Stein Paul, Rajasekaran Mahadevan, Parsons C Lowell
Division of Urology, University of California, Medical Center, San Diego, California 92103-8897, USA.
Urology. 2005 Oct;66(4):903-7. doi: 10.1016/j.urology.2005.05.021.
To test whether the presence of Tamm-Horsfall protein (THP) can limit the injury caused by low-molecular-weight (LMW) urinary cations using an in vivo rat bladder injury model. Previous studies have shown that normal urine contains LMW cations toxic to cultured bladder cells and that THP, a ubiquitous urinary glycoprotein, protects against this cytotoxic effect. THP may sequester and subsequently neutralize these toxic urinary cations.
A dialysis product of LMW (greater than 100 but less than 3500) was prepared from pooled 24-hour urine samples from healthy volunteers and evaluated for urothelial cell cytotoxicity. The LMW toxic factor (TF) was instilled into the bladders of Sprague-Dawley rats (n = 9) after recording the baseline urodynamic parameters, primarily nonvoiding contractions (NVCs). We also evaluated the ability of THP to block abnormal physiologic activity indicative of bladder injury caused by exposure to the TF (greater than 100 but less than 3500 molecular weight) by co-instillation of the TF with THP.
The TF had a significant cytotoxic effect in cultured rat (P < 0.01) and human (P < 0.01) bladder epithelial cells. Rat bladder NVCs increased significantly over baseline contractility when potassium chloride was infused after TF (1.68 +/- 0.11 NVC/min; P < 0.0001) but not after infusion of THP plus TF (0.28 +/- 0.085 NVC/min).
Normal urine contains a cationic factor that appears to increase urothelial permeability by injuring the mucosa, allowing potassium ions to penetrate the urothelium and depolarize underlying nerves and muscle. THP appears to neutralize the LMW fraction electrostatically and attenuate urothelial damage, resulting in suppression of potassium chloride-mediated bladder hyperactivity.
使用体内大鼠膀胱损伤模型，测试Tamm-Horsfall蛋白（THP）的存在是否能限制低分子量（LMW）尿阳离子所造成的损伤。既往研究表明，正常尿液含有对培养的膀胱细胞有毒的LMW阳离子，而THP是一种普遍存在的尿糖蛋白，可防止这种细胞毒性作用。THP可能螯合并随后中和这些有毒的尿阳离子。
从健康志愿者的24小时混合尿液样本中制备LMW（大于100但小于3500）的透析产物，并评估其对尿路上皮细胞的细胞毒性。在记录基线尿动力学参数（主要是非排尿收缩，NVCs）后，将LMW毒性因子（TF）注入Sprague-Dawley大鼠（n = 9）的膀胱。我们还通过将TF与THP共同注入，评估THP阻断由暴露于TF（分子量大于100但小于3500）引起的指示膀胱损伤的异常生理活动的能力。
TF对培养的大鼠（P < 0.01）和人（P < 0.01）膀胱上皮细胞具有显著的细胞毒性作用。当在TF后注入氯化钾时，大鼠膀胱NVCs较基线收缩力显著增加（1.68±0.11次NVC/分钟；P < 0.0001），但在注入THP加TF后则未增加（0.28±0.085次NVC/分钟）。
正常尿液含有一种阳离子因子，该因子似乎通过损伤黏膜增加尿路上皮通透性，使钾离子穿透尿路上皮并使下层神经和肌肉去极化。THP似乎通过静电作用中和LMW部分并减轻尿路上皮损伤，从而抑制氯化钾介导的膀胱活动亢进。
