Mechanism of Bladder Overactivity in Pelvic Ischemia

描述(由申请人提供)： 膀胱过度活动合并各种下尿路症状(LUTS)，包括尿频、急迫性尿失禁、夜尿和盆腔疼痛。膀胱过度活动和LUTS的发生率随着年龄的增长而增加。临床研究表明，退伍军人中膀胱过度活动和LUTS的患病率几乎是普通人群的五倍。据报道，与没有膀胱过度活动的退伍军人相比，有膀胱过度活动的退伍军人的生活质量得分更低。在大多数情况下，过度活跃的膀胱症状与失眠、焦虑、疲劳甚至抑郁有关。膀胱过度活动和下尿路结石的易感因素尚不清楚。在老年男性中，良性前列腺增生症(BPH)引起的膀胱出口梗阻一直被归咎于此。然而，尿动力学研究表明，在大约三分之一到一半以上的病例中，老年人的LUT与BPH或膀胱出口梗阻无关，这表明有其他可能性。非梗阻性膀胱对LUTS的具体作用仍不清楚。我们试图引入这一概念，即衰老相关的膀胱缺血是无梗阻、非神经源性过度活动膀胱发生发展的一个独立因素。我们的概念得到了临床证据的支持，这些证据表明，老年患者的膀胱缺血与下尿路结石密切相关。经直肠彩色多普勒超声血流记录显示，与无症状的年轻对照组相比，老年患者的膀胱血流量显著减少。结果表明，在这些患者中，膀胱血流量的减少与LUTS的严重程度显著相关。缺血是胃、肠、子宫和细支气管处平滑肌痉挛的主要原因之一。我们对兔模型的研究表明，动脉粥样硬化诱导的盆腔缺血会导致膀胱过度活动和排尿频率增加。在初步研究中，我们发现慢性膀胱缺血通过磷脂酰肌醇3-激酶(PI3-Kinase)/蛋白激酶B(Akt)途径激活了平滑肌细胞和神经纤维中的氧化还原生存信号。氧化应激通过PI3-激酶和Akt的表达上调氧化还原生存信号，并引发两种重要的促进生存的反应：1)增加线粒体密度和呼吸频率。(2)平滑肌细胞钙摄取增加。这些氧化还原生存反应增强了平滑肌收缩，并与膀胱过度活动和排尿功能障碍有关。抑制PI3-Kinase可降低膀胱平滑肌对收缩刺激的过度反应。基于这些观察结果，我们推测：“膀胱缺血时氧化还原生存信号通过PI3-K/Akt通路被激活，刺激平滑肌和神经线粒体呼吸，促进平滑肌细胞钙摄取，导致过度收缩和排尿功能障碍”。我们的总体目标是 利用我们成熟的动物和细胞培养模型系统，探索缺血和氧化还原信号在膀胱过度活动中的作用。“我们的具体目标是：1)明确PI3-K/Akt生存通路和线粒体呼吸链在缺血条件下对膀胱平滑肌收缩的氧化还原调节作用。2)明确神经氧化还原元件对膀胱缺血时平滑肌细胞PI3-K/Akt生存通路、线粒体呼吸和钙摄取的调节作用。3)研究氧化还原修饰的M受体对膀胱缺血时平滑肌细胞PI3-K/Akt存活通路、线粒体呼吸和钙摄取的调节作用。4)开发针对氧化还原信号、氧化还原元件和修饰受体的治疗策略，以预防或逆转盆腔缺血时增强的平滑肌收缩和膀胱过度活动。这些拟议的研究将阐明无梗阻、非神经源性膀胱过度活动的一些极具争议性的方面，并可能导致针对老年人膀胱过度活动的新的治疗策略。

DESCRIPTION (provided by applicant): Overactive bladder incorporates to a variety of lower urinary tract symptoms (LUTS) including urinary frequency, urge incontinence, nocturia and pelvic pain. The incidence of bladder overactivity and LUTS increases with age. Clinical studies suggest that the prevalence of bladder overactivity and LUTS among Veterans is almost five fold higher than its incidence in the general population. It has been reported that Veterans with overactive bladder have a worse quality of life score in comparison with Veterans without overactive bladder. In most cases, overactive bladder symptoms are associated with insomnia, anxiety, fatigue, and even depression. Factors predisposing to the development of bladder overactivity and LUTS are poorly understood. In the elderly male, bladder outlet obstruction due to benign prostatic hyperplasia (BPH) has long been blamed. However, urodynamic studies have shown that in approximately one third to more than one-half of cases, LUTS in the elderly are not associated with BPH or bladder outlet obstruction suggesting other possibilities. The specific features of non-obstructed bladder contributing to LUTS remain essentially unknown. We attempt to introduce the concept that aging-associated bladder ischemia is an independent factor in the development of non-obstructed non-neurogenic overactive bladder. Our concept is supported by clinical evidence of a close correlation between bladder ischemia and LUTS in the elderly patients. Blood flow recording with transrectal color Doppler ultrasonography has revealed a significant decrease in bladder blood flow in the elderly patients in comparison with asymptomatic younger controls. It was shown that decreased bladder blood flow significantly correlates with the severity of LUTS in these patients. Ischemia is one of the leading causes of smooth muscle spasm in the stomach, intestine, uterus, and bronchioles. Our studies with a rabbit model have shown that atherosclerosis-induced pelvic ischemia results in bladder overactivity and increased voiding frequency. In preliminary studies, we found that chronic bladder ischemia activated redox survival signaling via phosphoinositide 3-kinase (PI3-Kinase)/protein kinase B (Akt) pathway in smooth muscle cells and nerve fibers. Oxidative stress in cultured smooth muscle cells upregulated redox survival signaling via PI3-kinase and Akt expression and evoked two vital responses to promote survival: 1) Increase in mitochondrial density and respiration rate. 2) Increase in smooth muscle cell Ca++ uptake. These redox survival responses augmented smooth muscle contractions and were associated with bladder overactivity and voiding dysfunction. Inhibition of PI3-Kinase diminished bladder smooth muscle overreactivity to contractile stimuli. Based on these observations, we hypothesize that: "Activation of redox survival signaling via PI3-kinase/Akt pathway in bladder ischemia stimulates smooth muscle and neural mitochondrial respiration and promotes smooth muscle cell Ca++ uptake resulting in excessive contractile activity and voiding dysfunction". Our overall goal is to explore the role of ischemia and redox signaling in bladder overactivity using our well-established animal and cell culture model systems." Our specific aims are: 1) To define redox regulation of bladder smooth muscle contractility via PI3-kinase/Akt survival pathway and mitochondrial respiratory chain under the ischemic conditions. 2) To define regulation of smooth muscle cell PI3-kinase/Akt survival pathway, mitochondrial respiration and Ca++ uptake by neural redox elements in bladder ischemia. 3) To define regulation of smooth muscle cell PI3-kinase/Akt survival pathway, mitochondrial respiration, and Ca++ uptake by redox-modified muscarinic receptors in bladder ischemia. 4) To develop therapeutic strategies targeting redox signaling, redox elements and modified receptors to prevent or reverse augmented smooth muscle contractions and bladder overactivity in pelvic ischemia. The proposed studies will elucidate some of the highly controversial aspects of non-obstructed non-neurogenic overactive bladder and may lead to newer therapeutic strategies against bladder overactivity in the elderly population.