Therapeutic implications of the specific inhibition of causative matrix metalloproteinases in experimental colitis induced by dextran sulphate sodium
Therapeutic implications of the specific inhibition of causative matrix metalloproteinases in experimental colitis induced by dextran sulphate sodium
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DOI：
10.1002/path.1978
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发表时间：
2006-07-01
影响因子：
7.3
通讯作者：
Imai, K.
中科院分区：
文献类型：
--
作者：
Kobayashi, K.;Arimura, Y.;Imai, K.
在炎症性肠病(IBD)的炎症和伤口愈合过程中，细胞外基质动力学受到一系列基质金属蛋白酶(MMPs)的高度调控，对组织重建至关重要。与预期相反，到目前为止，关于基质金属蛋白酶抑制剂在实验性结肠炎模型中具有一些有益的治疗效果的报道有限。此外，针对某些肿瘤的基质金属蛋白酶抑制剂的临床试验也没有显示出任何治疗效果。缺乏成功的一个主要原因可能是对所需的抑制活性的准确谱存在明显的不确定性。由于肿瘤坏死因子α是结肠炎的关键介质，以剂量依赖的方式促进MNIP的产生，抗肿瘤坏死因子α药物治疗IBD的成功促使我们重新评估抑制基质金属蛋白酶的治疗潜力。首先，利用定量聚合酶链式反应(PCR)、免疫印迹和酶谱技术，我们确定了哪些MMPs与葡聚糖硫酸钠诱导的小鼠实验性结肠炎有关。接下来，我们研究了MAPK和NF-kappa B信号通路在这些基质金属蛋白酶基因表达调控中的独特作用。最后，我们研究了这些MHPS的转录调控是否有助于预防结肠炎，无论是间接使用MAPK和/或核因子kappa B信号通路的抑制剂，还是直接使用针对这些MMPs的siRNA。在结肠炎的临床病程之前，结肠组织中基质金属蛋白酶-3和基质金属蛋白酶-10的表达水平变化。接受这些信号抑制剂的小鼠结肠炎得到改善，同时抑制了基质金属蛋白酶的表达。此外，针对MMP3和MMP10的siRNA有效地降低了这些MMPs的转录，并降低了结肠炎的严重程度。我们得出结论，基质金属蛋白酶-3和基质金属蛋白酶-10在结肠炎的过度组织破坏中起因果作用。特异性抑制这些MMPs有望为IBD提供新的治疗方法。版权所有(C)2006年大不列颠和爱尔兰病理学会。
Extracellular matrix dynamics, crucial for tissue remodelling, are highly regulated by a cascade of matrix metalloproteinases (MMPs) during inflammation and wound healing processes in inflammatory bowel disease (IBD). Contrary to expectations, there are limited reports to date that MMP inhibitors have some beneficial therapeutic effects in experimental colitis models. Furthermore, clinical trials of MMP inhibitors against certain tumours have failed to show any therapeutic benefit. One major reason for this lack of success may be the apparent uncertainty about the precise spectrum of inhibitory activity required. Since tumour necrosis factor alpha (TNF alpha), a key mediator in colonic inflammation, promotes MNIP production in a dose-dependent manner, the therapeutic success of anti-TNF alpha agents against IBD motivated us to re-evaluate the therapeutic potential of MMP inhibition. First, using a quantitative polymerase chain reaction (PCR), western blotting, and zymography, we determined which MMPs were relevant to experimental colitis induced in mice by dextran sulphate sodium. Next, we examined a distinct role for MAPK and NF kappa B signalling pathways in the regulation of the expression of these MMP genes. Finally, we examined whether transcriptional regulation of these MHPs, either indirectly using inhibitors of MAPK and/or NF kappa B signalling pathways or directly using siRNA directed against these MMPs, contributes to the prevention of colitis. Changes in the expression level of colonic MMP-3 and MMP-10 preceded the clinical course of colitis. Colitis improved in mice that received these signal inhibitors, together with suppression of MMP expression. Moreover, siRNA that targeted MMP-3 and MMP-10 effectively reduced both the transcription of these MMPs and the severity of colitis. We conclude that MMP-3 and MMP-10 play a causal role in excess tissue destruction in colitis. Specific inhibition of these MMPs should provide novel therapeutics against IBD. Copyright (c) 2006 Pathological Society of Great Britain and Ireland.