Oxidative stress is one of the key mechanisms affecting the outcome throughout the course of organ transplantation. It is widely believed that the redox balance is dysregulated during ischemia and reperfusion (I/R) and causes subsequent oxidative injury, resulting from the formation of reactive oxygen species (ROS). Moreover, in order to alleviate organ shortage, increasing number of grafts is retrieved from fatty, older, and even non-heart-beating donors that are particularly vulnerable to the accumulation of ROS. To improve the viability of grafts and reduce the risk of posttransplant dysfunction, a large number of studies have been done focusing on the antioxidant treatments for the purpose of maintaining the redox balance and thereby protecting the grafts. This review provides an overview of these emerging antioxidant treatments, targeting donor, graft preservation, and recipient as well.
Ischemia/reperfusion injury (IRI) is present in many medical situations, specifically in organ transplantation. This event can lead to immediate and long-term graft dysfunction, such as allograft rejection, delayed graft function (DGF), and even primary nonfunction (PNF) [
Oxidative stress, known as an imbalance between the generation of ROS and antioxidant defense system, is the disease mechanism most commonly involved in IRI. It has been proven that ischemia initiates the noxious generation of ROS, while the reoxygenation process during reperfusion is responsible for most ROS production, activation of complement system, and inflammatory response [
The ROS-induced injurious effect on graft and recipient is related to various posttransplant complications. Besides, marginal grafts are significantly vulnerable to the oxidative stress and thus restrict graft pool, which aggravates organ shortage. To alleviate such adverse outcomes, a volume of preclinical and clinical studies against oxidative stress are under investigation, targeting consecutive process throughout the transplantation, including donor, graft preservation, and recipient as well. Despite some new discoveries in the mechanism against ROS, the clinical results remain controversial. Therefore, we summarize some advanced development of antioxidant treatments in organ transplantation and their corresponding mechanisms.
Local ischemic preconditioning (LIPC), a widely accepted antioxidant approach, is a brief period of ischemia/reperfusion that leads to tolerance of subsequent ischemia/reperfusion injury (IRI). In animal studies, LIPC has been proven to be an efficient tool to protect most organs (e.g., liver, kidney, heart, and intestine), particularly via antioxidant pathway [
Hydrogen is a reducing gas that displays antioxidant properties and exhibits protective effects against graft IRI and dysfunctions. Though application of mechanical ventilation (MV) in intensive care unit supports donor’s life, it can also provoke oxidative stress and inflammatory response, causing ventilator-induced lung injury (VILI) and reducing graft viability [
High levels of ROS play a pivotal role in transplant-associated IRI, especially in cadaveric donors. Antioxidant enzymes (AOEs), such as catalase and SOD that detoxify H2O2 and superoxide, are highly potent and specific agents to the ROS-induced injury and not consumed in reaction with ROS. However, due to inability to cross cell membrane barriers and fast elimination, a significant hurdle in the clinical translation lies in the insufficient delivery of these enzymes to targeted sites, especially the vascular endothelium suffering oxidative injury [
Application of vascular immune targeting AOEs to specific endothelial epitopes has been proven to be an effective donor preconditioning method in lung transplantation model. The nanosized conjugates, consisting of AOEs and specific antibodies, can be directed against the endothelial determinant accumulation in vascular endothelium after intravenous administration and eventually delivered into endothelial cell, thus alleviating oxidative stress. Platelet/endothelial cell adhesion molecule-1 (PECAM-1) is such an endothelial epitope and the specific nanosized particles (anti-PECAM/catalase conjugates) have been examined in a porcine lung transplantation model, in which the immune targeting treatment allows immediate reconstitution of pulmonary gas exchange and microcirculation, and improve both graft and recipient outcomes [
Liposomes are artificial vesicles consisting of one or more phospholipid layers, with an aqueous core enclosed; lipid-soluble antioxidants can be incorporated into the lipid bilayer, while water-soluble antioxidants (e.g., NAC and curcumin) can be encapsulated in the aqueous space. NAC is a well-known antioxidant which can function both as a ROS scavenger and as a precursor of reduced glutathione, thus modulating the redox status. To improve the bioavailability, NAC is encapsulated in the aqueous space of liposome, gaining a higher protective potency than the free drug. Liposomal NAC has been administered separately in rodents to protect lung [
Conclusively, immune targeting therapy and liposome formulation are promising approaches to facilitate the delivery of AOEs and nonenzymatic antioxidants before ischemia process. Though there is no associated animal transplantation study performed, we hold that the carriers can help the antioxidants administered to a donor quickly bind to endothelium and subsequently protect graft from IRI. However, these carriers must be carefully tested in terms of toxicity, activation of defense systems, inflammation or thrombosis, and aggregation in circulation and embolism of the microvasculature.
Ex vivo graft preservation is necessary for allocating and transporting the graft to its recipient. It has been widely accepted that primary occurrence of ROS-induced injury arises from the cellular alteration during the ischemia process, especially in cold preservation period. Several approaches including machine perfusion and modified preservation solutions have been developed to reduce the injury.
Machine perfusion (MP) is increasingly used as an alternative method to overcome the present shortage of donors by expanding the graft pool and prolong the storage time. It is a dynamic technique using a continuous flow of solutions to perfuse and maintain residual metabolism of the graft [
Polyethylene glycol (PEG), synthesized as liner or branched polymers in different sizes, functions as an alternation of hydroxyethyl starch (HES) contained in UW solution due to its low viscosity. As an “immunocamouflage” agent, PEG binds covalently to various biological surfaces and forms complexes with cell membrane lipids, membrane proteins, or carbohydrates, preventing osmotic swelling as well as lipid peroxidation (LPO) in graft cold storage. PEG is also an effective free radical scavenger and can modulate oxidative stress during preservation. Owing to these protective effects, several PEG-based preservation solutions, including Polysol, IGL-1 solution, and SCOT, have been developed for organ preservation.
Polysol solution is a colloid-based low-viscosity organ preservation solution containing vitamins, amino acid, and a variety of ROS scavengers (including allopurinol, glutathione, alpha-tocopherol, and ascorbic acid), which possess strong antioxidant capacity. Polysol solution is applied on a steatotic rat liver perfusion model and significantly attenuates LPO to nearly one fourth of that in HTK control [
Institute Georges Lopez-1 (IGL-1) solution is characterized by lower viscosity (1.250 mm2/s), higher sodium, and lower potassium compared with UW solution. The application of IGL-1 solution has been reported in the SCS of pancreas [
The Solution de Conservation des Organes et des Tissus (SCOT) has shown its protective potential in a pancreatic islet transplantation model, reducing IRI and ameliorating the long-term outcome of recipients’ immune response [
Hydrogen-rich preservation solution has been proven to have high antioxidant potential and tested in liver, kidney, pancreas, bone marrow, lung, and intestinal cold storage [
NO is a kind of free radical diatomic gas and gaseous signaling molecule. The protective potential of NO is associated with the reduction of superoxide anion-induced tissue toxicity and the inflammatory response. Furthermore, NO can modulate mitochondrial energy generation and thus decrease ROS formation during I/R period. Kageyama et al. [
Carbon monoxide (CO) is also a gaseous signaling molecule and possesses a high affinity for heme prosthetic group. CO supplemented to preservation solution has been proven to improve the graft function in experimental studies [
Hydrogen sulfide (H2S) is considered as the third gaseous signaling molecule with properties to help relax vascular smooth muscle, inhibit apoptosis, modulate inflammatory response, and alleviate oxidative stress [
One of the major sources of ROS is the mitochondria that are particularly vulnerable to oxidative injury. Mitochondrial damage may impair the electron flow and promote the formation of superoxide. Mitochondrial permeability transition (MPT) plays an essential role in cell death during IRI, induced by ROS and reversely aggravating the oxidative stress [
Ascorbic acid (AA) is a potent physiological extracellular scavenger of ROS. AA has been supplemented into HTK and Polysol solution to prevent ROS. Noticeably, high-concentrated AA has been reported to aggravate hepatic IRI owing to its excess reduction of iron [
Remote ischemic postconditioning (RIPoC) is induced by several cycles of I/R on a remote tissue (arm or leg) to produce systemic protection against IRI in distant organs, without direct access to the vessels of the organ of interest. RIPoC can increase antioxidant capacity of liver and kidney temporarily by reducing NF-
Similar to LIPC, local ischemic postconditioning (LIPoC) is defined as rapid and intermittent interruptions of blood flow in the early phase of reperfusion after a prolonged period of ischemia. In a canine autotransplantation model, after flushing and static preservation of the kidney for 24 hours, LIPoC was performed with six cycles of 10 or 30 seconds or three cycles of 1-minute I/R before final reperfusion. The result indicates enhanced level of expression of SOD and decreased levels of MDA, implying that LIPoC may protect the graft via an antioxidant pathway [
Oxidative stress is a common cause of PNF, DGF, and allograft rejection, especially in marginal donors. This review summarizes the innovative antioxidant treatments for the donor, graft preservation, or recipient designed to improve the graft viability and long-term outcome (Tables
(a) Characteristics of reviewed studies concerning antioxidant treatment for donor. (b) Characteristics of reviewed studies concerning antioxidant treatment for graft. (c) Characteristics of reviewed studies concerning antioxidant treatment for recipient.
Treatment | Subject | Organ | Model or disease | Effects |
---|---|---|---|---|
|
Rat [ |
Liver | I/R | NF- |
Human [ |
Liver | LiT | Apoptosis ↓, PNF ↓, AST ↑, HIF-1 | |
Human [ |
Liver | LiT | No beneficial effect | |
Human [ |
Liver | LiR | No beneficial effect | |
Human [ |
Liver | LiT | 10 min occlusion is optimal | |
Rat [ |
Liver | I/R | 5/8 min occlusion is optimal | |
|
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|
Mice [ |
Lung | MV | W/D ratio ↓, MDA ↓, Egr-1 ↓, TNF- |
Rat [ |
Lung | LuT | PO2 ↑, PCO2 ↓, ICAM-1 ↓, IL-1 | |
Rat [ |
Liver | I/R | NF- | |
Human [ |
Diabetic | T2DM | LDL ↓, SOD ↑ | |
Human [ |
Liver | HBV | HBV DNA ↓, ALT ↓, TBiL ↓, SOD ↑, GST ↑ | |
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|
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Immune targeting therapy | Pig [ |
Lung | LuT | Gas exchange ↑, W/D ratio ↓, Edema ↓, MDA ↓ |
Human [ |
Cell | HUVECs | VCAM ↑, TNF ↓, IL-1 | |
Liposome | Rat [ |
Lung | I/R | PO2 ↑, endothelin-1 ↓, iNOS ↓ |
Rat [ |
Liver | LPS-LiI | NPSH ↓, MDA ↓, 4-HNE ↓, ALT ↓, AST ↓, TNF- | |
Rat [ |
Lung | LPS-LuI | NPSH ↓, MDA ↓, 4-HNE ↓, MPO ↓, TNF- |
Treatment | Subject | Organ | Model or disease | Effects |
---|---|---|---|---|
|
Rat [ |
Liver | HMP | MP at 20°C is optimal, AST ↓, LDH ↓, ATP/ADP ↑, bile production ↑, TNF- |
Human [ |
Lung | LuT | Subtle beneficial effect | |
Rat [ |
Heart | HMP | Apoptosis ↓, MMP-2 ↓, H2O2 ↓, pAkt/Akt ↑ | |
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|
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Polysol solution | Rat [ |
Liver | SCS | AST ↓, GLDH ↓, PVP ↓, ATP ↑, O2 consumption ↑, bile production ↑, MDA ↓, W/D ratio ↓ |
Rat [ |
Liver | PLiT | PVF ↑, ALT ↓, LDH ↓, MDA ↓, VEGF ↑ | |
Human [ |
Kidney | KT | Acute rejection rate ↑ | |
IGL-1 solution | Pig [ |
Pancreas | PT | Same degree of safety and effectiveness with UW solution |
Human [ |
Kidney | KT | DGF ↓, Cr ↓, apoptosis ↓, Ccr ↑ | |
Pig [ |
Intestine | IAT | Acute cellular rejection ↓, iNOS ↑, necrosis ↓, apoptosis ↑, | |
Human [ |
Liver | LiT | Same degree of safety and effectiveness with UW solution | |
SCOT solution | Mice [ |
Pancreas | PT | PNF + DGF + allograft survival time ↑ |
Human [ |
Kidney | KT | Same degree of safety and effectiveness with UW solution | |
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|
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Hydrogen | Rat [ |
Liver | I/R | ALT ↓, HMGB1 ↓, MDA ↓, TNF- |
Rat [ |
Kidney | KT | Recipient survival rate ↑, Cr ↓, Ccr ↑, MDA ↓, 8-OHdG ↓ | |
Rat [ |
Intestine | IAT | MDA ↓, LDH ↓, EGR-1 ↓, IL-6 ↓, iNOS ↓, IL-1 | |
Nitric oxide | Rat [ |
Liver | LiT | ALT ↓, HA ↓, MDA ↓, eNOS ↑, iNOS ↓, ET-1 ↓, 8-OHdG ↓ |
Rat [ |
Lung | LuT | W/D ratio ↓, vascular resistance ↓, cGMP ↑, iNOS ↓, TNF- | |
Carbon monoxide | Rat [ |
Kidney | KT | Recipient survival ↑, IL-6 ↓, TNF- |
Rat [ |
Kidney | KT | ALAS-1 ↑, MDA ↓, IL-6 ↓, TNF- | |
|
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|
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Melatonin | Rat [ |
Liver | SCS | AST ↓, ALT ↓, BSP clearance ↑, vascular resistance ↓, eNOS ↑, TNF- |
Trolox | Pig [ |
Heart | HT | ET-1 ↓, MDA ↓, SOD ↑, TA ↓, LDH ↓, CK ↓, calcium ↓ |
Doxycycline | Rat [ |
Heart | HMP | Apoptosis ↓, MMP-2 ↓, H2O2 ↓, pAkt/Akt ↑ |
Treatment | Subject | Organ | Model or disease | Effects |
---|---|---|---|---|
|
||||
RIPoC | Human [ |
Kidney | KT | Cr ↓, pathology (—), GFR ↑, uNGAL ↓ |
Human [ |
Liver | LiT | No beneficial effect | |
Human [ |
Kidney | KT | No beneficial effect | |
LIPoC | Canine [ |
Kidney | KT | MDA ↓, MPO ↓, SOD ↑, apoptosis indices ↓, Cr ↓, BUN ↓, Ccr ↑ |
Human [ |
Kidney | KT | Safe but no beneficial effect |
ACR: acute cellular rejection; ALAS-1: 5-aminolevulinate synthase; ALT: alanine aminotransferase; AST: aminotransferase; ATP: adenosine triphosphate; BSP: bromosulfophthalein; BUN: blood urea nitrogen; Ccr: creatinine clearance; cGMP: cyclic guanosine monophosphate; Cox-2: cyclooxygenase-2; Cr: creatinine; DGF: delayed graft function; eNOS: endothelial nitric oxide synthase; ET-1: endothelin-1; GFR: glomerular filtration rate; GLDH: glutamate dehydrogenase; GST: glutathione S transferase; HA: hyaluronic acid; HBV: hepatitis B virus; HMP: hypothermic machine perfusion; HSP: heat shock protein; HT: heart transplant; HUVECs: human umbilical endothelial cells; IAT: intestinal allotransplantation; iNOS: inducible nitric oxide synthase; I/R: ischemia and reperfusion; KT: kidney transplantation; LDH: lactate dehydrogenase; LDL: low density lipoprotein; LIPoC: local ischemic postconditioning; LiR: liver resection; LiT: liver transplantation; LPS: lipopolysaccharide; LuT: lung transplantation; MDA: malondialdehyde; MPO: myeloperoxidase; MV: mechanical ventilation; NOS: nitric oxide synthase; NPSH: nonprotein thiols; pAkt: phosphorylated Akt; PARP: poly(ADP-ribose) polymerase; PLiT: partial liver transplantation; PNF: primary nonfunction; PT: pancreas transplantation; PVF: portal venous flow; PVP: portal venous pressure; RIPoC: remote ischemic postconditioning; TA: total antioxidants; TBiL: total bilirubin; TNF: tumor necrosis factor; TLR-4: toll-like receptor-4; T2DM: type 2 diabetes mellitus; SCS: static cold storage; SOD: superoxide dismutase; uNGAL: urine neutrophil gelatinase-associated lipocalin; VEGF: vascular endothelial growth factor; W/D: wet-to-dry; 4-HNE: 4-hydroxyalkenals; 8-OHdG: 8-hydroxy-2-deoxyguanosine.
Although SCS has been effective for decades on optimal organs preservation, the preservation protocol is not adapted to the increasing marginal grafts which is able to extend the graft pool. Thus, the novel antioxidant preservation solution, as well as various supplements, requires more mechanism researches and pragmatic RCT. Combined utilization of antioxidant approaches may be more promising than attempts to reinforce the antioxidant capacity of organs by a single agent functioning as ROS scavenger. Even though the antioxidant potential of NMP is still unclear, this approach is worth more intensive researches. To this end, though a combination of antioxidant treatments seem to provide the best outcome, accurate models for preclinical studies and unified protocols for clinical trials are needed before the treatments can be translated into clinical practical. Moreover, the potential adverse effect of local and systemic antioxidant interventions to donors, grafts, and recipients, such as host defense hazard and prooxidant effects, should not be neglected. Antioxidant administration should also be controlled at a gradual, controlled rate, thus avoiding burst release and comprising effect.
Ascorbic acid
Angiotensin-converting enzyme
Antioxidant enzymes
Coronary artery bypass grafting
Carbon monoxide
Cytochrome P450
Delayed graft function
Doxycycline
Hydroxyethyl starch
Hypothermic machine perfusion
Hemeoxygenase-1
Hydrogen-rich UW solution
Hydrogen-rich water
Hydrogen sulfide
Institute Georges Lopez-1
Inducible nitric oxide synthase
Ischemia and reperfusion
Ischemia/reperfusion injury
Local ischemic preconditioning
Local ischemic postconditioning
Lipid peroxidation
Liver transplantation
Malondialdehyde
Matrix metalloproteinases
Machine perfusion
Mitochondrial permeability transition
Mechanical ventilation
Non-heart-beating donors
Normothermic machine perfusion
Nitric oxide
Polyethylene glycol
Primary nonfunction
Platelet/endothelial cell adhesion molecule-1
Randomized clinical trial
Remote ischemic postconditioning
Solution de Conservation des Organes et des Tissus
Static cold storage
Subnormothermic machine perfusion
Superoxide dismutase
Ventilator-induced lung injury
Venous systemic oxygen persufflation.
The authors declare that they have no competing interests.
This work is supported by the National Natural Science Foundation of China (Grant no. 81470847).