Nonsteroid Anti-İnflamatuvar İlaçlarla Alevlenen Hava Yolu Hastalığında (N-Erd) Platelet-Lökosit Kümelerinin Rolünün Araştırılması

Abstract

Nonsteroidal anti-inflammatory drug exacerbated respiratory disease (N-ERD) is a heterogeneous disease characterized by severe clinical symptoms in patients with severe asthma and chronic rhinosinusitis, as well as nasal polyp formation, following administration of aspirin and other selective nonsteroidal anti-inflammatory drugs. Clinical characteristics of the disease do not normally appear all at once at the outset of the condition, but rather evolve in a pattern. Due to the disease's limited awareness, the information regarding its prevalence is highly limited. However, the general population prevalence of N-ERD is estimated to be 7% in adult asthmatic patients and 15% in severe asthmatic patients. Inhibition of cyclooxygenase-1 (COX-1) enzyme activity occurs after aspirin and nonsteroidal anti-inflammatory drug (NSAID) intake in N-ERD patients. This condition occurs when arachidonic acid (AA) metabolism is shifted in the direction of 5-lipoxygenase (5-LO), resulting in an excessive rise in cysteinyl leukotrienes (CysLT), a potent lipid mediator. Furthermore, although the pro-inflammatory lipid mediator Prostaglandin D2 is critically higher in N-ERD patients, the level of prostaglandin E2, exerting anti-inflammatory activities, is significantly lower in the state of N-ERD disease. Recent studies draw attention to the presence of platelet-leukocyte aggregation in N-ERD patients. Platelets, which cannot produce CysLT alone under normal conditions, can bind to leukocytes through their surface receptors (P-selectin, GPIIb / IIIa (Glycoprotein CD41/CD61) and CD40 for platelets; P-selectin glycoprotein ligand 1 (PSGL-1), macrophage adhesion molecule-1 (Mac-1) and CD40 for leukocytes) and then these platelet-leukocyte aggregates can contribute CysLT production. Aspirin desensitization (AD) is the only targeted therapy available for N-ERD, an asthma phenotype characterized by mast cell activation and CysLT production; daily administration of aspirin following AD has resulted in a significant improvement in the clinical course of many patients. In a recent study, it was shown that 83.5% of N-ERD patients can tolerate desensitization without any major complications. Although aspirin desensitization and daily administration of high-dose aspirin are successful for most of the patients with N-ERD, this success cannot be achieved in all patients and other types of treatment are required. Furthermore, the effect of AD treatment on platelet-neutrophil aggregates in N-ERD patients, as well as the relevance of this effect to disease pathophysiology, is unknown. However, there are also studies in the literature that focus on alternative anti-platelet therapies and investigate the causes of platelet-leukocyte aggregates, which are important in the pathogenesis of N-ERD. Within the scope of this thesis study, we determined the frequencies of platelet-adherent neutrophils in whole blood of subjects with N-ERD patients with and without AD, and then we compared them to those found in the whole blood of ATA and healthy controls. The aim of this study is to investigate the involvement of platelet-neutrophil aggregates and potentially associated molecules with this aggregation in N-ERD pathogenesis and potential N-ERD-associated molecules. As a result of the studies, the level of platelet-derived 12-HETE, one of the AA metabolites, the percentage of platelet-neutrophil aggregates, the plasma levels of sP-selectin and PF4 were found to be significantly higher in N-ERD patients compared to healthy controls. In addition, the percentage of platelet-neutrophil aggregates was positively correlated with urinary LTE4 concentration. However, AD treatment administered to N-ERD patients did not change the percentage of platelet-neutrophil aggregates. Based on these findings, suppression of platelet activation in patients with N-ERD is thought to be a potential therapeutic target for disease pathogenesis.