Annexin-1 is an endogenous gastroprotective factor against indomethacin-induced damage.
Adherence of neutrophils to the vascular endothelium is an early and critical event in the pathogenesis of gastric injury induced by NSAIDs. Pretreatment with glucocorticoids has been shown to prevent NSAID-induced neutrophil adherence and, in turn, to protect the stomach from injury. Some of the anti-inflammatory effects of glucocorticoids, including inhibition of neutrophil adherence, are mediated via the release of annexin-1. In this study, we assessed the contribution of annexin-1 to the protective actions of a glucocorticoid (dexamethasone) against indomethacin-induced gastric damage. Dexamethasone pretreatment markedly reduced the extent of indomethacin-induced gastric damage in rats. Immunoneutralization of annexin-1 resulted in a reversal of the gastroprotective actions of dexamethasone. Similarly, pretreatment with either of two antagonists of the formyl peptide receptor family, to which annexin-1 binds, reversed the gastroprotective effects of dexamethasone. The inhibitory effects of dexamethasone on indomethacin-induced leukocyte adherence in the mesenteric microcirculation were abolished by pretreatment with an antibody directed against annexin-1 or with an antagonist of the formyl peptide receptors. These results demonstrate that annexin-1 mediates the gastroprotective effects of a glucocorticoid against NSAID-induced damage. We propose that in some circumstances, annexin-1 plays an important role as an endogenous mediator of mucosal defense.
Mucosal Inflammation Research Group, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, T2N 4N1, Canada.
Renata C O
RC
Zanardo
Mauro
M
Perretti
John L
JL
Wallace
D000818:Animals; D017305:Annexin A1 / Q000502:physiology*; D000893:Anti-Inflammatory Agents / Q000633:toxicity; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000633:toxicity*; D002448:Cell Adhesion / Q000187:drug effects; D003907:Dexamethasone / Q000633:toxicity; D007213:Indomethacin / Q000633:toxicity*; D007958:Leukocyte Count; D008297:Male; D008642:Mesenteric Veins / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013152:Splanchnic Circulation / Q000187:drug effects; D013272:Stomach Diseases / Q000139:chemically induced / Q000517:prevention & control*
D017305:Annexin A1; D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003907:Dexamethasone; D007213:Indomethacin