Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment
Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor overactivity after intravesical resiniferatoxin treatment
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DOI：
10.1111/j.1464-410x.2003.04722.x
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发表时间：
2004-04-01
影响因子：
4.5
通讯作者：
Anand, P
中科院分区：
文献类型：
--
作者：
Brady, CM;Apostolidis, AN;Anand, P
目的比较前列腺素P9.5(PGP9.5)和瞬时受体潜在香草酸受体(TRPV1)在脊髓神经源性逼尿肌过度活动(NDO)患者膀胱内注射前后前列腺素P9.5(PGP9.5)和瞬时受体潜在香草酸受体(TRPV1)的免疫反应性，因为对辣椒素有反应的脊髓NDO患者膀胱上皮下PGP9.5染色的神经纤维减少，TRPV1在正常和过度活动的人膀胱中存在。在每次滴注后4周和临床反应最大时与对照组的活检组织进行比较。冰冻切片与兔抗TRPV1和PGP9.5抗体孵育，并用标准免疫组织化学方法进行评估。PGP9.5神经密度是由一名不知道样本来源的观察者使用神经计数格栅进行分析的。另外两个独立的观察者不知道对方的结果，使用了一个随机的评分表来评估TRPV1神经纤维的密度和强度。免疫组织化学结果与组织学结果(苏木精-伊红染色)、Mann-Whitney检验(P<；0.05显著)和Pearson检验相关性进行比较。结果8名对照组和20名脊髓NDO患者，14名(5名临床应答者和9名非应答者)接受了最大剂量的松脂毒素治疗。NDO组PGP9.5和TRPV1神经纤维较正常对照组增多(P分别为0.007和0.002)。在树脂毒素之前，两组患者的PGP9.5和TRPV1的免疫反应性相似。在有反应的患者中，治疗后PGP9.5和TRPV1阳性纤维减少(P=0.008)，而在无反应的患者中没有变化。治疗后TRPV1和PGP9.5的变化呈正相关(r=0.001.88，P<0.0 5)。结论白花蛇毒治疗后TRPV1和PGP9.5免疫反应神经纤维减少(至对照组织水平)，提示NDO患者神经纤维数量增加主要来源于感觉神经并表达TRPV1。由于有反应者和无反应者的基线神经纤维值相似，一个额外的因素可能解释了治疗结果的差异。
OBJECTIVETo compare PGP9.5 and transient receptor potential vanilloid receptor (TRPV1) suburothelial immunoreactivity between controls and patients with spinal neurogenic detrusor overactivity (NDO) before and after treatment with intravesical resiniferatoxin, as suburothelial PGP9.5-staining nerve fibres decrease in patients with spinal NDO who respond to intravesical capsaicin, and TRPV1 is present on these suburothelial nerve fibres in normal and overactive human urinary bladder.PATIENTS AND METHODSPatients with refractory NDO were enrolled in a prospective, randomized, parallel-group, double-blind, placebo-controlled trial using escalating doses of resiniferatoxin to a maximum of 1 mumol/L. Flexible cystoscopic bladder biopsies obtained at baseline, 4 weeks after each instillation and at the time of maximum clinical response were compared with biopsies taken from control subjects. Frozen sections were incubated with rabbit antibodies to TRPV1 and PGP9.5, and assessed using standard immunohistochemical methods. PGP9.5 nerve density was analysed using a nerve-counting graticule by an observer unaware of sample origin. Another two independent observers unaware of each other's results used a random grading scale to evaluate TRPV1 nerve fibre density and intensity. The immunohistochemistry results were compared with histology findings (haematoxylin-eosin), and the Mann-Whitney test used to assess any differences (P < 0.05 significant) and the Pearson test for correlation.RESULTSThere were eight controls and 20 patients with spinal NDO, 14 (five clinical responders and nine not) who received the maximum dose of resiniferatoxin. There were more PGP9.5 and TRPV1 nerve fibres in patients with NDO than in controls (P = 0.007 and 0.002, respectively). Immunoreactivity before resiniferatoxin was similar in both groups for both PGP9.5 and TRPV1. In responders there were fewer PGP9.5 and TRPV1-positive fibres after treatment (P = 0.008 for each) but no change in those not responding. Changes after treatment for TRPV1 correlated well with those for PGP9.5 (r = 0.88, P < 0.001).CONCLUSIONSThe decrease of PGP9.5 and TRPV1 immunoreactive nerve fibres in responders to resiniferatoxin (to levels in control tissues) suggests that the increased numbers of nerve fibres in patients with NDO are mainly of sensory origin and express TRPV1. As baseline nerve fibre values were similar in responders and nonresponders, an additional factor may account for the difference in treatment outcome.