Jurado-Escobar, RaquelDoña, InmaculadaBogas-Herrera, GadorPérez-Sánchez, NataliaSalas, MaríaLaguna, José J.Muñoz-Cano, RosaMayorga, CristobalinaTorres, María J.Cornejo-García, José A.2022-09-262022-09-262020-11-20Jurado-Escobar R, Doña I, Bogas-Herrera G, Pérez-Sánchez N, Salas M, Laguna JJ, et al. Platelet-Adherent Leukocytes Associated With Cutaneous Cross-Reactive Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs. Front Pharmacol. 2020 Nov 20;11:594427http://hdl.handle.net/10668/4135Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most highly consumed drugs worldwide and the main triggers of drug hypersensitivity reactions. The most frequent reaction, named cross-reactive NSAID-hypersensitivity, is due to the pharmacological activity of these drugs by blocking the cyclooxygenase-1 enzyme. Such inhibition leads to cysteinyl-leukotriene synthesis, mainly LTE4, which are responsible for the reaction. Although the complete molecular picture of the underlying mechanisms remains elusive, the participation of platelet-adherent leukocytes (CD61+) and integrins have been described for NSAID-exacerbated respiratory disease (NERD). However, there is a lack of information concerning NSAID-induced urticaria/angioedema (NIUA), by far the most frequent clinical phenotype. Here we have evaluated the potential role of CD61+ leukocytes and integrins (CD18, CD11a, CD11b, and CD11c) in patients with NIUA, and included the other two phenotypes with cutaneous involvement, NSAID-exacerbated cutaneous disease (NECD) and blended reactions (simultaneous skin and airways involvement). A group NSAID-tolerant individuals was also included. During the acute phase of the reaction, the three clinical phenotypes showed increased frequencies of CD61+ neutrophils, eosinophils, and monocytes compared to controls, which correlated with urinary LTE4 levels. However, no correlation was found between these variables at basal state. Furthermore, increased expressions of CD18 and CD11a were found in the three CD61+ leukocytes subsets in NIUA, NECD and blended reactions during the acute phase when compared with CD61-leukocyte subpopulations. During the acute phase, CD61+ neutrophils, eosinophils and monocytes showed increased CD18 and CD11a expression when compared with CD61+ leukocytes at basal state. No differences were found when comparing controls and CD61+ leukocytes at basal state. Our results support the participation of platelet-adherent leukocytes and integrins in cutaneous cross-hypersensitivity to NSAIDs and provide a link between these cells and arachidonic acid metabolism. Our findings also suggest that these reactions do not involve a systemic imbalance in the frequency of CD61+ cells/integrin expression or levels of LTE4, which represents a substantial difference to NERD. Although further studies are needed, our results shed light on the molecular basis of cutaneous cross-reactive NSAID-hypersensitivity, providing potential targets for therapy through the inhibition of platelet-leukocyte interactions.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Nonsteroidal anti-inflammatory drugs-hypersensitivityCysteinyl-leukotrienesTranscellular metabolismPlatelet-adherent leukocytesIntegrinsNSAIDsHypersensitivityIntegrinasAntiinflamatorios no esteroideosHipersensibilidadUrticariaMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Eicosanoids::Arachidonic Acids::Leukotrienes::SRS-A::Leukotriene E4Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Multienzyme Complexes::Prostaglandin-Endoperoxide Synthases::Cyclooxygenase 1Medical Subject Headings::Chemicals and Drugs::Lipids::Fatty Acids::Fatty Acids, Unsaturated::Arachidonic Acids::Arachidonic AcidMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Amino Acids::Amino Acids, Sulfur::CysteineMedical Subject Headings::Chemicals and Drugs::Biological Factors::Inflammation Mediators::Autacoids::Eicosanoids::LeukotrienesMedical Subject Headings::Anatomy::Cells::Blood Cells::Leukocytes::Granulocytes::EosinophilsMedical Subject Headings::Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::MonocytesMedical Subject Headings::Anatomy::Hemic and Immune Systems::Blood::Blood Cells::Leukocytes::Granulocytes::NeutrophilsMedical Subject Headings::Diseases::Chemically-Induced Disorders::Drug-Related Side Effects and Adverse Reactions::Drug HypersensitivityMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Inflammatory Agents::Anti-Inflammatory Agents, Non-SteroidalMedical Subject Headings::Diseases::Skin and Connective Tissue Diseases::Skin Diseases::Skin Diseases, Vascular::UrticariaMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Anti-Inflammatory AgentsMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Membrane Proteins::Receptors, Cell Surface::Receptors, Immunologic::Integrinsresearch article33658935open accessLeucocitosAntiinflamatorios no esteroideosIntegrinasLeucotrieno E4FenotipoPlaquetas10.3389/fphar.2020.5944271663-9812PMC7919189