Ro Yuuki, Hamada Chieko, Inaba Masanori, Io Hiroaki, Kaneko Kayo, Tomino Yasuhiko
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Nephrol Dial Transplant. 2007 Oct;22(10):2838-48. doi: 10.1093/ndt/gfm323. Epub 2007 Jun 2.
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.
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.
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.
It appears that the administration of the MMP inhibitor ONO-4817 might be a new approach to the amelioration of PS.
在伴有包裹性腹膜硬化（EPS）的腹膜透析患者以及葡萄糖酸氯己定诱导的腹膜硬化（PS）动物模型中，腹透液中明胶酶即基质金属蛋白酶-2的活性增加。本研究的目的是探讨基质金属蛋白酶抑制剂（ONO-4817），一种具有抗血管生成和抗浸润作用的抗癌药物，对葡萄糖酸氯己定诱导的PS大鼠腹膜纤维化发展的影响。
45只Sprague-Dawley（S-D）大鼠，腹腔注射生理盐水作为对照（n = 15），CH组（n = 15）腹腔注射葡萄糖酸氯己定（CH）（1.5 ml/100 g）。从研究开始至结束，对CH大鼠静脉注射ONO-4817（5 mg/大鼠）（ONO-4817组，n = 15）。给予ONO-4817 22天后，处死大鼠并获取壁层腹膜。通过逆转录-聚合酶链反应（RT-PCR）分析腹膜中转化生长因子-β（TGF-β）、α-平滑肌肌动蛋白（α-SMA）和I型胶原的基因表达。同时对腹膜组织进行免疫组织学评估。
ONO-4817显著抑制了间皮下层增厚和腹膜中I型胶原的积聚。ONO-4817还阻止了巨噬细胞数量和血管数量的增加。在接受ONO-4817治疗的大鼠中，腹膜中TGF-β、α-SMA和I型胶原的表达明显受到抑制。
看来给予MMP抑制剂ONO-4817可能是改善PS的一种新方法。
