The effect of OK-432 on rat experimental liver cirrhosis

In this study, we examined the effect of OK-432 (a biological response modi fier) on the production of matrix metalloproteinase (MMP)-9 in rat cultured Kupffer cells and on rat dimethylnitrosamine (DMN)-induced liver cirrhosis . Methods: In vitro. Kupffer cells were isolated from male Wistar rats and cultured for 24 hours. The MMP-9 mRNA expression in Kupffer cells and the activated type MMP-9 and a type IV collagenase activity in the medium with or without OK-432 were e xamined by Northern blot analysis, gelatin zymography and a type IV collage nase assay kit, respectively. In vivo. DMN was injected intraperitoneally i nto Wistar rats for 4 weeks, and liver cirrhosis was induced. The rats were then injected with OK-432 (1KE, 1/week) (OK-432 group) or saline (1ml, 1/w eek) (control group) for 4 weeks. The degree of hepatic fibrosis, the immun olocalization of alpha-smooth muscle actin (alpha-SMA) and type IV collagen , the MMP-9 mRNA expression by Northern blotting, and the activate MMP-9 de tection by gelatin zymography were compared between the OK-432 and control groups. Results: In vitro. A marked level of MMP-9 mRNA was present in Kupf fer cells cultured with medium containing OK-432, but was hardly observed i n the cells incubated with OK-432-free medium. Gelatin zymography showed 95 -KD activated type MMP-9 in culture medium treated with OK-432. The type IV collagenase activity in the medium treated with OK-432 was incr eased 24 to 48 hours after the treatment compared with that in the OK-432-f ree medium. In vivo. The deposition of extracellular matrix and the immunol ocalization of alpha-SMA and type IV collagen were markedly decreased in th e OK-432 group compared with the control group. However, the MMP-9 mRNA exp ression and active type MMP-9 were markedly increased in the OK-432 group c ompared with the control group. Conclusions: These results indicate that OK -432 exerts a beneficial effect of the production of MMP-9 in rat Kupffer c ells, and contributes to the improvement of DMN-induced liver cirrhosis in rats.