title: Over-expression of the LTC4 synthase gene in mice reproduces human aspirin-induced asthma.
abstract: BACKGROUND
  The pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin/non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lipoxygenase (5-LO) metabolites, particularly leukotriene C(4) (LTC(4) ). However, the role of LTC(4) in the development of AIA has yet to be conclusively demonstrated.
  
  
  OBJECTIVE
  The aim of this study was to evaluate the contribution of the lipid product LTC(4) secreted by the 5-LO pathway to the pathogenesis of AIA.
  
  
  METHODS
  To evaluate antigen-induced airway inflammation, the concentrations of T-helper type 2 cytokine in bronchoalveolar lavage fluid (BALF) obtained from LTC(4) synthase-transgenic (Tg) and wild-type (WT) mice after challenge with ovalbumin were measured. Subsequently, the ex vivo and in vivo effects of the NSAID sulpyrine were investigated in these Tg and WT mice by measuring the secretion of LTC(4) from sulpyrine-treated BAL cells and the levels of LTC(4) in BALF following challenge with sulpyrine. Finally, the sulpyrine-induced airway response by the administration of pranlukast, an antagonist of the cysteinyl (cs)-LT1 receptor, was analysed.
  
  
  RESULTS
  The concentrations of IL-4, -5, and -13 in BALF from Tg mice were significantly higher than those in WT mice. In addition, sulpyrine augmented the secretion of LTC(4) in BALF and by BAL cells in Tg mice, but not in WT mice. Additionally, the increased airway resistance induced by sulpyrine could be reduced by treatment with pranlukast. Furthermore, the secretion of LTC(4) from mast cells, eosinophils, and macrophages was increased in the allergen-stimulated LTC(4) synthase gene Tg mice, even in the absence of sulpyrine, as well as in BAL cells after sulpyrine.
  
  
  CONCLUSIONS
  The over-expression of the LTC(4) synthase in a mouse asthma model also replicates the key features of AIA. And our study supports that cys-LTs play a major role in the pathogenesis of AIA in patients with chronic asthma.
authors.affiliation: Department of Pulmonary Medicine and Clinical Immunology, Dokkyo University School of Medicine, Tochigi, Japan. hirokuni@dokkyomed.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Hirata
authors.forename: M
authors.initials: M
authors.lastname: Arima
authors.forename: Y
authors.initials: Y
authors.lastname: Fukushima
authors.forename: K
authors.initials: K
authors.lastname: Honda
authors.forename: K
authors.initials: K
authors.lastname: Sugiyama
authors.forename: T
authors.initials: T
authors.lastname: Tokuhisa
authors.forename: T
authors.initials: T
authors.lastname: Fukuda
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D055963:Asthma, Aspirin-Induced / Q000201:enzymology* / Q000276:immunology / Q000378:metabolism; D004177:Dipyrone / Q000627:therapeutic use; D004195:Disease Models, Animal; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017997:Leukotriene C4 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000009:adverse effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D017997:Leukotriene C4; D004177:Dipyrone; D010047:Ovalbumin; D005982:Glutathione Transferase; C041116:leukotriene-C4 synthase