Immunopathology of NSAID-gastropathy: inhibitory effects of interleukin-I and cyclosporin A.
The present study demonstrates that CSA is capable of inhibiting indomethacin-induced leukocyte adherence to the vascular endothelium, and can reduce the severity of indomethacin-induced gastric mucosal injury. These results are therefore consistent with the hypothesis that leukocyte (particularly neutrophil) adherence is a critical event in the pathogenesis of NSAID-induced gastropathy. The mechanism through which CSA inhibits leukocyte adherence is not clear, and warrants further investigation. This study also confirmed the protective effects of IL-1 in experimental NSAID-gastropathy, and demonstrates that one of the ways the IL-1 may protect the mucosa is through its ability to inhibit the release of proinflammatory mediators (e.g., PAF) and promote the release of antiinflammatory mediators (e.g., nitric oxide). IL-1 modulated the release of these mediators from peritoneal mast cells at doses in the pg/ml to ng/ml range. IL-1 can inhibit the ability of neutrophils to respond to chemotactic stimuli and can prevent LTB4-induced neutropenia. Inhibition of neutrophil function by IL-1 may therefore account for its ability to reduce NSAID-induced gastric mucosal injury. Whether or not effects of IL-1 on the production of mediators such as nitric oxide and PAF is an underlying mechanism for the inhibitory effects on neutrophil function remains to be determined.
Wallace
J L
JL
Gastrointestinal Research Group, Faculty of Medicine, University of Calgary, Alberta, Canada.
Hogaboam
C M
CM
Kubes
P
P
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D013276:Stomach Ulcer / Q000276:immunology* / Q000517:prevention & control
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007375:Interleukin-1; D016572:Cyclosporine