Ischemic Etiology of Obstructive Bladder Dysfunction

描述（申请人提供）：兔慢性部分出口梗阻模型已被证明是研究人类良性前列腺增生（BPH）继发膀胱梗阻病病理生理的良好模型。在兔模型和阻塞的人类膀胱组织中，我们已经确定了失代偿（功能失调）膀胱的四个特征：1)胆碱能失神经支配；2)线粒体功能障碍；3)肌浆网Ca2+ atp酶（SERCA）含量和活性降低；4)进行性结缔组织（CT）合成和再分布。我们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，在器官对梗阻的最初快速生长反应期间，膀胱壁出现短暂的局灶性缺氧区域，然后才观察到膀胱净血流量（BF）的减少。此外，在慢性梗阻兔的代偿性膀胱功能中，这些缺氧灶在平滑肌（SM）室中清晰可见。此外，对轻度梗阻膀胱的电镜检查显示神经和肌肉细胞膜和亚细胞膜的局灶性损伤，即损伤仅局限于评估范围内的特定细胞。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性局灶性缺氧区域，这种缺氧首先发生在器官对部分出口阻塞的初始反应期间的膀胱壁特定区域，并在代偿功能期间出现。在肌室中，这些缺氧灶是收缩和生化功能障碍以及平滑肌胶原合成的起始部位，并在进行性失代偿过程中继续发生。从代偿功能到终末期失代偿的进展是对局灶性缺氧从局部反应到全局反应的逐步变化的结果；当膜损伤和源于缺氧灶的胶原合成扩散到常氧组织时，代偿功能向失代偿功能的转变就发生了。这一假设的推论是，衰老伴随着膀胱抗氧化能力的丧失，导致对I/R损伤的敏感性增加，梗阻性膀胱功能障碍的进展速度加快。以下是我们的具体目的：具体目的1：表明I / R诱导的局灶性缺氧损伤始于对部分出口阻塞的初始反应，并持续到代偿功能。具体目标2“表明当缺氧灶的膜损伤扩散到膀胱壁的常氧区域时，从代偿到失代偿的转变发生，并且由于局部器官对局部缺氧的反应转变为全局器官对局部缺氧的反应而进展到终末期失代偿。”具体目的3：表明衰老导致膀胱抗氧化能力下降，并增加梗阻性膀胱功能障碍的进展。

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.