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.

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Leukotriene (LT) D₄ receptor in the granulation tissue formed in the air pouch-type allergic inflammation model in rats was analyzed. Membrane preparation of the granulation tissue obtained 3–9 days after the antigen challenge has specific binding sites of [³H]LTD₄. Scatchard analysis showed that the affinity (K_d) and the density (B_max) were not changed among the granulation tissue obtained 3-9 days after the antigen challenge. The K_d value in the granulation tissue (0.90 ± 0.12 nM) was close to that in the rat lung (1.00 ± 0.24 nM) and the guinea pig lung (0.86 nM). On the other hand, Bmax (62 ± 8 fmol/mg protein) in the granulation tissue was higher than that in the rat lung (21 ± 4 fmol/mg protein) but was far less than that in the guinea pig lung (405 fmol/mg protein). LTC₄ and LTE₄ inhibited the binding of [³H]LTD₄ to the membrane preparation of the granulation tissue in a concentration-dependent manner. IC₅₀ of LTC₄ and LTE₄ were 1 × 10^––7 and 2 × 10^––7M, respectively. A guanine nucleotide, guanyl-5’-yl-imido-diphosphate (GppNHp), reduced [³H]LTD₄ binding to the membrane preparation of the granulation tissue suggesting that LTD₄ receptors in the granulation tissue are associated with G proteins. These results indicate that LTD₄ binding sites in the granulation tissue are high affinity receptors for LTD₄. A possible role of LTD₄ in the recurrence of allergic inflammation in the chronic phase is discussed.

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