Schwentner C, Oswald J, Lunacek A, Pelzer A E, Fritsch H, Schlenck B, Karatzas A, Bartsch G, Radmayr C
Department of Pediatric Urology, Medical University Innsbruck, Innsbruck, Austria.
J Urol. 2008 Aug;180(2):694-700. doi: 10.1016/j.juro.2008.04.048. Epub 2008 Jun 13.
Vesicoureteral reflux is caused by a defective valve mechanism of the ureterovesical junction. Previous studies have revealed structural and metabolic changes in the intravesical ureter, impairing its contractile properties. Smooth musculature and nerves are replaced by collagen, while matrix degrading enzymes are over expressed. We investigated the presence of regulating cytokines and the extracellular matrix composition to elucidate further the pathophysiology of vesicoureteral reflux.
Ureteral endings were obtained from 28 children during antireflux surgery, and 14 age matched autopsy specimens served as controls. Routine histological sections were immunostained for insulin-like growth factor-1, nerve growth factor, transforming growth factor-beta1, tumor necrosis factor-alpha and vascular endothelial growth factor. Smooth muscle staining was supplemented by tenascin C, tetranectin and fibronectin detection. Staining patterns were investigated using computer assisted, high power field magnification analyses.
Tumor necrosis factor-alpha and transforming growth factor-beta1 were significantly more abundant in vesicoureteral reflux samples, whereas insulin-like growth factor-1, nerve growth factor and vascular endothelial growth factor were more prevalent in healthy controls. Fibronectin was intensely expressed in refluxing ureters, while it was scarce in healthy children. Tenascin C was notable within the urothelium of both groups. Only vesicoureteral reflux samples displayed tenascin C in the musculature and connective tissue. Tetranectin staining was only detected in vesicoureteral reflux.
Several cytokines are differentially expressed in primary refluxing ureters, indicating an ongoing tissue remodeling process in the ureterovesical junction region. Additionally, the smooth muscle coat is widely lacking, while extracellular matrix proteins typical for tissue shrinkage and reorganization are over expressed. These alterations are likely to contribute to the malfunctioning active ureteral valve mechanism in primary vesicoureteral reflux.
膀胱输尿管反流是由输尿管膀胱连接部瓣膜机制缺陷引起的。先前的研究已经揭示了膀胱内输尿管的结构和代谢变化，损害了其收缩特性。平滑肌组织和神经被胶原蛋白取代，而基质降解酶过度表达。我们研究了调节细胞因子的存在和细胞外基质组成，以进一步阐明膀胱输尿管反流的病理生理学。
在抗反流手术期间从28名儿童获取输尿管末端，并将14个年龄匹配的尸检标本作为对照。常规组织学切片针对胰岛素样生长因子-1、神经生长因子、转化生长因子-β1、肿瘤坏死因子-α和血管内皮生长因子进行免疫染色。通过检测腱生蛋白C、四连蛋白和纤连蛋白来补充平滑肌染色。使用计算机辅助的高倍视野放大分析研究染色模式。
肿瘤坏死因子-α和转化生长因子-β1在膀胱输尿管反流样本中明显更丰富，而胰岛素样生长因子-1、神经生长因子和血管内皮生长因子在健康对照中更普遍。纤连蛋白在反流输尿管中强烈表达，而在健康儿童中很少见。腱生蛋白C在两组的尿路上皮中都很明显。只有膀胱输尿管反流样本在肌肉组织和结缔组织中显示腱生蛋白C。仅在膀胱输尿管反流中检测到四连蛋白染色。
几种细胞因子在原发性反流输尿管中差异表达，表明输尿管膀胱连接部区域正在进行组织重塑过程。此外，平滑肌层广泛缺乏，而组织收缩和重组典型的细胞外基质蛋白过度表达。这些改变可能导致原发性膀胱输尿管反流中主动输尿管瓣膜机制的功能障碍。
