Toxic factors in human urine that injure urothelium
Toxic factors in human urine that injure urothelium
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DOI：
10.1111/j.1442-2042.2006.01301.x
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发表时间：
2006-04-01
影响因子：
2.6
通讯作者：
Parsons, C. Lowell
中科院分区：
文献类型：
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作者：
Rajasekaran, Mahadevan;Stein, Paul;Parsons, C. Lowell
目的：下尿渗透屏障的丧失和钾被动循环进入组织是间质性膀胱炎的始发事件。我们测试了正常尿液中的低分子量细胞毒性组分是否会导致大鼠对膀胱内钾敏感，以及硫酸化阴离子多糖多硫酸戊聚糖是否可以中和该组分的细胞毒性活性。方法：通过透析从正常人尿液中制备低分子量（> 100 < 3500）有毒尿液组分，并进一步研究冻干无盐产品（毒性因子）。麻醉的成年雄性斯普拉格-道利大鼠接受膀胱内注射钠或钾，并记录尿动力学参数，包括排尿次数和非排尿收缩。然后输注硫酸鱼精蛋白、再水化的毒性因子或毒性因子加戊聚糖多硫酸，然后输注钾，并重复尿动力学测量。使用培养的大鼠尿路上皮细胞在商业细胞毒性方案中评估毒性因子。结果：在毒性因子后输注钾时，大鼠膀胱非排尿性收缩明显增加（1.681+/-0.1131非排尿性收缩/分钟；P = 0.0004），但在毒性因子与戊聚糖多硫酸盐预混合后则没有。毒性因子对培养的大鼠膀胱上皮细胞具有显着（P < 0.001）的细胞毒作用；毒性因子加戊聚糖多硫酸盐的细胞毒性显着低于单独的毒性因子（P < 0.007）。结论：正常尿液中含有阳离子细胞毒性因子，它通过损伤粘膜来增加尿路上皮的通透性，使钾渗透尿路上皮并使下面的神经和肌肉去极化。多硫酸戊聚糖可中和毒性因子，减轻尿路上皮损伤，并抑制钾介导的膀胱过度活动。
Aim: Loss of the lower urinary permeability barrier and passive potassium cycling into tissue are an initiating event in interstitial cystitis. We tested whether a low molecular weight cytotoxic fraction from normal urine causes sensitivity to intravesical potassium in rats and whether the sulfated anionic polysaccharide pentosan polysulfate can neutralize this fraction's cytotoxic activity.Methods: A low molecular weight (> 100 < 3500) toxic urinary fraction was prepared from normal human urine by dialysis and the lyophilized, salt free product (toxic factor) further investigated. Anaesthetized adult male Sprague-Dawley rats received intravesical sodium or potassium, and urodynamic parameters, including number of voids and non-voiding contractions, were recorded. Then protamine sulfate, rehydrated toxic factor, or toxic factor plus pentosan polysulfate was infused, followed by potassium, and urodynamic measurements repeated. The toxic factor was evaluated in a commercial cytotoxicity protocol using cultured rat urothelial cells.Results: Rat bladder non-voiding contractions increased markedly over baseline when potassium was infused after toxic factor (1.681 +/- 0.1131 non-voiding contractions/min; P = 0.0004) but not after toxic factor premixed with pentosan polysulfate. Toxic factor had a significant (P < 0.001) cytotoxic effect in cultured rat bladder epithelial cells; toxic factor plus pentosan polysulfate was significantly less cytotoxic than toxic factor alone (P < 0.007).Conclusions: Normal urine contains a cationic cytotoxic factor that increases urothelial permeability by injuring the mucosa, allowing potassium to penetrate the urothelium and depolarize the underlying nerves and muscles. Pentosan polysulfate neutralizes the toxic factor, attenuates urothelial damage, and suppresses potassium-mediated bladder hyperactivity.