Preventive effect of rebamipide on gastric mucosal cell damage evoked by activation of formyl-methionyl-leucyl-phenylalanine receptors of rabbit neutrophils.

We investigated the underlying mechanism by which rebamipide exerts a preventive effect on neutrophil-mediated gastric mucosal cell damage. The release of 2',7'-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein (an index of cytotoxicity) was significantly increased by 16.7% (P < .05) when 2',7'-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein-acetomethyl ester (5 microM) loaded gastric mucosal cells were incubated with neutrophils (5 x 10(6) cells/well) that were activated by cytochalasin B (5 microM) and formyl-methionyl-leucyl-phenylalanine (fMLP) (1 nM). In the in vitro study, upon application of cytochalasin B and fMLP, formation of superoxide anion and release of myeloperoxidase increased with increased neutrophil aggregation. These parameters were attenuated by pretreatment with rebamipide (100-1000 microM) in a concentration-dependent manner. In the Scatchard analysis, the maximum binding of [3H]fMLP to neutrophils decreased from 0.57 to 0.44 pmol/2 x 10(6) cells (P < .05) by application of rebamipide (300 microM) with little change in K(D). Neutrophils isolated from rabbits orally treated with rebamipide (100 mg/kg for 3 days) also showed a decrease in the production of superoxide anion upon stimulation with fMLP and a decrease in the binding of [3H]fMLP to its receptors on the neutrophil plasma membrane (0.59-0.45 pmol/2 x 10(6) cells, P < .05). Taken together, it is suggested that the inhibitory effect of rebamipide on the neutrophil-mediated gastric mucosal cell injury is due, in part, to alterations in the neutrophil membrane that ultimately result in a decrease in the number of binding sites for fMLP to its receptors.