COX-1 and COX-2 conversely promote and suppress ischemia-reperfusion gastric injury in mice.
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.
Hiratsuka
Tetsuro
T
Third Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
Futagami
Seiji
S
Tatsuguchi
Atsushi
A
Suzuki
Kenji
K
Shinji
Yoko
Y
Kusunoki
Masanori
M
Shinoki
Kei
K
Nishigaki
Hitoshi
H
Fujimori
Shunji
S
Wada
Ken
K
Miyake
Kazumasa
K
Gudis
Katya
K
Tsukui
Taku
T
Sakamoto
Choitsu
C
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
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