Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumour necrosis factor-α
Prevention and treatment of experimental crescentic glomerulonephritis by blocking tumour necrosis factor-α
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DOI：
10.1093/ndt/16.3.518
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发表时间：
2001-03-01
影响因子：
6.1
通讯作者：
Pusey, CD
中科院分区：
文献类型：
--
作者：
Karkar, AM;Charles, JS;Pusey, CD
背景资料。控制肾小球肾炎进展的机制尚不清楚，但越来越多的证据表明，肿瘤坏死因子-α在肾小球炎症和瘢痕形成的许多方面发挥着核心作用。我们研究了肿瘤坏死因子-α的作用。在Wistar京都(WKY)大鼠新月体肾炎的实验模型中，利用其可溶性受体sTNFr P55，在肾炎建立前后持续阻断内源性肿瘤坏死因子-α。单次静脉注射0.1毫升肾毒性血清诱导大鼠肾小球肾炎。实验一在肾炎诱导前1h给予sTNFr P55 2 mg/kg，以后每天给药，直至第4天。实验2采用类似方案，但继续给药至第10天。在第三实验中，sTNFr P55治疗延至肾炎诱导后第4天至第10天。用标准方法评价治疗对大鼠肾功能、肾脏组织学、细胞浸润、活化、增殖及IL-1β表达的影响。在第一个实验中，sTNFr P55的短期治疗显著减少了蛋白尿和纤维素样坏死。还可减少肾小球细胞的浸润、活化和增殖。在第二个实验中，sTNFr P55的长期治疗导致蛋白尿和肾小球炎症的所有组织和细胞参数持续减少；特别是它完全阻止了新月体的发展。在第三个实验中，用sTNFr P55延迟治疗已确诊的肾炎显著减少了蛋白尿和肾小球炎症，包括新月体形成的发生率。在两个长期实验中，sTNFr P55治疗的大鼠肾小球IL-1β表达减少，血清IL-β浓度降低。本研究表明，在新月体肾炎大鼠模型中，中和内源性肿瘤坏死因子-α在预防急性肾小球炎症和新月体形成以及治疗已建立的疾病方面是有效的。这些结果可能对人类肾小球肾炎有治疗意义。
Background. The mechanisms controlling progression of glomerulonephritis are poorly understood, but there is increasing evidence that tumour necrosis factor-alpha (TNF-alpha plays a central role in many aspects of glomerular inflammation and scarring. We investigated the role of TNF-alpha. in an experimental model of crescentic glomerulonephritis in Wistar Kyoto (WKY) rats by continuously blocking endogenous TNF-alpha, using its soluble receptor sTNFr p55, both before and after establishment of nephritis.Methods. Glomerulonephritis was induced by a single intravenous injection of 0.1 mi nephrotoxic serum. In the first experiment, rats were pre-treated with sTNFr p55 2 mg/kg intraperitoneally 1 hour before induction of nephritis and on a daily basis thereafter until day 4. In the second experiment, a similar protocol was followed, but treatment with sTNFr p55 was continued until day 10. In the third experiment, treatment with sTNFr p55 was delayed until 4 days after induction of nephritis and continued until day 10. The effects of treatment on renal function, renal histology, cellular infiltration, activation and proliferation, and IL-1 beta expression were assessed by standard methods.Results. In the first experiment, short-term treatment with sTNFr p55 caused a marked reduction in albuminuria and fibrinoid necrosis. It also reduced glomerular cell infiltration, activation and proliferation. In the second experiment, prolonged treatment with sTNFr p55 caused a sustained reduction in albuminuria and all histological and cellular parameters of glomerular inflammation; in particular it completely prevented the development of crescents. In the third experiment, delayed therapy of established nephritis with sTNFr p55 significantly reduced albuminuria and glomerular inflammation, including the prevalence of crescent formation. In both long-term experiments, there was less glomerular expression of IL-1 beta and lower serum concentrations of IL-beta in sTNFr p55-treated rats.Conclusions. This study shows that neutralization of endogenous TNF-alpha is effective in preventing acute glomerular inflammation and crescent formation, and in treating established disease, in a rat model of crescentic nephritis. These results may have therapeutic implications for human glomerulonephritis.