Prostaglandin E₂ decrease in induced sputum of hypersensitive asthmatics during oral challenge with aspirin

Abstract

Background:A special regulatory role for prostaglandin E 2 (PGE 2 ) has been postulated in nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD).Objective: To investigate the effect of systemic aspirin (acetylsalicylic acid) administration on airway PGE 2 biosynthesis in induced sputum supernatant (ISS) among subjects with NERD or aspirin-tolerant asthma with chronic rhinosinusitis with nasal polyposis (ATA-CRSwNP), as well as healthy controls (HC). Methods:Induced sputum (IS) was collected from patients with NERD (n = 26), ATA-CRSwNP (n = 17), and HC (n = 21) at baseline and after aspirin challenge. Sputum differential cell count and IS supernatant (ISS) levels of prostanoids, PGE 2 , 8-iso-PGE 2 , tetranor-PGE-M, 8-iso-PGF 2 α, and leukotriene C 4 , D 4 , and E 4 , were determined using mass spectrometry. Urinary excretion of LTE 4 was measured by ELISA.Results: NERD subjects had elevated sputum eosinophilic count as compared to ATA-CRSwNP and HC (median NERD 9.1%, ATA-CRSwNP 2.1%, and HC 0.4%; P < 0.01). Baseline ISS levels of PGE 2 were higher in asthmatics as compared to HC at baseline (NERD vs HC P = 0.04, ATA-CRSwNP vs HC P < 0.05). Post-challenge ISS levels of PGE 2 compared to baseline significantly decreased in NERD and HC (P < 0.01 and P = 0.01), but not in ATA-CRSwNP. In NERD, a similar decrease in PGE 2 as in HC resulted from 2.8 times lower dose of aspirin. Conclusion:Aspirin-precipitated bronchoconstriction is associated with a decrease in airway PGE 2 biosynthesis. These results support the mechanism of PGE 2 biosynthesis inhibition as a trigger for bronchoconstriction in NERD. K E Y W O R D Seicosanoids, induced sputum, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease, oral aspirin challenge, prostaglandins Abbreviations: ATA-CRSwNP, aspirin-tolerant asthma with chronic rhinosinusitis with nasal polyposis; COX, cyclooxygenase; Cys-LTs, cysteinyl leukotrienes; HC, healthy control; LTC4, leukotriene C4; LTD4, leukotriene D4; LTE4, leukotriene E4; NERD, nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease; NSAIDs, nonsteroidal anti-inflammatory drugs; PGE2, prostaglandin E2; Tetranor-PGE-M, 9,15-dixo-11α-hydroxy-2,3,4,5-tetranor-prostan-1,20-dioic acid.

Progress in understanding hypersensitivity reactions to nonsteroidal anti‐inflammatory drugs

“…This pathogenic model proposed for NERD was supported by increased levels of CysLTs after ASA‐DPT and extended to NECD . Lower baseline levels of PGE2 and increased values of CysLTs were found in induced sputum from NERD compared with ATA patients with CRSwNP . Moreover, PGE2 decreased and CysLTs increased after ASA‐DPT in NERD, with significant differences compared with their basal values and with ATA .…”

The Biology of Prostaglandins and Their Role as a Target for Allergic Airway Disease Therapy

“…Conversely, the 5-lipoxygenase (5-LO) pathway, which metabolizes AA into LTs, is markedly upregulated in these patients, resulting in an extremely high level of CysLTs, which activate mast cells and eosinophils [10,182]. Addition of nonsteroidal anti-inflammatory drugs, especially COX-1 inhibitors, forces AA metabolism towards LT synthesis and further decreases PGE 2 production, resulting in the uncontrolled release of LTC 4 , LTD 4 , LTE 4 , and PGD 2 by countering the suppressive effect of PGE 2 on 5-LO [183][184][185].…”

Platelet-Adherent Leukocytes Associated With Cutaneous Cross-Reactive Hypersensitivity to Nonsteroidal Anti-Inflammatory Drugs

“…This pathogenic model was initially proposed for NERD (Szczeklik et al, 1975), and supported by the presence of increased levels of CysLTs after ASA challenge (Szczeklik et al, 1996;Antczak et al, 2002;Swierczynska et al, 2003;Sanak et al, 2004;Gaber et al, 2008), and further extended to NECD (Mastalerz et al, 2004;Setkowicz et al, 2009). Lower baseline levels of PGE2 and increased values of CysLTs have been found in induced sputum from NERD when compared with ASA-tolerant asthmatics and chronic rhinosinusitis with nasal polyposis patients (Mastalerz et al, 2019). Additionally, PGE2 decreased and CysLTs increased after ASA challenge in NERD (Mastalerz et al, 2019), with significant differences compared with their basal values and with ASA-tolerant asthmatics.…”

“…Lower baseline levels of PGE2 and increased values of CysLTs have been found in induced sputum from NERD when compared with ASA-tolerant asthmatics and chronic rhinosinusitis with nasal polyposis patients (Mastalerz et al, 2019). Additionally, PGE2 decreased and CysLTs increased after ASA challenge in NERD (Mastalerz et al, 2019), with significant differences compared with their basal values and with ASA-tolerant asthmatics. In both NIUA and NECD, we have recently reported increased LTE4 and 9a,11b-PGF2 levels after ASA challenge, which decreased at the basal state to values similar to those found in controls (Dona et al, 2019).…”