Inhibitory effects of matrix metalloproteinase inhibitor ONO-4817 on morphological alterations in chlorhexidine gluconate-induced peritoneal sclerosis rats.

BACKGROUND

The activity of gelatinase, matrix metalloproteinase-2, in effluent was increased in peritoneal dialysis patients with encapsulated peritoneal sclerosis (EPS) and in chlorhexidine gluconate-induced peritoneal sclerosing (PS) animal models. The objective of the present study was to investigate the effect of matrix metalloproteinase inhibitor (ONO-4817), an anticancer agent with anti-angiogenesis and anti-infiltration effects, on the development of peritoneal fibrosis in chlorhexidine gluconate-induced PS rats.

METHODS

Forty-five Sprague-Dawley (S-D) rats were intraperitoneally injected with saline as control (n = 15) or with chlorhexidine gluconate (CH) (1.5 ml/100 g) in the CH group (n = 15). ONO-4817 (5 mg/rat) was administered intravenously to CH rats (the ONO-4817 group, n = 15) from initiation to the end of the study. After 22 days of ONO-4817 administration, the rats were sacrificed and the parietal peritoneum was harvested. The gene expressions of transforming growth factor-beta (TGF-beta), alpha-smooth muscle actin (alpha-SMA) and type I collagen in the peritoneum were analysed by the reverse transcription-polymerase chain reaction (RT-PCR). Peritoneal tissues were also evaluated immunohistologically.

RESULTS

ONO-4817 significantly inhibited thickening of the submesothelial layer and accumulation of type I collagen in the peritoneum. ONO-4817 also prevented increases of the number of macrophages and blood vessels. The expressions of TGF-beta, alpha-SMA and type I collagen in the peritoneum were markedly suppressed in ONO-4817-treated rats.

CONCLUSION

It appears that the administration of the MMP inhibitor ONO-4817 might be a new approach to the amelioration of PS.