Abstract
Aspirin-exacerbated respiratory disease (AERD) is associated with constitutively elevated synthesis of bronchoconstrictor cysteinyl-leukotrienes, associated with increased expression of leukotriene (LT)C4 synthase and Th2 cytokines and airway eosinophilia. We examined whether interleukin-13 can increase LTC4 synthase gene transcription and cysteinyl-leukotriene synthesis in macrophages isolated from resected human lung tissue and whether an NSAID (indomethacin) can trigger further cysteinyl-leukotriene synthesis in these cells. Overnight culture of human lung macrophages with IL-13 (10 ng/mL) increased spontaneous and ionophore-stimulated production of cysteinyl-leukotrienes by 42% (P = 0.02) and 52% (P = 0.005), respectively, as quantified by enzyme immunoassays, but PCR gene transcription assays did not demonstrate an effect on LTC4S mRNA. The addition of indomethacin (100 μM) did not modulate cysteinyl-leukotriene production in either IL-13-treated or untreated macrophages. We conclude that while IL-13 enhances cysteinyl-leukotriene synthesis in human lung macrophages, it does not replicate the enhanced LTC4 synthase expression observed in the AERD lung nor confer sensitivity to NSAIDs.
Highlights
Aspirin-exacerbated respiratory disease (AERD) is a syndrome in which chronic asthma is accompanied by nonallergic hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs), leading to acute bronchoconstriction and exacerbation of other lower and upper airway symptoms [1, 2]
IL4 can powerfully upregulate LTC4 synthase expression and activity in human cord-blood mast cells [12], while IL-13 can upregulate the principal receptor for cysteinyl-leukotrienes, CysLT1R, on human airway smooth muscle cells [16] and on macrophages [14]
This suggested that increased IL-4/IL-13 activity may be responsible for upregulating tissue expression of LTC4 synthase, as observed in the upper and lower airways in AERD patients [7, 8], and for enhancing responsiveness to cys-LTs by increasing the expression of CysLT1 receptors, as described in AERD nasal biopsies [17]
Summary
Aspirin-exacerbated respiratory disease (AERD) is a syndrome in which chronic asthma is accompanied by nonallergic hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs), leading to acute bronchoconstriction and exacerbation of other lower and upper airway symptoms [1, 2]. The ability of classical NSAIDs to inhibit prostaglandin synthesis by cyclooxygenase (COX) isozymes, COX-1, is implicated in these acute exacerbations [3], but it is not known how they activate mast cells, eosinophils, macrophages, epithelium, and other cells to release a range of inflammatory mediators in susceptible subjects. Prominent among these mediators are the cysteinylleukotrienes (cys-LTs), which are potent bronchoconstrictor lipids synthesised by the 5-lipoxygenase (5-LO)/LTC4 synthase pathway [4]. Increased cys-LT production is prominent in the acute bronchoconstriction that results, but it is not understood why NSAIDs trigger the acute surge in cys-LT levels only in AERD subjects
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