Ischemic Etiology of Obstructive Bladder Dysfunction

描述(申请人提供)：兔慢性出口部分梗阻模型已被证明是研究人类良性前列腺增生症(BPH)继发梗阻性膀胱病的良好模型。在兔模型和梗阻的人膀胱组织中，我们已经确定了失代偿(功能障碍)膀胱的四个明显特征：1)胆碱能去神经；2)线粒体功能障碍；3)肌浆网(SR)钙ATPase(SERCA)含量和活性降低；4)结缔组织(CT)合成和重新分布。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，在器官对梗阻的快速生长反应开始时，膀胱壁出现一过性局灶性缺氧区，然后观察到膀胱净血流量(BF)的下降。此外，在慢性梗阻兔代偿膀胱功能期间，这些缺氧灶在平滑肌(SM)间隔内清晰可见。此外，对轻度梗阻的膀胱的EM检查显示神经和肌肉细胞和亚细胞膜的局灶性损伤，即损伤仅局限于评估视野内的特定细胞。从这些研究中，我们提出了以下假设：缺血/再灌注(I/R)引起的膜损伤起源于暂时性局灶性缺氧区，在器官对部分出口阻塞的初始反应期间，首先发生在膀胱壁的特定区域，并在代偿功能期间存在。在肌肉间室，这些缺氧灶是收缩和生化功能障碍以及在进行性失代偿过程中持续的平滑肌胶原合成的起始点。从代偿功能进展到终末期失代偿是从局部到全局对局灶性缺氧反应的渐进性变化的结果；从代偿功能到失代偿功能的转变发生在源于缺氧灶的膜损伤和胶原合成扩散到正常组织中。这一假说的推论指出，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，并增加梗阻性膀胱功能障碍的进展速度。以下是我们的具体目标：具体目标1：表明I/R引起的局灶性缺氧损伤始于对部分出口阻塞的初始反应，并持续到代偿功能中。具体目标2“表明，当起源于缺氧灶的膜损伤扩散到膀胱壁的正常缺氧区时，发生从代偿到失代偿的转变，而进展到终末期失代偿是由于局部向整体器官反应向局灶性低氧转变的结果。具体目标3：表明衰老导致膀胱抗氧化能力的降低和梗阻性膀胱功能障碍进展的增加。

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.