Mechanism of Bladder Overactivity in Pelvic Ischemia

描述（由申请人提供）： 膀胱过度活动症合并多种下尿路症状（LUTS），包括尿频、急迫性尿失禁、尿失禁和骨盆疼痛。膀胱过度活动和LUTS的发生率随年龄增加而增加。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症的退伍军人相比，患有膀胱过度活动症的退伍军人的生活质量评分更差。在大多数情况下，膀胱过度活动症与失眠，焦虑，疲劳，甚至抑郁症有关。诱发膀胱过度活动和下尿路症状的因素知之甚少。在老年男性中，由于良性前列腺增生（BPH）引起的膀胱出口梗阻一直被指责。然而，尿动力学研究表明，在大约三分之一至一半以上的病例中，老年人的LUTS与BPH或膀胱出口梗阻无关，这表明存在其他可能性。导致下尿路症状的非梗阻性膀胱的具体特征基本上仍不清楚。我们试图介绍的概念，年龄相关的膀胱缺血是一个独立的因素，在非梗阻性非神经源性膀胱过度活动症的发展。我们的概念得到了老年患者膀胱缺血和下尿路症状密切相关的临床证据的支持。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着减少。结果表明，膀胱血流量减少与这些患者的LUTS严重程度显著相关。缺血是胃、肠、子宫和细支气管平滑肌痉挛的主要原因之一。我们对家兔模型的研究表明，动脉粥样硬化诱导的盆腔缺血导致膀胱过度活动和排尿频率增加。在前期研究中，我们发现慢性膀胱缺血通过磷脂酰肌醇3-激酶（PI 3-Kinase）/蛋白激酶B（Akt）途径激活平滑肌细胞和神经纤维的氧化还原存活信号。培养的平滑肌细胞中的氧化应激通过PI 3-激酶和Akt表达上调氧化还原存活信号传导，并诱发两种重要反应以促进存活：1）线粒体密度和呼吸速率增加。2)平滑肌细胞Ca++摄取增加。这些氧化还原存活反应增强平滑肌收缩，并与膀胱过度活动和排尿功能障碍有关。抑制PI 3-激酶降低膀胱平滑肌对收缩刺激的过度反应性。基于这些观察结果，我们假设：“膀胱缺血中通过PI 3-激酶/Akt途径激活氧化还原存活信号刺激平滑肌和神经线粒体呼吸，并促进平滑肌细胞Ca++摄取，导致过度收缩活动和排尿功能障碍”。我们的总体目标是 使用我们完善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）探讨缺血状态下，PI 3-激酶/Akt存活通路和线粒体呼吸链对膀胱平滑肌收缩的氧化还原调节作用。2)明确膀胱缺血时平滑肌细胞PI 3-激酶/Akt生存途径、线粒体呼吸和神经氧化还原元件对Ca++摄取的调节。3)明确膀胱缺血时氧化还原修饰的毒蕈碱受体对平滑肌细胞PI 3-激酶/Akt存活通路、线粒体呼吸和Ca++摄取的调节。4)开发靶向氧化还原信号传导、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中增强的平滑肌收缩和膀胱过度活动。拟议的研究将阐明非梗阻性非神经源性膀胱过度活动症的一些极具争议的方面，并可能导致针对老年人群膀胱过度活动症的新的治疗策略。

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.