title: Implications of reactive oxygen species and cytokines in gastroprotection against stress-induced gastric damage by nitric oxide releasing aspirin.
abstract: OBJECTIVE
  Nitric oxide-releasing aspirin (NO-ASA) has been shown to inhibit cyclo-oxygenase and prostaglandin generation without causing mucosal damage, but the role of reactive oxygen species (ROS) and cytokines in the action of ASA and NO-ASA against acute gastric damage has been little studied.
  
  
  METHODS
  We compared the effect of NO-ASA and ASA on gastric lesions provoked by water-immersion and restraint stress (WRS), ischemia-reperfusion, and 100% ethanol. We determined the number and area of gastric lesions, gastric blood flow (GBF), plasma concentration of proinflammatory cytokines IL-1beta and TNFalpha, expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx), ROS generation, and the malondialdehyde (MDA) concentration as an index of lipid peroxidation.
  
  
  RESULTS
  Pretreatment with NO-ASA attenuated dose-dependently gastric erosions provoked by WRS, ischemia-reperfusion, and ethanol. In contrast, ASA aggravated significantly WRS-induced lesions, and this was accompanied by a fall in the GBF, suppression of prostaglandin E(2) generation, and significant rise in ROS chemiluminescence and in plasma TNFalpha and IL-1beta levels. ASA also enhanced significantly the mucosal MDA content and downregulated SOD and GPx mRNA, and these effects were markedly reduced by NO-ASA.
  
  
  CONCLUSIONS
  Coupling of NO to ASA attenuates stress, ischemia-reperfusion, and ethanol-induced damage due to mucosal hyperemia mediated by NO, which compensates for prostaglandin deficiency induced by ASA. ASA aggravates WRS damage via enhancement of ROS and cytokine generation and suppression of SOD and GPx, and these effects are counteracted by NO released from NO-ASA.
authors.affiliation: Department of Physiology, Jagiellonian University School of Medicine, 16 Grzegorzecka Str., 31-531 Cracow, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Brzozowski
authors.forename: Piotr  C
authors.initials: P
authors.lastname: Konturek
authors.forename: Stanislaw J
authors.initials: SJ
authors.lastname: Konturek
authors.forename: Slawomir
authors.initials: S
authors.lastname: Kwiecień
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Sliwowski
authors.forename: Robert
authors.initials: R
authors.lastname: Pajdo
authors.forename: Alexandra
authors.initials: A
authors.lastname: Duda
authors.forename: Agata
authors.initials: A
authors.lastname: Ptak
authors.forename: Eckhart G
authors.initials: EG
authors.lastname: Hahn
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects*; D001241:Aspirin / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives; D002492:Central Nervous System Depressants / Q000009:adverse effects; D016207:Cytokines / Q000494:pharmacology*; D000431:Ethanol / Q000009:adverse effects; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D005979:Glutathione Peroxidase / Q000096:biosynthesis / Q000494:pharmacology; D007103:Immobilization; D007511:Ischemia; D015227:Lipid Peroxidation; D008297:Male; D009569:Nitric Oxide / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000009:adverse effects* / Q000494:pharmacology; D012039:Regional Blood Flow; D013315:Stress, Psychological; D013482:Superoxide Dismutase / Q000096:biosynthesis / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002492:Central Nervous System Depressants; D016207:Cytokines; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D000431:Ethanol; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; C102148:nitroaspirin; D001241:Aspirin