Differential effects of aspirin and misoprostol on 15-hydroxyeicosatetraenoic acid generation by leukocytes from aspirin-sensitive asthmatic patients - 29/08/11

Doi : 10.1016/S0091-6749(03)01716-0

Marek L Kowalski, MD, PhD ^a,^⁎, Anetta Ptasinska, PhD ^a, Barbara Bienkiewicz, MD ^a, Rafal Pawliczak, MD, PhD ^a, Lawrence DuBuske, MD, PhD ^b
^a Department of Clinical Immunology and Allergy, Faculty of Medicine, Medical University of Lodz, Lodz, Poland
^b The Immunology Research Institute of New England, Boston, Mass, USA

Reprint requests: Marek L. Kowalski, MD, PhD, Department of Clinical Immunology and Allergy, Faculty of Medicine, Medical University, 251 Pomorska St, 92-213 Lodz, Poland

Abstract

Background

Although 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.

Objective

The 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).

Methods

Twenty-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.

Results

Unstimulated 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.

Conclusion

PBLs 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.

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Keywords : Aspirin sensitivity, 15-hydroxyeicosatetraenoic acid, asthma, misoprostol, leukotrienes, prostaglandins, lipoxins

Keywords : COX, 15-HETE, 15-LO, LTC₄, LXA₄, NSAID, PBL, PG

Esquema

Methods

Results

Basal and calcium ionophore–stimulated generation of eicosanoids

Effect of NSAIDs on PGE₂ generation

Effect of NSAIDs on 15-HETE generation

Differential effect of misoprostol on aspirin-induced 15-HETE generation in aspirin-sensitive and aspirin-tolerant patients

Effect of aspirin on generation of LXA₄ and LTC₄

Discussion

Supported in part by a grant from The Polish State Committee for Scientific Research 6P05B08921 and from The Immunology Research Institute of New England.