MECHANISMS OF CELL INJURY IN EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY
James A Mcateer, Associate Professor
Institution:
Grant 5P01DK043881-030002 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Extracorporeal shock wave lithotripsy (SWL) produces renal side effects including structural damage to the microvasculature and tubular epithelium and alterations in kidney function. The objective of the proposed research is to determine the mechanisms of shock w ave (SW) cell injury in the kidney. Acoustic cavitation during SWL produces liquid microjets capable of disrupting cells, and generates reactive oxygen molecules (ROM) that may contribute to cell injury. Thus, SW-generated cavitation produces two phenomena that may cause cell injury. Therefore, we pose two hypotheses to address cellular response to these two potentially cell-disruptive features of SW treatment 1) that shock wave-induced cavitation damages cell and organellar membranes, and 2) that SWL cell injury occurs by an ROM-mediated mechanism. We will characterize immediate versus delayed injury, determine if membrane damage is dependent upon cavitation, determine by electron spin resonance (ESR) if SWs alter membrane permeability, will assess cell functional parameters that are dependent on membrane integrity, will determine the extent of mitochondrial injury and correlate cell functional changes with alterations in cell ultrastructure. Also, we will determine if membrane"stabilizing agents" reduce the severity of cell injury. We will identify by ESR the free radical species produced by SWL and localize their site of production, characterize injury when anti-oxidant defense mechanisms are altered, determine if ROM scavengers reduce or prevent injury and will assess for mitochondrial injury resulting in alterations in cell respiration. Also, we hypothesize 3) that mechanical stress other than cavitation contributes to cell injury. We will test this idea by assessing injury when cavitation and stress are regulated. Additional studies will examine the influence of the physical parameters of SW delivery on the severity of cell injury. Experiments will be performed on cultured cell line models of the renal tubule (LLC-PK1) and the vascular endothelium (HUVEC), and on isolated kidney tubules, purified kidney mitochondria and plasma membrane preparations. Our goal is to contribute to the foundation of information necessary to establish improved SWL protocols so that renal injury is reduced or eliminated.
Keywords: cellular pathology, iatrogenic disease, kidney function, lithotripsy, morphology, antioxidant, cell membrane, cellular respiration, free radical oxygen, mechanical stress, membrane permeability, mitochondrial membrane, animal tissue, clone cell, laboratory rabbit, statistics /biometry, tissue /cell culture
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MECHANISMS OF SHOCK WAVE ACTION FOR IMPROVED SWL
James A Mcateer, Associate Professor
Indiana Univ-purdue Univ At Indianapolis 620 Union Drive, Room 618 Indianapolis, In 462025167
Grant 5P01DK043881-130002 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZDK1
Abstract: Project 2 Mechanisms of Shock Wave Action for Improved SWL The goal of Project 2 is to find ways to improve lithotripsy. To reach this goal we have identified three main objectives. We will 1) provide an objective basis for the choice of lithotripter settings for SW-rate and power used in treating kidney stones (Aims 1 and 2), 2) determine the role of cavitation bubble cluster dynamics in stone fragmentation and find ways for the urologist to enhance the positive action of cavitation in stone breakage (Aims 3 and 4), and 3) evaluate the efficacy and safety of newer generation lithotripters, including a promising dual pulse lithotripter (Aims 5 and 6). Project 2 experiments will be highly interactive with the other projects of this Program Project Grant. In collaboration with Projects 3 and 4 we will utilize high-speed photography, dual passive cavitation detection and B-scan ultrasound to determine the mechanism responsible for improved stone breakage at slow SW-rate, and will find the balance between SW-rate and power that gives improved stone comminution. In studies with Project 1 we will use a new animal model for stone implantation in the pig kidney and the ureter to help evaluate the effect of lithotfipter settings on stone breakage. With our colleagues in Projects 3 and 4 we will analyze cavitation bubble activity in vitro, to determine how the environment of a stone--that is, its tissue boundaries and the composition of the fluid that bathes the stoneminfluence cavitation bubble dynamics involved in stone fragmentation. Using our in vivo stone implantation model and our Project 1 animal model of renal injury in SWL, and in collaboration with projects 3 and 4, we will evaluate and compare the efficacy and safety of different types of lithotripters -- including the electrohydraulic Dornier HM3, the electromagnetic Dornier Compact Delta (a newer generation tight-focal-zone, high power machine), and the Direx Duet dual-pulse lithotripter. Thus, project 2 will find ways to improve how lithotripsy is performed using conventional lithotripters, evaluate newer machines so that we can learn to use them more safely and effectively, and test a promising new concept for dual pulse SW delivery that has the potential to improve SWL.
Keywords: biomedical equipment development, biomedical equipment safety, biophysics, kidney function, lithotripsy, nephrolithiasis, sound, ultrasound biological effect, biomechanics, cellular pathology, disease /disorder proneness /risk, epithelium, injury, kidney disorder, mechanical stress, morphology, oxidative stress, physical property, renal ischemia /hypoxia, renal tubule, vascular endothelium, photography, swine, tissue /cell culture
Project start date: 2007-07-01
Project end date: 2009-06-30
Grants awarded to James A Mcateer
PHYSICAL MECHANISMS OF TISSUE DAMAGE IN SWL
James A Mcateer, Associate Professor
Indiana Univ-purdue Univ At Indianapolis 620 Union Drive, Room 618 Indianapolis, In 462025167
Grant 5R01DK055674-04 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZRG1
Abstract: 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.
Keywords: human therapy evaluation, kidney disorder, lithotripsy, biophysics, mechanical stress, laboratory rabbit, laboratory rat, tissue /cell culture
Project start date: 2000-08-01
Project end date: 2006-06-30
5R01DK055674-04 (2003): $262894
5R01DK055674-02 (2001): $232776
1R01DK055674-01A1 (2000): $240579
MECHANISMS OF SHOCK WAVE ACTION FOR IMPROVED SWL
James A Mcateer, Associate Professor
Indiana Univ-purdue Univ At Indianapolis 620 Union Drive, Room 618 Indianapolis, In 462025167
Grant 2P01DK043881-10A10002 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZDK1
Abstract: Project 2 Mechanisms of Shock Wave Action for Improved SWL The goal of Project 2 is to find ways to improve lithotripsy. To reach this goal we have identified three main objectives. We will 1) provide an objective basis for the choice of lithotripter settings for SW-rate and power used in treating kidney stones (Aims 1 and 2), 2) determine the role of cavitation bubble cluster dynamics in stone fragmentation and find ways for the urologist to enhance the positive action of cavitation in stone breakage (Aims 3 and 4), and 3) evaluate the efficacy and safety of newer generation lithotripters, including a promising dual pulse lithotripter (Aims 5 and 6). Project 2 experiments will be highly interactive with the other projects of this Program Project Grant. In collaboration with Projects 3 and 4 we will utilize high-speed photography, dual passive cavitation detection and B-scan ultrasound to determine the mechanism responsible for improved stone breakage at slow SW-rate, and will find the balance between SW-rate and power that gives improved stone comminution. In studies with Project 1 we will use a new animal model for stone implantation in the pig kidney and the ureter to help evaluate the effect of lithotfipter settings on stone breakage. With our colleagues in Projects 3 and 4 we will analyze cavitation bubble activity in vitro, to determine how the environment of a stone--that is, its tissue boundaries and the composition of the fluid that bathes the stoneminfluence cavitation bubble dynamics involved in stone fragmentation. Using our in vivo stone implantation model and our Project 1 animal model of renal injury in SWL, and in collaboration with projects 3 and 4, we will evaluate and compare the efficacy and safety of different types of lithotripters -- including the electrohydraulic Dornier HM3, the electromagnetic Dornier Compact Delta (a newer generation tight-focal-zone, high power machine), and the Direx Duet dual-pulse lithotripter. Thus, project 2 will find ways to improve how lithotripsy is performed using conventional lithotripters, evaluate newer machines so that we can learn to use them more safely and effectively, and test a promising new concept for dual pulse SW delivery that has the potential to improve SWL.
Keywords: biomedical equipment development, biomedical equipment safety, biophysics, kidney function, lithotripsy, nephrolithiasis, sound, ultrasound biological effect, biomechanics, cellular pathology, disease /disorder proneness /risk, epithelium, injury, kidney disorder, mechanical stress, morphology, oxidative stress, physical property, renal ischemia /hypoxia, renal tubule, vascular endothelium, photography, swine, tissue /cell culture
Project start date: 2004-07-01
Project end date: 2009-06-30