A monoclonal antibody against the CD18 leukocyte adhesion molecule prevents indomethacin-induced gastric damage in the rabbit.
The role of leukocyte adherence in the mechanism of gastropathy induced by nonsteroidal antiinflammatory drugs was investigated using a rabbit model. Gastric damage was induced by intragastric instillation of indomethacin [5 mg/mL] for a period of 30 minutes. Histologically, this treatment resulted in extensive vascular congestion and leukocyte margination within the mucosa. Pretreatment with a monoclonal antibody [IB-4] directed against the common beta subunit of the CD11/CD18 adhesion glycoprotein complex significantly (P less than 0.05) reduced both the vasocongestion and the prevalence of leukocyte margination. Macroscopically, indomethacin treatment resulted in the formation of numerous hemorrhagic lesions in the corpus region of the stomach. Pretreatment with IB-4 reduced the extent of gastric hemorrhagic damage by approximately 85% (P less than 0.001). Damage in the group pretreated with IB-4 did not differ significantly from that in rabbits that did not receive indomethacin. In separate experiments, the dose of IB-4 used was shown to completely suppress the recruitment of granulocytes in response to two different agonists. These results support the hypothesis that leukocyte adherence to the vascular endothelium is an important event in the pathogenesis of ulceration induced by nonsteroidal antiinflammatory drugs. Leukocytes might contribute to ulceration by occluding microvessels, thereby reducing mucosal blood flow, and by releasing various mediators, proteases, and free radicals that can produce tissue necrosis.
Wallace
J L
JL
Gastointestinal Research Group, University of Calgary, Alberta, Canada.
Arfors
K E
KE
McKnight
G W
GW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D018821:CD18 Antigens; D002448:Cell Adhesion / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005753:Gastric Mucosa / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D007962:Leukocytes / Q000502:physiology*; D008297:Male; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D016028:Receptors, Leukocyte-Adhesion / Q000276:immunology*; D013272:Stomach Diseases / Q000139:chemically induced
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000954:Antigens, Surface; D018821:CD18 Antigens; D016028:Receptors, Leukocyte-Adhesion; D007213:Indomethacin