Prostaglandin EP receptor agonists differentially modulate aspirin-induced generation of 15-HETE in aspirin-sensitive asthmatics

Abstract

Rationale Aspirin triggers generation of 15-hydroxyeicosaterraenoic acid (15-HETE) in peripheral blood leukocytes from aspirin-sensitive (AS) but not aspirin-tolerant (AT) patients with asthma/rhinosinusitis. The aim of this study was to determine the effect of prostaglandin EP receptor agonists (misoprostol and sulprostone) on aspirin-induced 15-HETE generation. Methods Peripheral blood leukocytes (PBLs) were isolated from AS and AT patients with asthma, and the 15-HETE release into the cell supernatant was measured with a specific immunoassay (Assay Design, MA). Results Incubation of PBLs from AS asthmatics with 200μM of lysine-aspirin significantly increased generation of 15-HETE (mean increase +260%) but lysine-aspirin did not affect 15-HETE generation in PBLs from AT asthmatics. Preincubation of cells with misoprostol or sulprostone did not affect basal 15-HETE in AS or AT patients. However, both misoprostol and sulprostone inhibited in a dose-dependent manner the ASA-induced increase in 15-HETE generation in AS asthmatics (maximal inhibition being 89% and 80% after misoprostol and sulprostone respectively). In contrast in AT patients preincubation of PBLs with misoprostol or sulprostone resulted in a significant increase in generation of 15-HETE after addition of 200μM lysine-aspirin. The maximal increase of 15-HETE generation was observed with 10 μg/ml of misoprostol or sulprostone (+73% and +86% respectively). Conclusions Our data suggest that aspirin-triggered 15-HETE release is differentially regulated by prostaglandin EP receptors in PBLs from AS and AT asthmatics.