OK-432 treatment increases matrix metalloproteinase-9 production and improves dimethylnitrosamine-induced liver cirrhosis in rats

Kupffer cells are major matrix metalloproteinase-producing cells in the liv er. The production of metalloproteinases in Kupffer cells may contribute to the improvement of liver fibrosis inducing liver cirrhosis. In this study, we examined the effect of the OK-432 (a biological response modifier) on t he dimethylnitrosamine-induced liver cirrhosis in rats. Dimethylnitrosamine (10 mu g/ml) was injected intraperitoneally into 20 male Wistar rats 3x/we ek for 4 weeks. For the subsequent 4 weeks, the animals were injected with saline (1 ml, 1x/week) (Group I, n=10) or OK-432 (1 Klinishe Einheit, 1x/we ek) (Group II, n=10). The control rats were injected with 1 ml saline for t he initial 4 weeks and subsequent 4 weeks (Group III, n=10). The degree of hepatic fibrosis, the immunolocalization of type IV collagen, hyaluronic ac id, and alpha-smooth muscle actin, and the mRNA expression by Northern blot ting and the activity by gelatin zymography of metalloproteinase-9 were eva luated. Serum aminotransferase, hyaluronic acid, interleukin-1 beta and tum or necrosis factor-alpha levels were measured. The deposition of alpha-smoo th muscle actin and extracellular matrix containing type IV collagen and hy aluronic acid was markedly suppressed by OK-432. The mRNA expression and th e activity of metalloproteinase-9 were markedly increased by OK-432. The se rum aminotransferase and hyaluronic acid levels were decreased by OK-432. T he serum interleukin-1 and tumor necrosis factor-ct values were lower than the detectable limit in all samples from all three groups. These results in dicate that OK-432 increased the production of metalloproteinase-9 and impr oved the par dimethylnitrosamine-induced liver cirrhosis. OK-432 is suggest ed to be useful for the treatment of liver cirrhosis.