H2S supplementation: A novel method for successful organ preservation at subnormothermic temperatures

Juriasingani, Smriti; Akbari, Masoud; Chan, Justin; Whiteman, Matthew; Şener, Alp

doi:10.1016/j.niox.2018.10.004

Cited by 37 publications

(29 citation statements)

References 48 publications

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“…Others have shown that lower MMP can be associated with an increased risk of delayed graft function after kidney transplantation [47]. In addition to hibernation, the effects of gasotransmitters H 2 S, CO and NO, have been shown to decrease ROS formation, potentially via mitochondria [48–50].…”

Section: Discussionmentioning

confidence: 99%

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

et al. 2019

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Background Hypothermia, leading to mitochondrial inhibition, is widely used to reduce ischemic injury during kidney preservation. However, the exact effect of hypothermic kidney preservation on mitochondrial function remains unclear. Methods We evaluated mitochondrial function [i.e. oxygen consumption and production of reactive oxygen species (ROS)] in different models (porcine kidney perfusion, isolated kidney mitochondria, and HEK293 cells) at temperatures ranging 7–37 °C. Results Lowering temperature in perfused kidneys and isolated mitochondria resulted in a rapid decrease in oxygen consumption (65% at 27 °C versus 20% at 7 °C compared to normothermic). Decreased oxygen consumption at lower temperatures was accompanied by a reduction in mitochondrial ROS production, albeit markedly less pronounced and amounting only 50% of normothermic values at 7 °C. Consequently, malondialdehyde (a marker of ROS-induced lipid peroxidation) accumulated in cold stored kidneys. Similarly, low temperature incubation of kidney cells increased lipid peroxidation, which is due to a loss of ROS scavenging in the cold. Conclusions Lowering of temperature highly affects mitochondrial function, resulting in a progressive discrepancy between the lowering of mitochondrial respiration and their production of ROS, explaining the deleterious effects of hypothermia in transplantation procedures. These results highlight the necessity to develop novel strategies to decrease the formation of ROS during hypothermic organ preservation. Electronic supplementary material The online version of this article (10.1186/s12967-019-2013-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

et al. 2019

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“…Additionally, its protective effect was seen on PCMs, supportively suggesting that AP39 protection is universal, independent of cell types. Indeed, AP39 protection has been demonstrated in many other types of cells …”

Section: Discussionmentioning

confidence: 99%

Supplementing preservation solution with mitochondria-targeted H2S donor AP39 protects cardiac grafts from prolonged cold ischemia–reperfusion injury in heart transplantation

Zhu

Juriasingani

et al. 2019

American Journal of Transplantation

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Heart transplant has been accepted as the standard treatment for end-stage heart failure. Because of its susceptibility to ischemia-reperfusion injury, the heart can be preserved for only 4 to 6 hours in cold static preservation solutions. Prolonged ischemia time is adversely associated with primary graft function and long-term survival. New strategies to preserve donor hearts are urgently needed. We demonstrate that AP39, a mitochondria-targeting hydrogen sulfide donor, significantly increases cardiomyocyte viability and reduces cell apoptosis/death after cold hypoxia/reoxygenation in vitro. It also decreases gene expression of proinflammatory cytokines and preserves mitochondria function. Using an in vivo murine heart transplant model, weshow that preserving donor hearts with AP39-supplemented University of Wisconsin solution (n = 7) significantly protects heart graft function, measured by quantitative ultrasound scan, against prolonged cold ischemia-reperfusion injury (24 hours at 4°C), along with reducing tissue injury and fibrosis. Our study demonstrates that

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“…Besides the direct mitochondrial effects[17], H 2 S acts anti-inflammatory[18] and inhibits apoptosis[19]. Although H 2 S showed protective effects during room-temperature static storage[20], until now, neither systemically administered[21] or gaseous administered[22] H 2 S induced successful hypometabolism in larger mammals.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen sulphide-induced hypometabolism in human-sized porcine kidneys

et al. 2019

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BackgroundSince the start of organ transplantation, hypothermia-forced hypometabolism has been the cornerstone in organ preservation. Cold preservation showed to protect against ischemia, although post-transplant injury still occurs and further improvement in preservation techniques is needed. We hypothesize that hydrogen sulphide can be used as such a new preservation method, by inducing a reversible hypometabolic state in human sized kidneys during normothermic machine perfusion.MethodsPorcine kidneys were connected to an ex-vivo isolated, oxygen supplemented, normothermic blood perfusion set-up. Experimental kidneys (n = 5) received a 85mg NaHS infusion of 100 ppm and were compared to controls (n = 5). As a reflection of the cellular metabolism, oxygen consumption, mitochondrial activity and tissue ATP levels were measured. Kidney function was assessed by creatinine clearance and fractional excretion of sodium. To rule out potential structural and functional deterioration, kidneys were studied for biochemical markers and histology.ResultsHydrogen sulphide strongly decreased oxygen consumption by 61%, which was associated with a marked decrease in mitochondrial activity/function, without directly affecting ATP levels. Renal biological markers, renal function and histology did not change after hydrogen sulphide treatment.ConclusionIn conclusion, we showed that hydrogen sulphide can induce a controllable hypometabolic state in a human sized organ, without damaging the organ itself and could thereby be a promising therapeutic alternative for cold preservation under normothermic conditions in renal transplantation.

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H2S supplementation: A novel method for successful organ preservation at subnormothermic temperatures

Cited by 37 publications

References 48 publications

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

Renal temperature reduction progressively favors mitochondrial ROS production over respiration in hypothermic kidney preservation

Supplementing preservation solution with mitochondria-targeted H2S donor AP39 protects cardiac grafts from prolonged cold ischemia–reperfusion injury in heart transplantation

Hydrogen sulphide-induced hypometabolism in human-sized porcine kidneys

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