Montelukast Inhibits Platelet Activation Induced by Plasma From COVID-19 Patients.

Marina Camera,Paola Canzano,Marta Brambilla,G Enrico Rovati

doi:10.3389/fphar.2022.784214

Marina Camera, Paola Canzano + Show 2 more

Open Access

https://doi.org/10.3389/fphar.2022.784214

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Abstract

Leukotrienes are important pro-inflammatory lipid mediators derived from the arachidonic acid metabolism. In particular, cysteinyl leukotrienes, namely LTC4, LTD4, and LTE4 are involved in many of the principal features of asthma, while more recently they have also been implicated in cardiovascular diseases. COVID-19 is characterized by an overwhelming state of inflammation, sometimes resulting in an acute respiratory distress syndrome. Furthermore, severe COVID-19 patients present an endothelial cell damage characterized by a hyperinflammatory/procoagulant state and a widespread thrombotic disease. Leukotriene receptor antagonists, such as montelukast, have long been proven to have an efficacy in asthma, while more recently they have been suggested to have a protective role also in cardiovascular diseases. As elevated levels of LTE4 have been detected in bronchoalveolar lavage of COVID-19 patients, and montelukast, in addition to its anti-inflammatory properties, has been suggested to have a protective role in cardiovascular diseases, we decided to investigate whether this drug could also affect the platelet activation characteristic of COVID-19 syndrome. In this contribution, we demonstrate that montelukast inhibits platelet activation induced by plasma from COVID-19 patients by preventing the surface expression of tissue factor (TF) and P-selectin, reducing the formation of circulating monocyte– and granulocyte–platelet aggregates, and, finally, in completely inhibiting the release of TFpos-circulating microvesicles. These data suggest the repurposing of montelukast as a possible auxiliary treatment for COVID-19 syndrome.

Highlights

Leukotrienes (LTs) are important pro-inflammatory lipid mediators derived from the metabolism of the arachidonic acid
Plasma from COVID-19 patients significantly increased the number of TFpos- and P-selectinpos-platelets (Figure 1) and the formation of total and TFpos platelet–monocyte and platelet–granulocyte aggregates (Figure 2) as well as the release of total and plateletderived TFpos circulating MVs (Figure 3), highlighting the marked prothrombotic phenotype associated with both TFbearing cells and MVs
Preincubation of healthy subjects (HS) platelets with montelukast concentration dependently prevented the induction of TFpos- and P-selectinpos-platelets by COVID-19 plasma, being both completely inhibited at 1 μM (Figure 1)

Summary

Introduction

Leukotrienes (LTs) are important pro-inflammatory lipid mediators derived from the metabolism of the arachidonic acid. Cysteinyl leukotrienes (cysteinyl-LTs), namely LTC4, LTD4, and LTE4 are synthesized in vivo by immunocompetent cells such as mast cells, eosinophils, basophils, and monocytes/macrophages (Haeggstrom and Funk, 2011). They are involved in many principal features of asthma, such as bronchoconstriction, hyperresponsiveness, and inflammatory cell recruitment (Sokolowska et al, 2021); more recently, they have been implicated in other. The biological actions of cysteinyl-LTs are mediated by two officially recognized G-protein-coupled receptors: CysLT1 and CysLT2. They differ in localization and binding affinities for the different cysteinyl-LTs as well as in their biological activities (Back et al, 2014)

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