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      A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes

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          SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) has wreaked havoc during the global pandemic of 2020 infecting millions and leaving over a half million dead. As a new virus, not previously in the human population, but with similarities to other coronaviruses causing severe acute respiratory distress syndrome (SARS/ARDS), and no known treatments, the race to re-purpose existing drugs and to enlist novel therapeutics is underway. In the half-year since the first cases, we have acquired substantial knowledge of this virus and the clinical course of COVID-19 progression. Results from early clinical trials have revealed two treatments (remdesivir, dexamethasone) that mitigate disease progression but clearly, there is much room for improvement. Initial case reports indicated many succumb to COVID-19 of hypoxic respiratory failure due to ARDS. However, ensuing studies revealed an atypical, immune cell-sequestered, vasculature-inflamed state leading to multiorgan thrombotic complications and end organ failure likely due to hyperinflammatory host responses. This Perspective focuses on a potential mechanism for a key COVID-19 disease progression turning point related to vascular and airway inflammation. The leukotriene lipid mediators have been overlooked with discussion centering on cytokine storms unleashing the deadly form of COVID-19. Leukotrienes possess some of the most potent known activities on immune cell trafficking and vascular leakage. We offer a simple treatment paradigm using two generic drugs targeting the hyperinflammatory response that characterizes the turning point from mild to severe/critical COVID-19 by targeting leukotriene biosynthesis with zileuton (Zyflo ® controlled release formulation) and antagonism of the cysteinyl leukotriene 1 receptor with montelukast (Singulair ®).

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          Most cited references 50

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          Leukotrienes and lipoxins: structures, biosynthesis, and biological effects

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            Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes.

            Arachidonic acid is metabolised either by cyclooxygenases to produce prostaglandins and thromboxanes or by lipoxygenases to produce mono-, di- and trihydroxyeicosatetraenoic acids (HETEs). Polymorphonuclear leukocytes (PMNs) release HETEs, including mono- and dihydroxy fatty acids, when exposed to stimuli such as the calcium ionophore A23187 (refs 1, 2). The mono-HETEs are assumed to be of particular importance with respect to effects on leukocyte function because they have been shown to possess both chemotactic and chemokinetic activities towards PMNs and eosinophils. However, we have now shown that the chemokinetic and aggregating activities released from rat and human PMNs exposed to ionophore A23187 (ref. 5) are not due to the release of mono-HETEs but to that of 5, 12-di-HETE (leukotriene B). This compound is active over the concentration range 10 pg ml-1 to 5 ng ml-1.
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              Leukotriene B4 receptor BLT1 mediates early effector T cell recruitment.

              Leukotriene B4 (LTB4) was originally described as a potent lipid myeloid cell chemoattractant, rapidly generated from innate immune cells, that activates leukocytes through the G protein-coupled receptor BLT1. We report here that BLT1 is expressed on effector CD4+ T cells generated in vitro as well as in vivo when effector T cells migrate out of the lymphoid compartment and are recruited into peripheral tissues. BLT1 mediated LTB4-induced T helper type 1 (T(H)1) and T(H)2 cell chemotaxis and firm adhesion to endothelial cells under flow, as well as early CD4+ and CD8+ T cell recruitment into the airway in an asthma model. Our findings show that the LTB4-BLT1 pathway is involved in linking early immune system activation and early effector T cell recruitment.

                Author and article information

                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                06 August 2020
                06 August 2020
                : 11
                1Department of Biomedical and Molecular Sciences, Queen’s University , Kingston, ON, Canada
                2Scientific Research Division, Novateur Ventures Inc. , Vancouver, BC, Canada
                Author notes

                Edited by: Dieter Steinhilber, Goethe University Frankfurt, Germany

                Reviewed by: G.Enrico Rovati, University of Milan, Italy; Oliver Werz, Friedrich Schiller University Jena, Germany

                *Correspondence: Colin D. Funk, funkc@ 123456queensu.ca

                This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

                Copyright © 2020 Funk and Ardakani

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 79, Pages: 8, Words: 3330


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