Montelukast Inhibits Platelet Activation Induced by Plasma From COVID-19 Patients
Marina Camera, Paola Canzano, Marta Brambilla, G Enrico Rovati
Frontiers in Pharmacology, doi:10.3389/fphar.2022.784214
Leukotrienes are important pro-inflammatory lipid mediators derived from the arachidonic acid metabolism. In particular, cysteinyl leukotrienes, namely LTC 4 , LTD 4 , and LTE 4 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 LTE 4 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 TF pos -circulating microvesicles. These data suggest the repurposing of montelukast as a possible auxiliary treatment for COVID-19 syndrome.
ETHICS STATEMENT The studies involving human participants were reviewed and approved by the Ethical Committee of the institution (number 2020_06_16_18). The patients/participants provided their written informed consent to participate in this study.
AUTHOR CONTRIBUTIONS MC: helped in designing the study and was a major contributor in the discussion of results and the writing of the manuscript. PC and MB: performed the experiments and participated in writing the manuscript. GR: conceived the study and was a major contributor in the discussion of the data and in the writing of the manuscript.
SUPPLEMENTARY MATERIAL The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2022.784214/ full#supplementary-material Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's Note: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors, and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
Ackermann, Verleden, Kuehnel, Haverich, Welte et al., Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2015432Aigner, Pietrantonio, Bessa De Sousa, Michael, Schuster et al., The Leukotriene Receptor Antagonist Montelukast as a Potential COVID-19 Therapeutic, Front. Mol. Biosci,
doi:10.3389/fmolb.2020.610132Archambault, Zaid, Rakotoarivelo, Turcotte, Doré et al., High Levels of Eicosanoids and Docosanoids in the Lungs of Intubated COVID-19 Patients, FASEB J,
doi:10.1096/fj.202100540RArnardottir, Pawelzik, Öhlund Wistbacka, Artiach, Hofmann et al., Stimulating the Resolution of Inflammation through Omega-3 Polyunsaturated Fatty Acids in COVID-19: Rationale for the COVID-Omega-F Trial, Front. Physiol,
doi:10.3389/fphys.2020.624657Austen, Maekawa, Kanaoka, Boyce, The Leukotriene E(4) Puzzle: Finding the Missing Pieces and Revealing the Pathobiologic Implications, J. Allergy Clin. Immunol,
doi:10.1016/j.jaci.2009.05.046Barré, Sabatier, Annweiler, Montelukast Drug May Improve COVID-19 Prognosis: A Review of Evidence, Front. Pharmacol,
doi:10.3389/fphar.2020.01344Bäck, Powell, Dahlén, Drazen, Evans et al., Update on Leukotriene, Lipoxin and Oxoeicosanoid Receptors: IUPHAR Review 7, Br. J. Pharmacol,
doi:10.1111/bph.12665Bäck, Yurdagul, Tabas, Öörni, Kovanen, Inflammation and its Resolution in Atherosclerosis: Mediators and Therapeutic Opportunities, Nat. Rev. Cardiol,
doi:10.1038/s41569-019-0169-2Canzano, Brambilla, Porro, Cosentino, Tortorici et al., Platelet and Endothelial Activation as Potential Mechanisms behind the Thrombotic Complications of COVID-19 Patients, JACC: Basic Translational Sci,
doi:10.1016/j.jacbts.2020.12.009Capra, Ambrosio, Riccioni, Rovati, Cysteinyl-leukotriene Receptor Antagonists: Present Situation and Future Opportunities, Curr. Med. Chem,
doi:10.2174/092986706778742963Capra, Bäck, Barbieri, Camera, Tremoli et al., Eicosanoids and Their Drugs in Cardiovascular Diseases: Focus on Atherosclerosis and Stroke, Med. Res. Rev,
doi:10.1002/med.21251Chen, Hoiland, Stukas, Wellington, Sekhon, Confronting the Controversy: Interleukin-6 and the COVID-19 Cytokine Storm Syndrome, Eur. Respir. J,
doi:10.1183/13993003.03006-2020England, Abdulla, Biggs, Lee, Hay et al., Weathering the COVID-19 Storm: Lessons from Hematologic Cytokine Syndromes, Blood Rev,
doi:10.1016/j.blre.2020.100707Funk, Ardakani, A Novel Strategy to Mitigate the Hyperinflammatory Response to COVID-19 by Targeting Leukotrienes, Front. Pharmacol,
doi:10.3389/fphar.2020.01214Funk, Leukotriene Modifiers as Potential Therapeutics for Cardiovascular Disease, Nat. Rev. Drug Discov,
doi:10.1038/nrd1796Haeggström, Funk, Lipoxygenase and Leukotriene Pathways: Biochemistry, Biology, and Roles in Disease, Chem. Rev,
doi:10.1021/cr200246dHasegawa, Ichiyama, Hashimoto, Suzuki, Hirano et al., Functional Expression of Cysteinyl Leukotriene Receptors on Human Platelets, Platelets,
doi:10.3109/09537101003615394Heavey, Soberman, Lewis, Spur, Critical Considerations in the Development of an Assay for Sulfidopeptide Leukotrienes in Plasma, Prostaglandins,
doi:10.1016/0090-6980(87)90035-9Hoxha, Rovati, Cavanillas, The Leukotriene Receptor Antagonist Montelukast and its Possible Role in the Cardiovascular Field, Eur. J. Clin. Pharmacol,
doi:10.1007/s00228-017-2242-2Hoxha, Tedesco, Quaglin, Malaj, Pustina et al., Montelukast Use Decreases Cardiovascular Events in Asthmatics, Front. Pharmacol,
doi:10.3389/fphar.2020.611561Ingelsson, Yin, Bäck, Nationwide Cohort Study of the Leukotriene Receptor Antagonist Montelukast and Incident or Recurrent Cardiovascular Disease, J. Allergy Clin. Immunol,
doi:10.1016/j.jaci.2011.11.052Maeba, Ichiyama, Ueno, Makata, Matsubara et al., Effect of Montelukast on Nuclear Factor kappaB Activation and Proinflammatory Molecules, Ann. Allergy Asthma Immunol,
doi:10.1016/S1081-1206(10)61326-9Mamedova, Capra, Accomazzo, Gao, Ferrario et al., CysLT1 Leukotriene Receptor Antagonists Inhibit the Effects of Nucleotides Acting at P2Y Receptors, Biochem. Pharmacol,
doi:10.1016/j.bcp.2005.10.003Marchandot, Curtiaud, Trimaille, Sattler, Grunebaum et al., Vaccine-induced Immune Thrombotic Thrombocytopenia: Current Evidence, Potential Mechanisms, Clinical Implications, and Future Directions, Eur. Hear. J. Open,
doi:10.1093/ehjopen/oeab014Nishiga, Wang, Han, Lewis, Wu, COVID-19 and Cardiovascular Disease: from Basic Mechanisms to Clinical Perspectives, Nat. Rev. Cardiol,
doi:10.1038/s41569-020-0413-9Sala, Murphy, Voelkel, Sanghai, Tranmer, Taming the Cytokine Storm: Repurposing Montelukast for the Attenuation and Prophylaxis of Severe COVID-19 Symptoms, Drug Discov. Today,
doi:10.1016/j.drudis.2020.09.013Sokolowska, Rovati, Diamant, Untersmayr, Schwarze et al., Current Perspective on Eicosanoids in Asthma and Allergic Diseases: EAACI Task Force Consensus Report, Part I. Allergy,
doi:10.1111/all.14295Tahan, Jazrawi, Moodley, Rovati, Adcock, Montelukast Inhibits Tumour Necrosis Factor-Alpha-Mediated Interleukin-8 Expression through Inhibition of Nuclear Factor-kappaB P65-Associated Histone Acetyltransferase Activity, Clin. Exp. Allergy,
doi:10.1111/j.1365-2222.2008.02963.xTaus, Salvagno, Canè, Fava, Mazzaferri et al., Platelets Promote Thromboinflammation in SARS-CoV-2 Pneumonia, Arterioscler. Thromb. Vasc. Biol,
doi:10.1161/ATVBAHA.120.315175Woszczek, Chen, Alsaaty, Nagineni, Shelhamer, Concentration-dependent Noncysteinyl Leukotriene Type 1 Receptor-Mediated Inhibitory Activity of Leukotriene Receptor Antagonists, J. Immunol,
doi:10.4049/jimmunol.0900071Wu, Mcgoogan, Characteristics of and Important Lessons from the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases from the Chinese Center for Disease Control and Prevention, JAMA,
doi:10.1001/jama.2020.2648{ 'indexed': { 'date-parts': [[2023, 10, 24]],
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'abstract': '<jats:p>Leukotrienes are important pro-inflammatory lipid mediators derived from the '
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'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 '
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'cardiovascular diseases. As elevated levels of LTE<jats:sub>4</jats:sub> 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 TF<jats:sup>pos</jats:sup>-circulating microvesicles. '
'These data suggest the repurposing of montelukast as a possible auxiliary treatment for '
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'year': '2020',
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'year': '2020',
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'volume': '76',
'author': 'Sokolowska',
'year': '2021',
'journal-title': 'Allergy'},
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'first-page': '805',
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'Interleukin-8 Expression through Inhibition of Nuclear Factor-kappaB '
'P65-Associated Histone Acetyltransferase Activity',
'volume': '38',
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'DOI': '10.1161/ATVBAHA.120.315175',
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'volume': '40',
'author': 'Taus',
'year': '2020',
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