Virginia Commonwealth University.¹

What did the authors hypothesize?

They hypothesized that controlling excessive pulmonary inflammation via stimulating the resolution of inflammatory responses is as important as antiviral therapies.¹

Serious respiratory viral infection causes massive lung cell destruction and cellular debris that activate inflammasome leading to excessive release of proinflammatory cytokines. Known as cytokine storm, it contributes to severe inflammation and systemic organ failure.²

Specialized pro-resolving mediators are biosynthesized to actively orchestrate key resolution events of acute inflammation. These bioactive compounds, such as resolvins, protectins, and maresins, promote macrophage clearance of cellular debris and counter the release of proinflammatory cytokines, thereby averting cytokine storm and allowing for tissue repair and healing.³

What existing research prompted the authors to propose the use of specialized pro-resolving mediators in the management of the current pandemic?

• In several infectious disease models, specialized pro-resolving mediators enhanced clearance of invading microbes including influenza virus and terminated inflammation.^3-6
• In a mouse model, the specialized pro-resolving mediator 17-hydroxydocosahexaenoic acid (17-HDHA) promoted B lymphocytic activity and increased production of antibodies against influenza virus.⁵
• The specialized pro-resolving mediator resolvin D2 (RvD2) inhibited the activation of NLRP3 inflammasome (the most clinically relevant inflammasome) in macrophages during the resolution process.⁷
• The specialized pro-resolving mediator protectin D1 (PD1) inhibited influenza viral replication in a model of human lung cells, and improved the survival and pathology of severe influenza in mice.⁶
• Thrombosis, a common consequence of infection including the current pandemic, is linked to poor patient outcome.^8,9 In a mouse model, the specialized pro-resolving mediator resolvin D4 (RvD4) facilitated inflammation resolution, attenuated pathologic thrombosis and promoted clot removal.¹⁰

How does stimulating inflammation resolution differ from classic anti-inflammation?

Targeting cytokine storm and the hyperinflammatory state as a result of severe viral infection has been challenging. Immunologists have expressed concerns that classic anti-inflammatory medications that aim to target overactive immune response may suppress immunity, delay the elimination of pathogens, and increase susceptibility to secondary infection.¹¹ Also, anti-inflammatory medications targeting individual pro-inflammatory cytokines may not target the right type of cytokines and may not be sufficient in preventing infection progression.¹¹

Authors of the commentary suggested that, by going further upstream to stimulate macrophage-mediated clearance of cellular debris, it may enhance inflammation resolution and may be more effective in countering excessive productions of pro-inflammatory cytokines, thereby averting the potentially fatal cytokine storm. Promoting inflammation resolution therefore may be a novel therapeutic approach to reduce acute respiratory distress syndrome (ARDs) and complications associated with the current pandemic.¹

View the abstract of the commentary

Citations 

1. Panigrahy D et al. Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19? Cancer Metastasis Rev. 2020:1-4.
2. Mehta P et al. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395:1033-1034.
3. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510:92-101.
4. Tam VC et al. Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation. Cell. 2013;154:213-227.
5. Ramon S et al. The specialized proresolving mediator 17-HDHA enhances the antibody-mediated immune response against influenza virus: a new class of adjuvant? J Immunol. 2014;193:6031-6040.
6. Morita M et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell. 2013;153:112-125.
7. Lopategi A et al. Frontline science: specialized proresolving lipid mediators inhibit the priming and activation of the macrophage NLRP3 inflammasome. J Leukoc Biol. 2019;105:25-36.
8. Beristain-Covarrubias N et al. Understanding infection-induced thrombosis: lessons learned from animal models. Front Immunol. 2019;10:2569.
9. Connors JM et al. COVID-19 and its implications for thrombosis and anticoagulation. Blood. 2020 [online ahead of print].
10. Cherpokova D et al. Resolvin D4 attenuates the severity of pathological thrombosis in mice. Blood. 2019;134:1458-1468.
11. Zhang W et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The perspectives of clinical immunologists from China. Clin Immunol. 2020;214:108393.