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  1. Immunopharmacology Group
  2. Southampton General Hospital
  3. Southampton SO16 6YD
  4. UK
  5. Department of Immunology & Rheumatology
  6. Harvard Medical School
  7. Boston
  8. Massachusetts
  9. USA
  10. Department of Medicine
  11. University School of Medicine
  12. Krakow
  13. Poland

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In a recent editorial in ThoraxMitchell and Belvisi1 cite the findings of Sousa and colleagues2 to support a theory that aspirin induced adverse respiratory reactions are caused by excessive formation of 15-HETE and 15-epilipoxins due to the acetylation of cyclo-oxygenase 2 (COX-2) in the lungs of aspirin sensitive asthmatic (ASA) patients by aspirin. Sousa and colleagues reported greater immunoreactivity for the cytokine inducible isoform of COX-2 in the bronchial biopsy specimens of asthmatic patients compared with normal subjects, suggesting a role for COX-2 derived pro-inflammatory prostanoids in the asthmatic airway.2 This group also reported a greater proportion of COX-2 immunostaining localised to submucosal mast cells and eosinophils in bronchial biopsy specimens of ASA patients compared with those of non-aspirin sensitive asthmatic (NASA) patients.2

The paradigm put forward by Mitchell and Belvisi has a number of internal contradictions and is not supported by recent experimental evidence. Firstly, Sousa and colleagues found that the overall expression of COX-2 was, in fact, similar in ASA and NASA biopsy specimens,2 a finding supported by our group.3 Thus, there is no reason why aspirin induced synthesis of 15-HETE or 15-epilipoxins should be abnormal in the ASA lung. Secondly, 15-HETE produced by aspirin acetylation of COX-2 is predominantly or exclusively the 15R-HETE stereoisomer, which is biologically inactive.4 Thirdly, the active isomer 15S-HETE and its metabolites are extremely weak bronchoconstrictors, while it is well established that adverse respiratory reactions to aspirin and other NSAIDs are caused by the more potent bronchoconstrictors, cysteinyl leukotrienes (cys-LTs), as such reactions are blocked by specific leukotriene synthesis inhibitors and cys-LT receptor antagonists.5 Fourthly, and most critically, among the NSAIDs only aspirin covalently acetylates COX-2 and generates 15-HETE, yet patients with ASA show extensive cross sensitivity to other NSAIDs which do not share …

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