Indomethacin-induced gastric injury and leukocyte adherence in arthritic versus healthy rats.
OBJECTIVE
Arthritic patients are at greater risk of developing nonsteroidal anti-inflammatory drug (NSAID)-induced ulcers than other NSAID users. Leukocyte adherence to the vascular endothelium has been suggested to play an important role in the pathogenesis of experimental NSAID-associated gastropathy. The aim of this study was to examine the role of leukocyte adherence in NSAID-induced gastric injury in healthy and adjuvant-induced arthritic rats.


METHODS
Leukocyte adherence was examined using intravital microscopy before and after indomethacin administration. The role of CD18 and intercellular adhesion molecule 1 (ICAM-1) in indomethacin-induced gastric injury and leukocyte adherence was examined using specific monoclonal antibodies against these molecules.


RESULTS
Indomethacin (5-10 mg/kg) caused significantly more gastric damage in arthritic than normal rats, and the former group had significantly greater levels of leukocyte adherence to mesenteric postcapillary venules under basal conditions. Dexamethasone markedly reduced basal and indomethacin-induced leukocyte adherence and the extent of gastric damage. In arthritic rats, pretreatment with a monoclonal antibody directed against ICAM-1 significantly reduced gastric damage and leukocyte adherence to the levels observed in healthy rats, whereas an antibody directed against CD18 had no effect.


CONCLUSIONS
Indomethacin-induced damage in healthy and arthritic rats is largely dependent on ICAM-1 expression. The increased susceptibility of arthritic rats to indomethacin-induced gastric injury may be partly related to elevated levels of ICAM-1-dependent leukocyte adherence.
McCafferty
D M
DM
Intestinal Disease Research Unit, Faculty of Medicine, University of Calgary, Alberta, Canada.
Granger
D N
DN
Wallace
J L
JL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D001169:Arthritis, Experimental / Q000150:complications*; D018821:CD18 Antigens / Q000502:physiology; D002448:Cell Adhesion; D003907:Dexamethasone / Q000494:pharmacology; D007213:Indomethacin / Q000009:adverse effects*; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013276:Stomach Ulcer / Q000139:chemically induced*
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018821:CD18 Antigens; D018799:Intercellular Adhesion Molecule-1; D003907:Dexamethasone; D007213:Indomethacin