Abstract
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 μM) loaded gastric mucosal cells were incubated with neutrophils (5 × 106 cells/well) that were activated by cytochalasin B (5 μM) and formyl-methionyl-leucyl-phenylalanine (fMLP) (1 nM). In thein 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 μM) 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 × 106 cells (P < .05) by application of rebamipide (300 μM) with little change inKD. 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 × 106 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.
Footnotes
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Send reprint requests to: Dr. Ki Whan Hong, Professor, Department of Pharmacology, College of Medicine, Pusan National University, Ami-Dong 1-Ga, Seo-Gu, Pusan 602-739, Korea.
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↵1 This study was supported by research funds from Korea Otsuka Pharmaceutical Co., Ltd.
- Abbreviations:
- MPO
- myeloperoxidase
- fMLP
- formyl-methionyl-leucyl-phenylalanine
- GMC
- gastric mucosal cell
- PMA
- phorbol myristate acetate
- BCECF-AM
- 2′,7′-bis-(2-carboxyethyl)-5-(and -6)-carboxyfluorescein, acetomethyl ester
- BSS
- balanced salt solution
- Received September 4, 1996.
- Accepted December 5, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
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