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上尿路结石的消除。尽管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带来健康风险。现在有充分的证据表明，SWL引起肾脏创伤，主要是血管损伤，冲击波治疗引起的急性损伤可导致一些个体严重的长期并发症。老年人新发高血压)。因此，SWL的安全性存在问题。改善SWL、改变碎石机冲击波的特性和/或制定新的患者方案以使治疗更安全、更有效是可行的。然而，基本的信息是缺失的，使这些改进得以实现：碎石机冲击波如何引起组织损伤尚不清楚；SWL肾损伤的物理机制尚未确定。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验证SWL肾脏损伤是由于碎石机冲击波的两个突出特征：声空化和剪切应力造成的假设。修订后的提案有四个具体目标1和2已根据审稿人的意见进行了广泛修订。目的1将使用孤立的肾脏来表征由于空化引起的血管损伤，确定空化以外的机械力是否会导致组织损伤，并将测试这样一种观点，即当肾脏处于增加的静水压力（抑制空化检测和定量，以表征血液中空化的开始和传播）时，可以通过给药SW来抑制SWL中的肾脏损伤。并验证血管损伤取决于冲击波引起的肾血流量减少的观点。我们将评估血管系统支持空化的潜力，并确定空化如何受到血管大小的影响。在Aim 3中，我们将使用培养的细胞模型来确定空化是否导致肾小管损伤，而在Aim 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，减少或消除严重的急性冲击波引起的肾损伤，导致不可逆的肾损伤。

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.