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Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation

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Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation International Journal of Molecular Sciences Review Review: Ischemia Reperfusion Injury—A Translational Perspective in Organ Transplantation André Renaldo Fernández 1, Rodrigo Sánchez-Tarjuelo 2,3, Paolo Cravedi 4 , Jordi Ochando 2,3 and Marcos López-Hoyos 1,5,* 1 Immunology, Universitary Hospital Marqués de Valdecilla- Research Institute IDIVAL Santander, 390008 Santander, Spain; [email protected] 2 Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected] (R.S.-T.); [email protected] (J.O.) 3 Immunología de Trasplantes, Centro Nacional de Microbiología, Instituto de Salud Carlos III, 28220 Majadahonda (Madrid), Spain 4 Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; [email protected] 5 Red de Investigación Renal (REDINREN), 28040 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-942-292759 Received: 30 September 2020; Accepted: 11 November 2020; Published: 13 November 2020 Abstract: Thanks to the development of new, more potent and selective immunosuppressive drugs together with advances in surgical techniques, organ transplantation has emerged from an experimental surgery over fifty years ago to being the treatment of choice for many end-stage organ diseases, with over 139,000 organ transplants performed worldwide in 2019. Inherent to the transplantation procedure is the fact that the donor organ is subjected to blood flow cessation and ischemia during harvesting, which is followed by preservation and reperfusion of the organ once transplanted into the recipient. Consequently, ischemia/reperfusion induces a significant injury to the graft with activation of the immune response in the recipient and deleterious effect on the graft. The purpose of this review is to discuss and shed new light on the pathways involved in ischemia/reperfusion injury (IRI) that act at different stages during the donation process, surgery, and immediate post-transplant period. Here, we present strategies that combine various treatments targeted at different mechanistic pathways during several time points to prevent graft loss secondary to the inflammation caused by IRI. Keywords: ischemia reperfusion injury; cell metabolism; innate immunity; hypoxia; cell death; RNA interference 1. Introduction Organ shortage remains a major unresolved problem in organ transplantation. There is an increasing demand for organ transplantation worldwide, but there are not enough organs to meet the increasing demand. To increase the pool of organs available for transplantation the use of extended criteria to include donation after circulatory death (DCD) has been recently adopted [1,2]. Although greatly needed, these extended-criteria organs are known to suffer from more ischemic damage, which is in turn associated with suboptimal results [3,4]. In kidney transplantation, ischemia/reperfusion injury (IRI) is known to underlie the clinical entity of delayed graft function (DGF) [5]. The challenge is to be able to use those organs without compromising early and long-term success. To accomplish this, Int. J. Mol. Sci. 2020, 21, 8549; doi:10.3390/ijms21228549 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8549 2 of 21 there is an urgent need to better understand the mechanistic insights into the molecular and cellular events triggered by IRI. Int. J. Mol.IRI Sci. is a 20 multifactorial20, 21, x FOR PEER inflammatory REVIEW condition with underlying factors that include hypoxia,2 of 22 metabolic stress, leukocyte extravasation, cellular death pathways, and activation of the immune response. In this review, we describe the main pathways involved in IRI and enumerate various response. In this review, we describe the main pathways involved in IRI and enumerate various mechanisms of action of previously known IRI mediators. Of note, these underlying pathways are mechanisms of action of previously known IRI mediators. Of note, these underlying pathways are common to most tissues, although they might have different effects depending on the organ. In common to most tissues, although they might have different effects depending on the organ. In addition, addition, we summarize potential therapeutic approaches aimed at reducing the detrimental effects we summarize potential therapeutic approaches aimed at reducing the detrimental effects of IRI in of IRI in both preclinical experimental studies and in human clinical trials. both preclinical experimental studies and in human clinical trials. 2. Metabolic Stress The initiating insult during ischemia injury is hypoxiahypoxia (Figure(Figure1 1).). LowLow oxygenoxygen levelslevels depletedeplete ATP inin mitochondriamitochondria andand switchswitch toto anaerobicanaerobic cellularcellular metabolism.metabolism. Decreased ATP impairs normal functioningfunctioning of of the the Na/K Na/K pump, pump, sequestering sequestering Na Na inside inside the the cell, cell, and and it impairs it impairs calcium calcium excretion. excretion. The Theintracellular intracellular calcium calcium overload overload generates generates reactive reactive oxygen oxygen species species(ROS) and (ROS) the andactivation the activation of NADPH of NADPHoxidase. oxidase.To prevent To preventthe detrimental the detrimental effects eofffects these of thesemolecules molecules,, Yücel Yücel et al et. blocked al. blocked the thefunction function of ofNADPH NADPH oxidase oxidase using using apocynin, apocynin, a anatural natural NADPH NADPH oxidase oxidase inhibitor inhibitor found found in in plants plants [6] [6].. The The study demonstrated that apocynin strengthens the antioxidantantioxidant defensive system, increases glutathioneglutathione production,production, andand limitslimits thethe cellularcellular stressstress derivedderived fromfrom ischemiaischemia inin anan experimentalexperimental animalanimal model.model. Figure 1. Cellular events involved in ischemia/reperfusion injury (IRI). (1) Hypoxia following death of the donor induces metabolic stress, vascular permeability, and cellular apoptosis. (2) In the ischemic graft,Figure danger 1. Cellular signaling events pathways involved are in potentialischemia therapeutic/reperfusion targets injury for (IRI optimization.). (1) Hypoxia (3) following IRI generates death a sterileof the inflammatorydonor induces response metabolic in thestress, recipient vascular due permeability to the events, presentand cellular in (2). apoptosis. Treatments (2) based In the on theischemic use of graft, complement danger signaling and (Tumor pathways Necrosis are Factor) potential TNF therapeutic inhibitors are targets used for to decrease optimization. the immune (3) IRI response,generates asa sterile well as inflammatory cell therapy withresponse myeloid-derived in the recipient suppressor due to the cells events (MDSCs) present and in (2) hematopoietic. Treatments stembased cells on the (HSCs), use of which complement are important and (Tumor in controlling Necrosis this Factor) response. TNF inhibitors are used to decrease the immune response, as well as cell therapy with myeloid-derived suppressor cells (MDSCs) and ROShematopoietic production stemwas cells previously(HSCs), which thought are important to be due in controlling to non-specific this respons dysregulatione. at the electron transport chain level [7]. However, Chouchani et al. [8] showed that during ischemia, a pool of succinateROS production accumulates was and previously drives the thought reverse to be action due ofto non the- electronspecific dysregulation transport chain at the complex electron I, generatingtransport chain superoxides. level [7]. ThisHowever, mechanism Chouchani can also et al. be [8] inhibited showed by that rotenone, during which ischemia prevents, a pool ROS of production,succinate accumulates thus interfering and drives with thethe pro-inflammatory reverse action of responsethe electron that transport drives IL-1B chain production complex inI, activatedgenerating macrophages superoxides. [9 ].This Although mechanism direct can succinate also be removal inhibited in the by donor rotenone, organ which has not prevents been studied, ROS production, thus interfering with the pro-inflammatory response that drives IL-1B production in activated macrophages [9]. Although direct succinate removal in the donor organ has not been studied, a more proximal intervention that minimizes the harmful effects of IRI has provided promising results. In a randomized clinical trial of 40 liver recipients, α-lipoic acid (ALA) was given before liver reperfusion; then, qPCR was used to evaluate the activation of a panel of protective genes involved in hypoxia and ROS production after reperfusion [10]. The study demonstrated that ALA Int. J. Mol. Sci. 2020, 21, 8549 3 of 21 a more proximal intervention that minimizes the harmful effects of IRI has provided promising results. In a randomized clinical trial of 40 liver recipients, α-lipoic acid (ALA) was given before liver reperfusion; then, qPCR was used to evaluate the activation of a panel of protective genes involved in hypoxia and ROS production after reperfusion [10]. The study demonstrated that ALA inactivates ROS, regenerates endogenous antioxidants, such as glutathione and vitamin E, chelates metals, and repairs tissue damage due to oxidative stress. Moreover, it regulates protective signals during IRI, such as the hypoxia inducible factor 1 alpha (HIF-1a), which has been shown to protect from IRI through transcriptional activation of the Heme Oxygenase-1
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