醛固酮受体拮抗剂联合ACEI抗腹膜纤维化机制的研究

目的①药物干预腹膜纤维化的机制研究;②观察单核细胞趋化蛋白-1(MCP-1)、C-JUN/AP-1在大鼠腹膜间皮细胞的表达及其在药物干预后的变化,探讨腹膜透析后腹膜纤维化的机制及解决办法。方法50只Wistar大鼠随机分5组。除A组余腹腔内每日注入20ml4.25%百特透析液,试验第1、3、5、7d腹腔注射脂多糖(LPS)0.6ml/(kg·h),B组腹膜纤维化模型组;C组西拉普利10mg/(kg·d)灌胃;D组安体舒通100mg/(kg·d)灌胃。E组联合给药组。30d后收集大鼠腹膜做病理(HE染色,Masson染色),免疫组化查腹膜间皮细胞MCP-1、C-JUN/AP-1的表达,并腹膜透析液计数腹水中细胞总数和巨噬细胞数及测定转化生长因子-β(TGF-β)的浓度。结果给药组(C、D、E组)的腹膜病理改变比模型组(B组)轻,转化生长因子-β的浓度下降具有统计学意义。各组腹膜间皮细胞均有MCP-1的表达,毛细血管和小静脉内皮细胞都可见其表达,联合给药组腹膜纤维化程度最轻,腹水巨噬细胞计数少,MCP-1、C-JUN/AP-1的表达少。结论联合应用醛固酮(ALDO)受体拮抗剂及ACEI能有效的防治腹膜纤维化。机制可能为抑制腹膜间皮细胞C-JUN/AP-1表达,在转录的水平上降低TGF-β活性,并抑制MCP-1表达,抑制腹膜炎性反应,减轻纤维化。

The effect and mechanism of aldosterone receptor blocker and angiotensin-converting enzyme inhibitor on peritoneal fibrosis

Objective To investigate the effect and mechanism of aldosterone receptor blocker and angio- tensin-converting enzyme inhibitor on peritoneal fibrosis. Methods Fifty male Wistar rats were randomly divided into 5 groups. Group A (n = 10) was the control group, and groups B, C, D and E (n = 10 / each group) were treated with intraperitoneal injection of 20 ml 4.25% Beter dialysate daily. On days 1, 3, 5 and 7, rats were given intraperito- neal injection of lipopolysaccharides (LPS) 0.6 mg/kg/day. Group B (n=10) was used as the model of peritoneal fibrosis. Rats in group C were given angiotensin-converting enzyme inhibitor 10 mg/kg/day by gastric gavage in the morning once a day. Rats in group D were treated with aldosterone receptor blocker 100 mg/kg/day by gastric gavage once a day. Those in group E were treated with angiotensin-converting enzyme inhibitor as well as aldosterone receptor blocker. Rats were sacrificed after the treatment for 30 days. Their parietal peritoneum was stained with HE and Masson methods. In the peritoneal dialysate fluid from rat abdominal cavity, total cells and macrophage cells were counted, and TGF-a in the fluid was measured. MCP-1 and C-JUN/AP-1 were examined in peritoneal mesothe- lial cells by immunohistochemical staining. Results Less pathological changes in peritoneum and low TGF-a in the dialysate were found in the treated groups (groups C, D and E) than those in the untreated group (group B). The expression of MCP-1 was found in peritoneal mesothelial cells as well as in the endothelial cells on capillary and small veins. Group E showed less peritoneal fibrosis, lower number of macrophages in the dialysate, and lower expression of MCP-1 and C-JUN/AP-1 in peritoneal mesothelial cells. Conclusions Aldosterone receptor blocker in combination with angiotensin-converting enzyme inhibitor effectively inhibited peritoneal fibrosis by the inhibition of inflammation reaction and fibrosis processes. This effect may be related to the decrease level of MCP-1 and C-JUN/ AP-1 in peritoneal mesothelial cells and the inhibition of TGF-a and MCP-1 expression.