Role of endothelial adhesion molecules in NSAID-induced gastric mucosal injury.
A number of recent studies have demonstrated that neutrophil adherence to the vascular endothelium is a critical early event in the pathogenesis of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs). Although a role in this process for the leukocyte adhesion molecule, CD11/CD18, has been demonstrated, the involvement of endothelial adhesion molecules has not previously been examined. Therefore, using monoclonal antibodies directed against a number of endothelial adhesion molecules (ICAM-1, P-selectin, E-selectin), we studied the role of these molecules in the production of mucosal injury after indomethacin administration and in indomethacin-induced leukocyte adherence. As previously shown in the rabbit, anti-CD18 markedly reduced (by 75%) the severity of damage induced by indomethacin in the rat. Moreover, this antibody completely prevented indomethacin-induced leukocyte adherence. Similarly, anti-ICAM-1 significantly attenuated (by 74%) the severity of indomethacin-induced gastric injury while also markedly reducing leukocyte adherence (by 83%). Anti-P-selectin and anti-E-selectin produced only small (approximately 35%), but statistically significant, reductions of mucosal injury, but only anti-P-selectin significantly affected indomethacin-induced leukocyte adherence (by approximately 50%). These results demonstrate that indomethacin-induced leukocyte adherence and mucosal injury are dependent on the expression of CD18 and ICAM-1. P-selectin also appears to play a small, but important, role in these processes, whereas the role of E-selectin remains equivocal. These studies support the hypothesis that interactions at the leukocyte-endothelium interface are critical in the pathogenesis of NSAID-induced mucosal injury, and this interface may represent a rational target for therapies aimed at preventing this form of injury.
Wallace
J L
JL
Gastrointestinal Research Group, University of Calgary, Alberta, Canada.
McKnight
W
W
Miyasaka
M
M
Tamatani
T
T
Paulson
J
J
Anderson
D C
DC
Granger
D N
DN
Kubes
P
P
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000502:physiology*; D018821:CD18 Antigens; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000502:physiology*; D019040:E-Selectin; D005753:Gastric Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007213:Indomethacin / Q000633:toxicity*; D018799:Intercellular Adhesion Molecule-1; D008297:Male; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D016028:Receptors, Leukocyte-Adhesion / Q000502:physiology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D019007:P-Selectin; D010980:Platelet Membrane Glycoproteins; D016028:Receptors, Leukocyte-Adhesion; D018799:Intercellular Adhesion Molecule-1; D007213:Indomethacin