Differential Effects of Aspirin and Misoprostol on 15-Hydroxyeicosatetraenoic Acid Generation by Leukocytes from Aspirin-Sensitive Asthmatic Patients

Abstract

BackgroundAlthough the mechanisms of aspirin-induced rhinosinusitis-asthma appear to be related to arachidonic acid abnormalities, only recently has a specific aspirin-triggered enhancement of 15-hydroxyeicosatetraenoic acid (15-HETE) generation in nasal polyp epithelial cells from aspirin-sensitive patients been demonstrated.ObjectiveThe aim of this study was to assess generation of 15-HETE and other eicosanoids by peripheral blood leukocytes (PBLs) from aspirin-sensitive and aspirin-tolerant asthmatic patients and modulation of 15-HETE generation by a prostaglandin (PG) E1 analogue (misoprostol).MethodsTwenty-four aspirin-sensitive patients with asthma-rhinosinusitis and 18 aspirin-tolerant asthmatic patients were studied, and eicosanoids released from PBLs were assessed by means of enzyme immunoassays.ResultsUnstimulated PBLs from aspirin-sensitive and aspirin-tolerant patients generated similar amounts of PGE2, leukotriene C4, and 15-HETE, but lipoxin A4 release was significantly less in aspirin-sensitive patients (300 ± 70 pg/mL) in comparison with that seen in aspirin-tolerant patients (690 ± 100 pg/mL, P < .05). Cell incubation with 2, 20, or 200 μmol/L aspirin resulted in a dose-dependent increase in 15-HETE generation (mean change of +85%, +189%, and +284% at each aspirin concentration, respectively) only in aspirin-sensitive asthmatic patients. Naproxen stimulated 15-HETE generation in aspirin-sensitive asthmatic patients, but indomethacin or specific COX-2 inhibitors (NS-398 and celecoxib) did not affect 15-HETE release. A synthetic PGE1 analogue (misoprostol) inhibited aspirin-induced 15-HETE release but enhanced 15-HETE generation by aspirin in leukocytes from aspirin-tolerant patients. After preincubation with misoprostol, aspirin induced a dose-dependent production of lipoxin A4 in both groups.ConclusionPBLs from patients with aspirin-sensitive rhinosinusitis-asthma might be specifically triggered by aspirin to generate 15-HETE. Metabolism of 15-HETE is differentially regulated by misoprostol in aspirin-tolerant and aspirin-sensitive asthmatic patients.