Prostaglandin E2 systemic production in patients with asthma with and without aspirin hypersensitivity

Abstract

Background: A special regulatory role for prostaglandin E 2 has been postulated in aspirin-induced asthma. A study was undertaken to investigate the effects of aspirin on the systemic production of prostaglandin E 2 and cysteinyl leucotrienes in patients with asthma. Methods: The urinary concentrations were determined of two main prostaglandin E 2 metabolites (13,14-dihydro15keto-PGE 2 using a commercial enzyme immunoassay and 9,15-dioxo-11a-hydroxy-2,3,4,5-tetranor-prostane-1,20-dioic acid by gas chromatography/mass spectrometry) and leucotriene E 4 using an immunoassay. Determinations were performed at baseline and following oral aspirin and celecoxib challenges in two well-defined asthma phenotypes: aspirin-sensitive and aspirin-tolerant patients.Results: Aspirin precipitated bronchial reactions in all aspirin-sensitive patients but in none of the aspirintolerant patients. Celecoxib 400 mg was well tolerated by all patients except for one with aspirin-induced asthma. At baseline, the mean levels of prostaglandin E 2 metabolites did not differ between the groups. Following different aspirin provocation doses, the mean levels of the two main prostaglandin E 2 metabolites were decreased in the aspirin-tolerant group but remained unchanged in the aspirin-sensitive group. The dose of aspirin had no effect on the magnitude of the response on the prostaglandin E 2 metabolites and its duration. In both groups, urinary prostaglandin E 2 metabolites decreased following celecoxib challenge. No correlation was found between prostaglandin E 2 metabolites and leucotriene E 4 . Conclusions: Aspirin-precipitated asthmatic attacks are not associated with changes in the systemic production of prostaglandin E 2 . In contrast, the systemic production of prostaglandin E 2 becomes depressed by aspirin in nonsensitive patients. This different response might indicate COX-1-dependent prostaglandin E 2 control of inflammatory cells in aspirin-induced asthma. Thus, PGE 2 is released during the clinical reactions to aspirin through an alternative COX-2 pathway. The clinical implications of this finding are in line with current observations of good tolerance of the selective COX-2 inhibitors in aspirinsensitive patients.Prostaglandin E 2 (PGE 2 ) is a bioactive compound formed by actions of cyclooxygenase (COX) and specific PGE synthases.1 In human airways PGE 2 is produced by many cells including epithelium, smooth muscle, alveolar cells, macrophages, phagocytes and lymphocytes.1 2 In vitro, PGE 2 relaxes smooth muscle and displays a number of inhibitory effects on mast cell degranulation, synthesis of leucotriene B 4 , activation of granulocytes and T cells.3-5 PGE 2 elicits a large number of biological effects acting through four receptors: EP1, EP2, EP3 and EP4. [6][7][8] The response of target cells to PGE 2 varies according to the spectrum of receptors they express.PGE 2 might be of special importance in aspirininduced asthma. This is a distinct clinical syndrome affecting 5-10% of adults with asthma. Asthma attacks trigge...

Altered Inhibitory Function of the E-Type Prostanoid Receptor 4 in Eosinophils and Monocytes from Aspirin-Intolerant Patients

“…This is in contrast to Schafer et al [34] who found reduced basal levels of PGE 2 in peripheral blood cells; however, they also observed that arachidonic acid stimulation resulted in increased PGE 2 levels, which were not different between aspirin-tolerant and AERD patients. We found that pretreatment with acetylsalicylic acid caused inhibition of PGE 2 by more than 80% in both groups, which is in contrast to findings of Mastalerz et al [32] who described that the concentration of PGE metabolites in urine was not inhibited by aspirin in aspirin-sensitive patients. It should be noted, however, that this measurement also involves the renal tubular generation of PGE 2 .…”

“…In contrast, no differences in PGE 2 and COX were detected at basal conditions in fibroblasts from nasal polyps and bronchial tissue, but when stimulated, reduced PGE 2 release and COX-2 induction were observed [30,31]. Also, the basal levels of urinary PGE 2 metabolites of AERD patients were not different from those of healthy controls [32], while elevated PGE 2 levels in bronchoalveolar lavage fluid were detected in AERD patients, which were inhibited by aspirin challenge [33]. In our study, we found no differences in PGE 2 release, neither under basal nor LPS-stimulated conditions in adherent monocytes isolated from peripheral blood of AERD patients and healthy controls.…”

Expression of Arachidonate Metabolism Enzymes and Receptors in Nasal Polyps of Aspirin-Hypersensitive Asthmatics

“…Peripheral blood leukocytes and bronchial fibroblasts of AH patients undersynthesize PGE 2 at baseline, which places them at a disadvantage as they lack sufficient amounts of this anti-inflammatory prostaglandin to antagonize the proinflammatory action of leukotrienes. Recent studies by Roca-Ferrer et al [43] and Mastalerz et al [44] support the hypothesis of COX-1-dependent PGE 2 control of inflammation in aspirin hypersensitivity.…”

“…Against the background of insufficient COX-2-derived PGE 2 production, COX-1-derived PGE 2 may become crucial to maintain an unstable eicosanoid balance in the airways [44]. The altered response of inflammatory cells to aspirin may also be involved in this process, but it cannot be excluded that changes in receptor expression prelude the symptoms of the disease.…”

Targeted eicosanoid lipidomics of exhaled breath condensate provide a distinct pattern in the aspirin-intolerant asthma phenotype

“…Patterns of eicosanoid mediators in subjects with AIA have previously been reported in several biological matrices: blood plasma, 15 bronchoalveolar lavage fluid, 16 nasal lavage fluid, 17,18 sputum, 19,20 and urine 21,22 and, to a much lesser extent, EBC. 23,24 After the oral aspirin challenge test, the starkest differences in eicosanoid production were found in urine, 21,22 reflecting increased systemic biosynthesis of cysteinyl LTs, the main eicosanoid culprit for asthmatic attack. In aspirin-intolerant subjects, even those in stable clinical condition, increased LTE 4 urinary excretion is a hallmark of the disease.…”