title: Differential effects of aspirin and misoprostol on 15-hydroxyeicosatetraenoic acid generation by leukocytes from aspirin-sensitive asthmatic patients.
abstract: BACKGROUND
  Although the mechanisms of aspirin-induced rhinosinusitis-asthma appear to be related to arachidonic acid abnormalities, only recently has a specific aspirin-triggered enhancement of 15-hydroxyeicosatetraenoic acid (15-HETE) generation in nasal polyp epithelial cells from aspirin-sensitive patients been demonstrated.
  
  
  OBJECTIVE
  The aim of this study was to assess generation of 15-HETE and other eicosanoids by peripheral blood leukocytes (PBLs) from aspirin-sensitive and aspirin-tolerant asthmatic patients and modulation of 15-HETE generation by a prostaglandin (PG) E(1) analogue (misoprostol).
  
  
  METHODS
  Twenty-four aspirin-sensitive patients with asthma-rhinosinusitis and 18 aspirin-tolerant asthmatic patients were studied, and eicosanoids released from PBLs were assessed by means of enzyme immunoassays.
  
  
  RESULTS
  Unstimulated PBLs from aspirin-sensitive and aspirin-tolerant patients generated similar amounts of PGE(2), leukotriene C(4), and 15-HETE, but lipoxin A(4) release was significantly less in aspirin-sensitive patients (300 +/- 70 pg/mL) in comparison with that seen in aspirin-tolerant patients (690 +/- 100 pg/mL, P <.05). Cell incubation with 2, 20, or 200 micromol/L aspirin resulted in a dose-dependent increase in 15-HETE generation (mean change of +85%, +189%, and +284% at each aspirin concentration, respectively) only in aspirin-sensitive asthmatic patients. Naproxen stimulated 15-HETE generation in aspirin-sensitive asthmatic patients, but indomethacin or specific COX-2 inhibitors (NS-398 and celecoxib) did not affect 15-HETE release. A synthetic PGE(1) analogue (misoprostol) inhibited aspirin-induced 15-HETE release but enhanced 15-HETE generation by aspirin in leukocytes from aspirin-tolerant patients. After preincubation with misoprostol, aspirin induced a dose-dependent production of lipoxin A(4) in both groups.
  
  
  CONCLUSIONS
  PBLs from patients with aspirin-sensitive rhinosinusitis-asthma might be specifically triggered by aspirin to generate 15-HETE. Metabolism of 15-HETE is differentially regulated by misoprostol in aspirin-tolerant and aspirin-sensitive asthmatic patients.
mesh_terms: D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001241:Aspirin / Q000009:adverse effects*; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis; D004361:Drug Tolerance; D015777:Eicosanoids / Q000096:biosynthesis; D005260:Female; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis*; D066298:In Vitro Techniques; D007476:Ionophores / Q000494:pharmacology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D017997:Leukotriene C4 / Q000096:biosynthesis; D044045:Lipoxins; D008297:Male; D008875:Middle Aged; D016595:Misoprostol / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015777:Eicosanoids; D006893:Hydroxyeicosatetraenoic Acids; D007476:Ionophores; D044045:Lipoxins; C040527:lipoxin A4; D016595:Misoprostol; D017997:Leukotriene C4; C025984:15-hydroxy-5,8,11,13-eicosatetraenoic acid; D015232:Dinoprostone; D001241:Aspirin