title: COX-1 and COX-2 conversely promote and suppress ischemia-reperfusion gastric injury in mice.
abstract: OBJECTIVE
  Neutrophil activation followed by free radical production is a feature that is common to the various forms of gastric injury. However, the roles of cyclooxygenase (COX)-1 and -2 in neutrophil activation have yet to be clarified in the gastric mucosa. We examined the roles of both COX-1 and COX-2 in neutrophil activation and free radical production in ischemia-reperfusion (IR) injury in the gastric mucosa of mice.
  
  
  METHODS
  Ischemia was induced by clamping the celiac artery for 30 min, then removing the clamp for 90 min. SC-560, a selective COX-1 inhibitor; NS-398, a selective COX-2 inhibitor; or rebamipide, a mucoprotective agent, was administered to mice 60 min before ischemia. Gastric damage was evaluated histologically and by measuring myeloperoxidase (MPO) activity. Expressions of COX protein and intercellular adhesion molecule (ICAM)-1 were evaluated by Western blot analysis and ELISA, respectively. Effects of these drugs on thiobarbituric acid reactive substances (TBARS) and gastric blood flow were also evaluated.
  
  
  RESULTS
  COX-2 expression was induced in gastric mucosa 60 min after reperfusion, whereas COX-1 expression remained unaltered. Localization of COX-1 and ICAM-1 in IR-injured mucosa was observed mainly in endothelial cells, while COX-2 expression was detected in mesenchymal cells such as mononuclear cells, spindle-like cells and endothelial cells. SC-560 significantly decreased gastric blood flow at the reperfusion point and reduced gastric mucosal injury in IR mice. Furthermore, SC-560 pretreatment significantly reduced MPO activity, TBARS levels and ICAM-1 expression. In contrast, NS-398 significantly increased ICAM-1 expression, MPO activity and TBARS levels, and aggravated gastric damage in IR mice. Rebamipide pretreatment reduced both COX-2 expression and IR injury.
  
  
  CONCLUSIONS
  In IR mice, COX-2 protects the gastric mucosa by down-regulating ICAM-1 expression, whereas COX-1 is involved in up-regulating reperfusion flow, thereby aggravating the mucosa.
authors.affiliation: Third Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Hiratsuka
authors.forename: Seiji
authors.initials: S
authors.lastname: Futagami
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tatsuguchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shinji
authors.forename: Masanori
authors.initials: M
authors.lastname: Kusunoki
authors.forename: Kei
authors.initials: K
authors.lastname: Shinoki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nishigaki
authors.forename: Shunji
authors.initials: S
authors.lastname: Fujimori
authors.forename: Ken
authors.initials: K
authors.lastname: Wada
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Miyake
authors.forename: Katya
authors.initials: K
authors.lastname: Gudis
authors.forename: Taku
authors.initials: T
authors.lastname: Tsukui
authors.forename: Choitsu
authors.initials: C
authors.lastname: Sakamoto
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D015153:Blotting, Western; D002445:Celiac Artery / Q000601:surgery; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005753:Gastric Mucosa / Q000098:blood supply* / Q000201:enzymology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D017078:Laser-Doppler Flowmetry; D008026:Ligation; D008565:Membrane Proteins; D051379:Mice; D008813:Mice, Inbred ICR; D009578:Nitrobenzenes / Q000627:therapeutic use; D009195:Peroxidase / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism*; D011720:Pyrazoles / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D015427:Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D013449:Sulfonamides / Q000627:therapeutic use; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D009578:Nitrobenzenes; D011720:Pyrazoles; D015363:Quinolones; C115461:SC 560; D013449:Sulfonamides; D017392:Thiobarbituric Acid Reactive Substances; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D018799:Intercellular Adhesion Molecule-1; D009195:Peroxidase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C052785:rebamipide; D000409:Alanine