Jurado-Escobar Raquel, Doña Inmaculada, Bogas-Herrera Gador, Pérez-Sánchez Natalia, Salas María, Laguna José J, Muñoz-Cano Rosa, Mayorga Cristobalina, Torres María J, Cornejo-García José A
Allergy Research Group, Instituto de Investigación Biomédica de Málaga-IBIMA, Malaga, Spain.
Departamento de Medicina, Universidad de Málaga, Malaga, Spain.
Front Pharmacol. 2020 Nov 20;11:594427. doi: 10.3389/fphar.2020.594427. eCollection 2020.
Nonsteroidal 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 CD61leukocyte 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.
非甾体抗炎药（NSAIDs）是全球消费最为广泛的药物之一，也是药物过敏反应的主要诱因。最常见的反应，即交叉反应性非甾体抗炎药超敏反应，是由于这些药物通过阻断环氧化酶-1酶的药理活性所致。这种抑制作用会导致半胱氨酰白三烯的合成，主要是白三烯E4（LTE4），它是引发该反应的原因。尽管潜在机制的完整分子图景仍不明确，但血小板黏附白细胞（CD61）和整合素在非甾体抗炎药加重的呼吸道疾病（NERD）中的作用已有描述。然而，关于非甾体抗炎药诱发的荨麻疹/血管性水肿（NIUA），这是迄今为止最常见的临床表型，却缺乏相关信息。在此，我们评估了CD61白细胞和整合素（CD18、CD11a、CD11b和CD11c）在NIUA患者中的潜在作用，并纳入了另外两种有皮肤受累的表型，即非甾体抗炎药加重的皮肤疾病（NECD）和混合反应（皮肤和气道同时受累）。还纳入了一组对非甾体抗炎药耐受的个体。在反应的急性期，与对照组相比，这三种临床表型的CD61中性粒细胞、嗜酸性粒细胞和单核细胞频率增加，且与尿LTE4水平相关。然而，在基础状态下，这些变量之间未发现相关性。此外，与CD61白细胞亚群相比，在急性期，NIUA、NECD和混合反应的三个CD61白细胞亚群中CD18和CD11a的表达增加。在急性期，与基础状态下的CD61白细胞相比，CD61中性粒细胞、嗜酸性粒细胞和单核细胞的CD18和CD11a表达增加。在比较基础状态下的对照组和CD61白细胞时未发现差异。我们的结果支持血小板黏附白细胞和整合素参与对非甾体抗炎药的皮肤交叉超敏反应，并为这些细胞与花生四烯酸代谢之间提供了联系。我们的研究结果还表明，这些反应并不涉及CD61细胞频率/整合素表达或LTE4水平的系统性失衡，这与NERD有很大不同。尽管还需要进一步研究，但我们的结果揭示了皮肤交叉反应性非甾体抗炎药超敏反应的分子基础，通过抑制血小板-白细胞相互作用为治疗提供了潜在靶点。
