Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?

Abstract

Severe coronavirus disease is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophagemediated 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. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.

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“…The study on inflammation resolution of the cytokine and eicosanoid storm in COVID‐19 by Panigrahy et al [ 81] opened an opportunity for better understanding of the myriad of molecules involved in type II pneumocyte infection by SARS‐CoV‐2. The authors propose that cell death produces “cells debris” in alveoli and other tissues; such debris can activate an eicosanoid storm with prostaglandins and leucotrienes, which generate a strong inflammatory response in a matter of minutes.…”

“…The authors propose that cell death produces “cells debris” in alveoli and other tissues; such debris can activate an eicosanoid storm with prostaglandins and leucotrienes, which generate a strong inflammatory response in a matter of minutes. [ 81 This hyper‐inflammatory response may result from a deficit of adequate mechanisms for inflammation resolution. [ 81] The human body expresses endogenous pro‐resolution lipids with the goal of terminating the inflammatory reaction through clearance of cellular debris.…”

“…Specialized pro‐resolving mediators (SPMs) (Figure 3) include resolvins, lipoxins and protectins, which are bioactive lipid autacoids that mediate endogenous resolution through macrophage phagocytosis pathways and by countering the release of pro‐inflammatory cytokines/chemokines. [ 81] Downregulation of the inflammatory reaction caused by eicosanoid storm was previously observed in the resolution of infectious diseases such as influenza. [ 81] …”

“…[ 81] Downregulation of the inflammatory reaction caused by eicosanoid storm was previously observed in the resolution of infectious diseases such as influenza. [ 81] …”

“…SPM precursors include the 17‐hydroxydocosahexaenoic acid (17‐HDHA), a derivative of omega‐3 fatty acid. [ 81] Docosahexaenoic acid (DHA) is a primary structural component of the cerebral cortex, skin and retina. The enzyme CYP2C9 metabolizes DHA to epoxydocoapentanoic acids.…”