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Clinical & Experimental Allergy

Involvement of 15-lipoxygenase and prostaglandin EP receptors in aspirin-triggered 15-hydroxyeicosatetraenoic acid generation in aspirin-sensitive asthmatics

Authors


Correspondence:
Marek L. Kowalski, Department of Immunology, Rheumatology and Allergy, Faculty of Medicine, Medical University of Lodz, 251 Pomorska Str., 92-215 Lodz, Poland. E-mail: Marek.Kowalski@csk.umed.lodz.pl

Summary

Background The mechanism of aspirin (acetylsalicylic acid: ASA) hypersensitivity in asthmatic patients is related to arachidonic acid metabolism abnormalities, and specific triggering by ASA of 15-hydroxyeicosatetraenoic acid (15-HETE) generation was observed in leucocytes from aspirin-sensitive (AS) but not from aspirin-tolerant (AT) asthmatics.

Objective The aim of this study was to identify the enzymatic pathway involved in ASA-induced 15-HETE generation in AS asthmatics and to assess the regulatory role of prostaglandin EP receptors.

Methods Peripheral blood leucocytes (PBLs) were isolated from AS (n=18) and AT (n=20) asthmatics and challenged with ASA, with and without pre-incubation with caffeic acid (CA) [15-lipoxygenase (15-LO) inhibitor] or prostaglandin receptor non-specific (misoprostol, sulprostone) and specific EP1–4 receptors agonists. Eicosanoids were measured in supernatants using specific immunoassays.

Results Aspirin triggered 15-HETE generation in PBLs of AS asthmatics (mean increase 292%) but not in AT asthmatics and inhibited prostaglandin2 (PGE2) generation in both groups of patients to the same degree. Leucocytes from AS patients produced less PGE2, both before and after ASA incubation. Pre-incubation of PBLs with CA decreased basal 15-HETE production in all patients and completely inhibited ASA-induced 15-HETE generation in AS asthmatics. CA did not change basal PGE2 production but enhanced induced by ASA inhibition of PGE2. Non-specific agonists of EP receptors (misoprostol and sulprostone) did not affect basal 15-HETE production but inhibited in a dose-dependent manner the ASA-induced increase of 15-HETE generation in AS asthmatics. On the contrary, in AT asthmatics, pre-incubation of PBLs with misoprostol or sulprostone resulted in a significant increase in 15-HETE generation after addition of ASA (200 μm). EP1–3 receptor agonists inhibited (range 72–94%) the ASA-induced 15-HETE production significantly.

Conclusion Our study demonstrated that ASA-triggered 15-HETE generation involves the activation of 15-LO and is modulated by prostaglandin EP1–3 receptors. The relevance of these observations to the mechanism of in vivo ASA-induced asthmatic attack remains to be established.

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