Ischemic Etiology of Obstructive Bladder Dysfunction

描述（由申请方提供）：已证明慢性部分出口梗阻家兔模型是研究继发于良性前列腺增生（BPH）的人类梗阻性膀胱疾病病理生理学的极佳模型。在兔模型和阻塞的人膀胱组织中，我们已经确定了失代偿（功能障碍）膀胱的四个定义特征：1）胆碱能去神经支配; 2）线粒体功能障碍; 3）肌浆网（SR）Ca 2 + ATP酶（SERCA）含量和活性降低;以及4）进行性结缔组织（CT）合成和再分布。 本实验室最近的研究结果表明，兔膀胱对部分出口梗阻的反应是不均匀的，在器官对梗阻的快速生长反应开始时，膀胱壁出现短暂的局灶性缺氧区，然后观察到膀胱净血流量（BF）的任何下降。 此外，这些缺氧灶在慢性梗阻兔的补偿膀胱功能期间的平滑肌（SM）隔室内清晰可见。此外，轻度梗阻膀胱的EM检查显示神经和肌肉细胞和亚细胞膜的局灶性损伤，即，损伤仅局限于所评估的区域内的特定细胞。从这些研究中，我们提出了以下假设：缺血/再灌注（I/R）诱导的膜损伤起源于短暂的局灶性缺氧区域，首先发生在膀胱壁的特定区域，在器官对部分出口梗阻的初始反应期间，并在代偿功能期间存在。在肌肉区室中，这些缺氧灶是在进行性失代偿期间持续的收缩和生化功能障碍以及平滑肌胶原蛋白合成的起始位点。 从代偿功能进展到终末期失代偿是由于对局灶性缺氧的局部至整体反应的渐进变化;从代偿功能到失代偿功能的转变是由于膜损伤和源于缺氧灶的胶原蛋白合成扩散到含氧量正常的组织中。 这一假说的一个推论是，衰老伴随着膀胱中抗氧化潜力的丧失，导致对I/R损伤的敏感性增加和阻塞性膀胱功能障碍进展速率增加。以下是我们的具体目标：具体目标1：表明I / R诱导的局灶性缺氧损伤开始于对部分出口梗阻的初始反应期间，并持续到代偿功能期间。具体目标2”表明当源于缺氧灶的膜损伤扩散到膀胱壁的含氧量正常区域时，发生从代偿到失代偿的转变，并且进展到终末期失代偿是由于对局灶性缺氧的器官反应从局灶性转变为全局性。具体目标3：表明衰老导致膀胱抗氧化能力降低和梗阻性膀胱功能障碍进展加快。

DESCRIPTION (provided by applicant): The rabbit model of chronic partial outlet obstruction has proven to be an excellent model for the study of the pathophysiology of human obstructed bladder disease secondary to benign prostatic hyperplasia (BPH). In the rabbit model and in obstructed human bladder tissue, we have identified four defining characteristics of the decompensated (dysfunctional) bladder: 1) cholinergic denervation; 2) mitochondrial dysfunction; 3) decreased sarcoplasmic reticulum (SR) Ca2+ATPase (SERCA) content and activity; and 4) progressive connective tissue (CT) synthesis and redistribution. Results of our recent studies revealed that the rabbit urinary bladders response to partial outlet obstruction is non-uniform, areas of transient focal hypoxia appeared in the bladder wall during the organs initial rapid growth response to obstruction, before any decrease in net bladder blood flow (BF) was observed. Furthermore, these hypoxic foci were clearly visible within the smooth muscle (SM) compartment during compensated bladder function in chronically obstructed rabbits. In addition, EM examination of mildly obstructed bladders revealed focal damage to nerve and muscle cellular and subcellular membranes, i.e., damage was localized only to specific cells within the fields evaluated. From these studies, we have developed the following hypothesis: Ischemia / reperfusion (I/R) - induced membrane damage originates in areas of transient focal hypoxia that first occur in specific regions of the bladder wall during the organs initial response to partial outlet obstruction and are present during compensated function. In the muscle compartment these hypoxic foci are the initiation sites for the contractile and biochemical dysfunctions and smooth muscle collagen synthesis that continue during progressive decompensation. Progression from compensated function to end-stage decompensation occurs as a result of a graduated change from a focal to global response to focal hypoxia; the shift from compensated to decompensated function occurs as membrane damage and collagen synthesis originating in hypoxic foci spreads into normoxic tissue. A corollary of this hypothesis states that aging is accompanied by a loss of antioxidant potential in the bladder resulting in increased sensitivity to I/R damage and increased rate of progression of obstructive bladder dysfunction. The following are our specific aims: Specific Aim 1: To show that I / R - induced focal hypoxic damage begins during the initial response to partial outlet obstruction and continues into and during compensated function. Specific Aim 2" To show that the shift from compensation to decompensation occurs when membrane damage originating in the hypoxic foci spreads into normoxic areas of the bladder wall and that progression to end-stage decompensation occurs as a result of a shift from a focal to a global organ response to focal hypoxia. Specific aim 3: To show that aging results in decreased antioxidant potential of the bladder and an increase in the progression of obstructive bladder dysfunction.