PHYSICAL MECHANISMS OF TISSUE DAMAGE IN SWL

冲击波碎石术（SWL）已被证明是非常有效的治疗消除上尿路结石。虽然SWL被广泛认为是有效和安全的，但越来越多的人担心碎石术也会造成健康风险。 现在有充分的文献记载，SWL导致肾脏创伤，主要是血管损伤，并且冲击波治疗引起的急性损伤可导致某些个体的严重的长期并发症（e.g.new老年人的高血压发作）。因此，SWL的安全性受到质疑。 改善SWL、改变碎石机冲击波的性质和/或导出新的患者方案以使治疗更安全和更有效是可行的。 然而，基本的信息是缺失的，将允许这样的改进：如何碎石机冲击波造成组织损伤是未知的，负责肾损伤的物理机制，在SWL尚未确定。本项目的目的是确定SWL中组织损伤的物理机制。 我们提出了一种基于生物物理学的体外方法来测试这一假设，即肾损害在SWL是由于两个突出的特点，碎石机冲击波：声空化和剪切应力。该修订提案有四个具体目标，1和2已根据审查员的意见进行了广泛的修订。目的1将使用离体肾脏来表征由于空化引起的血管创伤，确定除空化之外的机械力是否有助于组织损伤，并且将测试当肾脏处于增加的静水压力下时通过施用SW可以抑制SWL中的肾损伤的想法（以抑制空化检测和定量，以表征血液中空化的开始和传播，并验证血管损伤取决于冲击波引起的肾血流速度降低的观点。 我们将评估血管系统支持空化的潜力，并确定空化如何受血管尺寸的影响。 在目标3中，我们将使用培养的细胞模型来确定空化是否是肾小管损伤的原因，在目标4中，我们将确定剪切应力如何导致SWL细胞损伤。本项目的主要目标是确定SWL中组织损伤的物理机制，以便制定策略使SWL更安全，减少或消除导致不可逆肾损伤的严重急性休克波诱导的肾损伤。

Shock wave lithotripsy (SWL) has proven to be very effective treatment for the elimination of upper urinary tract stone. Although SWL is widely regarded as effective and safe there is growing concern that lithotripsy also poses a health risk. It is now well documented that SWL causes trauma to the kidney, dominated by vascular injury, and that the acute damage caused by shock wave treatment can lead to serious long-term complications in some individuals )e.g.new onset hypertension in the elderly). Thus, the safety of SWL is in question. It is feasible to improve SWL, to change the properties of lithotripter shock waves and/or derive new patient protocols to make treatment safer and more effective. However, basic information is missing that would allow such improvements to be made: how lithotripter schock waves cause tissue damage is unknown; the physical mechanisms responsible for kidney damage in SWL have yet to be determined. The objective of this project is to determine the physical mechanisms of tissue damage in SWL. We propose a biophysics- based in vitro approach to test the hypothesis that kidney damage in SWL is due to two prominent features of lithotripter shock waves: acoustic cavitation and shear stress. This revised proposal has four Specific Aims 1 and 2 have undergone extensive revisions in response to reviewers' commetns. Aim 1 will use isolated kidneys to characterize vascular trauma due to cavitation, determine if mechanical forces other than cavitation contribute to tissue damage, and will test the idea that kidney damage in SWL can be inhibited by administering SW's when the kidney is under increased hydrostatic pressure (to suppress cavitation detection and quantitation to characterize the inception and propagation of cavitation in blood, and test the idea that vascular damage is dependent upon a shock wave- induced reduction in the rate of renal blood flow. We will assess the potential for the vasculature to support cavitation and determine how cavitation is affected by vessel size. In Aim 3 we will use cultured cell models to determine if cavitation is responsible for damage to renal tubules, and in Aim 4 we will determine how shear stress contributes to SWL cell injury. The main goal of this project is to determine the physical mechanisms that are responsible for tissue damage in SWL, so that strategies can be developed to make SWL safer, to reduce or eliminate the significant acute schock wave-induced renal trauma that leads to irreversible kidney damage.