Aspirin Exacerbated Respiratory Disease Involves a Cysteinyl Leukotriene-Driven IL-33-Mediated Mast Cell Activation Pathway

Abstract

Aspirin exacerbated respiratory disease (AERD), a severe eosinophilic inflammatory disorder of the airways, involves overproduction of cysteinyl leukotrienes (cysLTs), activation of airway mast cells (MCs), and bronchoconstriction in response to nonselective cyclooxygenase inhibitors that deplete homeostatic prostaglandin (PG)E 2 . The mechanistic basis for MC activation in this disorder is unknown. We now demonstrate that patients with AERD have markedly increased epithelial expression of the alarmin-like cytokine IL-33 in nasal polyps, as compared to polyps from aspirin tolerant (AT) controls. The murine model of AERD, generated by dust mite priming of mice lacking microsomal PGE 2 synthase (ptges −/− mice), shows a similar upregulation of IL-33 protein in the airway epithelium, along with marked eosinophilic bronchovascular inflammation. Deletion of LTC 4 synthase (LTC 4 S), the terminal enzyme needed to generate cysLTs, eliminates the increased IL-33 content of the ptges −/− lungs and sharply reduces pulmonary eosinophilia and basal secretion of MC products. Challenges of dust mite-primed ptges −/− mice with lysine aspirin (Lys-ASA) induce IL-33-dependent MC activation and bronchoconstriction. Thus, IL-33 is a component of a cysLT-driven innate type 2 immune response that drives pathogenic MC activation and contributes substantially to AERD pathogenesis.

Eosinophil production of prostaglandin D 2 in patients with aspirin-exacerbated respiratory disease

“…Expression of LTC 4 S in eosinophils drives much of the over-production of CysLTs 24 with additional components driven by the activation of mast cells 3, 5, 26, 27 and platelet-adherent neutrophils 28 . While contributing to many of the untoward effects of AERD, as evinced by the beneficial effects of leukotriene modifiers 29 , increasing attention has been given to contributions from PGD 2 .…”

Characteristics of NSAID‐induced hypersensitivity reactions in childhood

“…Furthermore, lung tissue lysates from PGE synthase −/− NERD-like mice showed that IL-33 is responsible from mast cell activation after a challenge with lysine-aspirin and LTE 4 is responsible for IL-33-dependent mast cell activation and airflow obstruction. 27 In a case series involving three children and adolescents with NERD, 24-hours urinary levels of prostaglandin D2, histamine, and 11β prostaglandin F2α, as well as serum IL-5 and IL-13 levels, are increased. 28 Additionally, mild baseline eicosanoid imbalance is detected in three adolescents aged 17 (2 of them) and 13 years using in vitro functional eicosanoid test.…”

“…Western blots of whole nasal polyp lysates from patients with NERD and lung tissue lysates from PGE synthase −/− NERD‐like mice reveal high interleukin‐33 (IL‐33) expression compared to controls without NERD. Furthermore, lung tissue lysates from PGE synthase −/− NERD‐like mice showed that IL‐33 is responsible from mast cell activation after a challenge with lysine‐aspirin and LTE 4 is responsible for IL‐33–dependent mast cell activation and airflow obstruction . In a case series involving three children and adolescents with NERD, 24‐hours urinary levels of prostaglandin D2, histamine, and 11β prostaglandin F2α, as well as serum IL‐5 and IL‐13 levels, are increased .…”

Contemporary management of chronic rhinosinusitis with nasal polyposis in aspirin‐exacerbated respiratory disease: an evidence‐based review with recommendations

“…Likewise, studies have demonstrated decreased production of anti‐inflammatory prostaglandin E 2 (PGE 2 ) and reduced expression of COX‐2, an enzyme important in PGE 2 synthesis in nasal polyp tissue from patients with AERD . These alterations in arachidonic acid metabolism are associated with increased mast cell activation and eosinophilic inflammation of the upper and lower airways …”