Pravastatin inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats
Pravastatin inhibits the Rho/CCN2/extracellular matrix cascade in human fibrosis explants and improves radiation-induced intestinal fibrosis in rats
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DOI：
10.1158/1078-0432.ccr-07-0625
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发表时间：
2007-09-15
影响因子：
11.5
通讯作者：
Vozenin-Brotons, Marie-Catherine
中科院分区：
文献类型：
--
作者：
Haydont, Valrie;Bourgier, Celine;Vozenin-Brotons, Marie-Catherine
目的：放疗后肠道并发症是由跨壁纤维化引起的，影响癌症幸存者的生活质量。放射性纤维化被认为是永久性和不可逆的，但最近，它的动态性质被显示出来，为抗纤维化治疗的发展提供了新的机会。在这些新靶点中，我们确定了Rho/ROCK通路，并考虑研究普伐他汀治疗是否抑制Rho通路激活并引发抗纤维化作用。实验设计：用普伐他汀孵育后，在呈现辐射纤维化重塑的人体外植体中监测Rho和ROCK活性。随后对CCN2、I型胶原和纤维连接蛋白表达的调节进行了体外和放射性肠病引起的肠平滑肌细胞的评估。然后，在大鼠慢性辐射纤维化（19 Gy x射线）模型中，在饮用水中给予30 mg/kg/d普伐他汀治疗，探讨了普伐他汀抗纤维化作用的治疗相关性。结果：普伐他汀对粘膜下间充质细胞Rho活性有特异性抑制作用。普伐他汀还能在放射性肠病分离的人体外植体和平滑肌细胞中引起ROCK抑制和随后的CCN2产生。I型胶原蛋白和纤维连接蛋白的抑制确实发生，表明普伐他汀调节间充质细胞的分泌表型。最后，治疗性普伐他汀可改善大鼠放射性肠病。这种结构的改善与减少CCN2的沉积和随后减少的细胞外基质沉积有关。结论：普伐他汀靶向已形成的纤维化是一种有效、安全的治疗放射性肠病的抗纤维化策略，且易于应用于临床。
Purposes: Intestinal complications after radiotherapy are caused by transmural fibrosis and impair the quality of life of cancer survivors. Radiation fibrosis was considered permanent and irreversible, but recently, its dynamic nature was shown, providing new opportunities for the development of antifibrotic therapies. Among these new targets, we identified the Rho/ROCK pathway and thought to investigate whether pravastatin treatment inhibits Rho pathway activation and elicits an antifibrotic action.Experimental Design: Rho and ROCK activities were monitored in human explants presenting radiation fibrosis remodeling after incubation with pravastatin. Subsequent modulation of CCN2, type I collagen, and fibronectin expression were assessed ex vivo and in intestinal smooth muscle cells derived from radiation enteropathy. Then, the therapeutic relevance of the antifibrotic action of pravastatin was explored in vivo in a rat model of chronic radiation fibrosis (19 Gy X-rays) treated with 30 mg/kg/d pravastatin in the drinking water.Results:The results obtained with human explants show that pravastatin specifically inhibits Rho activity in submucosal mesenchymal cells. Pravastatin also elicits ROCK inhibition, and subsequent CCN2 production in human explants and smooth muscle cells isolated from radiation enteropathy. Inhibition of type I collagen and fibronectin does occur, showing that pravastatin modulates the secretory phenotype of mesenchymal cells. Lastly, curative pravastatin administration improves radiation enteropathy in rats. This structural improvement is associated with decreased deposition of CCN2 and subsequent decreased extracellular matrix deposition.Conclusion: Targeting established fibrosis with pravastatin is an efficient and safe antifibrotic strategy in radiation- induced enteropathy, and is easily transferable into the clinic.