ICAM-1 and P-selectin expression in a model of NSAID-induced gastropathy.
A growing body of experimental evidence suggests that neutrophilic polymorphonuclear leukocyte (PMN)-endothelial cell interactions play a critical role in the pathophysiology of nonsteroidal anti-inflammatory drug (NSAID)-induced gastropathy. The objective of this study was to directly determine whether the expression of endothelial cell adhesion molecules is enhanced in a model of NSAID-induced gastropathy. Gastropathy was induced in male Sprague-Dawley rats via oral administration of indomethacin (Indo, 20 mg/kg). Lesion scores, blood-to-lumen clearance of 51Cr-EDTA (mucosal permeability), and histological analysis (epithelial necrosis) were used as indexes of gastric mucosal injury. Gastric mucosal vascular expression of intercellular adhesion molecule 1 (ICAM-1) or P-selectin were determined at 1 and 3 h after Indo administration using the dual radiolabeled monoclonal antibody (MAb) technique. For some experiments, a blocking MAb directed at either ICAM-1 (1A29) or P-selectin (RMP-1) or their isotype-matched controls was injected intravenously 10 min before Indo administration. We found that P-selectin expression was significantly increased at 1 h but not 3 h after Indo administration, whereas ICAM-1 expression was significantly increased at both 1 and 3 h after Indo treatment. The blocking ICAM-1 and P-selectin MAbs both inhibited Indo-induced increases in lesion score, mucosal permeability, and epithelial cell necrosis. However, the Indo-induced gastropathy was not associated with significant PMN infiltration into the gastric mucosal interstitium, nor did Indo reduce gastric mucosal blood flow. We propose that NSAID-induced gastric mucosal injury may be related to the expression of P-selectin and ICAM-1; however, this mucosal injury does not appear to be dependent on the extravasation of inflammatory cells or mucosal ischemia.
Morise
Z
Z
Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport 71130, USA.
Komatsu
S
S
Fuseler
J W
JW
Granger
D N
DN
Perry
M
M
Issekutz
A C
AC
Grisham
M B
MB
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005753:Gastric Mucosa / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism*; D007213:Indomethacin; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D019007:P-Selectin / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects; D013276:Stomach Ulcer / Q000139:chemically induced / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019007:P-Selectin; D018799:Intercellular Adhesion Molecule-1; D007213:Indomethacin