Possible involvement of mast‐cell activation in aspirin provocation of aspirin‐induced asthma

Abstract

Background: Although there is increasing evidence of the importance of cysteinyl leukotrienes (LT) as mediators of aspirin‐induced bronchoconstriction in aspirin‐sensitive asthma, the cellular origin of the LT is not yet clear. Methods: Urinary concentrations of leukotriene E4 (LTE4), 11‐dehydrothromboxane B2, 9α,11β‐prostaglandin F2, and Nτ‐methylhistamine were measured during the 24 h following cumulative intravenous administration of increasing doses of lysine aspirin to asthmatic patients. In addition, the urinary concentrations of these metabolites were measured on 5 consecutive days in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti‐inflammatory drugs. Results: In aspirin‐induced asthma patients (AIA, n=10), the basal concentration of urinary LTE4, but not the other metabolites, was significantly higher than that in aspirin‐tolerant asthma patients (ATA, n=10). After intravenous aspirin provocation, the AIA group showed a 13.1‐fold (geometric mean) increase in excretion of LTE4 during the first 3 h, and 9α,11β‐prostaglandin F2 also increased in the AIA group during the first 0–3 h and the 3–6 h collection period. Nτ‐methylhistamine excretion was also increased, but to a lesser degree. Adminis‐tration of aspirin caused significant suppression of 11‐dehydrothromboxane B2 excretion in both the AIA and ATA groups. When the percentage of maximum increase of each metabolite from the baseline concentrations was compared between the AIA group and the ATA group, a significantly higher increase in excretion of LTE4, 9α,11β‐prostaglandin F2, and Nτ‐methylhistamine was observed in the AIA group than the ATA group. An increased excretion of LTE4 and 9α,11β‐prostaglandin F2 has been detected in a patient who suffered an asthma attack after percutaneous administration of nonsteroidal anti‐inflammatory drugs. Conclusions: Considering that human lung mast cells are capable of producing LTC4, prostaglandin D2, and histamine, our present results support the concept that mast cells, at least, may participate in the development of aspirin‐induced asthma.

Challenge of Isolated Sputum Cells Supports in vivo Origin of Intolerance Reaction to Aspirin/Non-Steroidal Anti-Inflammatory Drugs in Asthma

“…The AIA group had higher baseline values of urinary LTE 4 as compared to the ATA group (table 1), confirming the characteristic phenotype of AIA [2,7,8,9,10,11,12]. …”

“…Suggestions of aspirin-induced activation of platelets from patients with AIA [27] have not been replicated [18]. Moreover, despite in vivo evidence that mast cell activation occurs during aspirin-induced bronchoconstriction [9,10,11,28,29,30,31,32], Wang et al [33] could not trigger activation of blood-derived mast cells from subjects with AIA by ex vivo exposure to aspirin. The present study therefore gives support to the concept that aspirin/NSAID intolerance is a unique and not yet completely understood in vivo reaction in which presumably many cells interact in a complex fashion that, however, requires contact with the target tissue in the airways.…”

“…Thus, urinary leukotriene (LT) E 4 concentrations are significantly elevated at baseline in AIA patients and increase further after aspirin challenge [7,8,9,10,11,12]. There are also higher baseline levels of CysLTs in saliva, ex vivo stimulated blood and induced sputum samples collected from AIA patients as compared to patients with aspirin-tolerant asthma (ATA) [13].…”

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…Within 3 h of ingestion of aspirin or NSAIDs, individuals with AIA develop bronchoconstriction, often accompanied by rhinorrhea, conjunctival irritation, and scarlet flush . Compared with normal individuals or subjects with aspirin-tolerant asthma, patients with AIA have increased baseline levels of cysteinyl LTs in urine (Christie et al, 1991;Higashi et al, 2004;Micheletto et al, 2006) exhaled air (Antczak et al, 2002), and in saliva and induced sputum (Gaber et al, 2008), levels that are further enhanced by aspirin challenge (Ortolani et al, 1987;Sladek and Szczeklik, 1993;Szczeklik et al, 1996) and that might be derived, at least in part, from MCs (Sladek and Szczeklik, 1993;O'Sullivan et al, 1996;Mita et al, 2001a). Although a definite explanation for this syndrome is not yet available, a large body of evidence supports the possibility that patients with AIA are particularly dependent on the bronchoprotective and anti-inflammatory properties of prostaglandin E 2 (Stevenson and Szczeklik, 2006) and that inhibition of COX-1 in these patients triggers MC activation and release of LTs as well as histamine and tryptase (Picado et al, 1992).…”

Analysis of the Mechanism for the Development of Allergic Skin Inflammation and the Application for Its Treatment: Aspirin Modulation of IgE-Dependent Mast Cell Activation: Role of Aspirin-Induced Exacerbation of Immediate Allergy

“…Mast cells express the high-affinity IgE receptor (FcεRI) on their cell surface, and antigen crosslinking of FcεRI triggers biochemical cascades that lead to degranulation, cys-LTs and PGs secretion, and cytokine production. Moreover, mast cells are suggested to be responsible for cys-LT overproduction in ASA intolerance (10,11). In addition, several studies have shown that an atopic background (high levels of serum IgE) is a risk factor for NSAID sensitivity (12).…”