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Ischemia-reperfusion (IR) injury is a kind of injury resulting from the restoration of the blood supply after blood vessel closure during liver transplantation and is the main cause of graft failure. The pathophysiological mechanisms of hepatic IR include a variety of oxidative stress responses. Hepatic IR is characterized by ischemia and hypoxia inducing oxidative stress, immune response and apoptosis. Fat-denatured livers are also used as donors due to the lack of liver donors. Fatty liver is less tolerant to IR than normal liver. Heme oxygenase (HO) is an enzyme that breaks down hemoglobin to bilirubin, ferrous iron and carbon monoxide (CO). Inducible HO subtype HO-1 is an important protective molecule in mammalian cells used to improve acute and chronic liver injury owing to its characteristic anti-inflammatory and anti-apoptotic qualities. HO-1 degrades heme, and its reaction product CO has been shown to reduce hepatic IR injury and increase the survival rate of grafts. As an induced form of HO, HO-1 also exerts a protective effect against liver IR injury and may be useful as a new strategy of ameliorating this kind of damage. This review summarizes the protective effects of HO-1 in liver IR injury, especially in fatty liver.

Fatty liver has lower tolerance against ischemia-reperfusion (I/R) injury in liver operations, including liver transplantation. Seeking to ameliorate liver injury following I/R in fatty liver, we examined the protective effect of hydrogen (H 2 ) saline on I/R liver injury in a methionine and choline-deficient plus high fat (MCDHF) diet-induced fatty liver mouse model. Saline containing 7 ppm H 2 was administrated during the process of I/R. Livers were obtained and analyzed. Primary hepatocytes and Kupffer cells (KCs) were obtained from fatty liver and subjected to hypoxia/reoxygenation. Apoptosis-related proteins and components of the signaling pathway were analyzed after treatment with hydrogen gas. The MCDHF I/R group showed higher levels of AST and ALT in serum, TUNEL-positive apoptotic cells, F4/80 immunopositive cells, mRNA levels of inflammatory cytokines, constituents of the signaling pathway, pro-apoptotic molecules in liver, and KCs and/or primary hepatocytes, compared to the control group. In contrast, H 2 treatment significantly suppressed the signs of I/R injury in fatty liver. Moreover, the expression of Bcl-2, HO-1, and Sirt1 in liver, KCs, and hepatocytes by hydrogen gas were increased, whereas caspase activation, Bax, and acetylation of p53 were suppressed by hydrogen gas. These results demonstrated that H 2 treatment ameliorated I/R liver injury in a fatty liver model by reducing hepatocyte apoptosis, inhibiting macrophage activation and inflammatory cytokines, and inducing HO-1 and Sirt1 expression. Taken togather, treatment with H 2 saline may have a protective effect and safe therapeutic activity during I/R events, such as in liver transplantation with fatty liver.

Steatosis has a low tolerance against ischemia-reperfusion injury (IRI). To prevent IRI in the steatotic liver, we attempted to elucidate the protective effect of astaxanthin (ASTX) in the steatotic liver model by giving mice a methionine and choline-deficient high fat (MCDHF) diet. Levels of lipid peroxidation and apoptosis, the expression of inflammatory cytokines and heme oxygenase (HO)-1, in the liver were assessed. Reactive oxygen species (ROS), inflammatory cytokines, apoptosis-related proteins and members of the signaling pathway were also examined in isolated Kupffer cells and/or hepatocytes from the steatotic liver. ASTX decreased serum ALT and AST levels, the amount of TUNEL, F4/80, or 4HNE-positive cells and the mRNA levels of inflammatory cytokines in MCDHF mice by IRI. Moreover, HO-1 and HIF-1α, phosphorylation of Akt and mTOR expressions were increased by ASTX. The inflammatory cytokines produced by Kupffer, which were subjected to hypoxia and reoxygenation (HR), were inhibited by ASTX. Expressions of Bcl-2, HO-1 and Nrf2 in hepatocytes by HR were increased, whereas Caspases activation, Bax and phosphorylation of ERK, MAPK, and JNK were suppressed by ASTX. Pretreatment with ASTX has a protective effect and is a safe therapeutic treatment for IRI, including for liver transplantation of the steatotic liver.

Background: One of the major events in ischemia-reperfusion (I/R)-induced heart injury in cardiac transplantation is the generation of reactive oxygen species. We hypothesized that a novel preservation solution called SBI-SEIIKU II (SS-II) contains 3 antioxidant reagents: L-cysteine, glycine, ascorbic acid/ascorbic acid-2-phosphate magnesium, which can block the generation of reactive oxygen species to result in a prolongation of the cold storage time via attenuating I/R injury., Methods: C57BL/6CrSlc(B6) mice underwent syngeneic mice heterotopic heart transplantation, and the animals were derived into 3 groups: recipients with nonpreserved grafts (control group), recipients with grafts preserved in histidine-tryptophan-ketoglutarate (HTK) for 24 and 48 hours (HTK group), and recipients with grafts preserved in SS-II for 24 and 48 hours (SS-II group)., Results: After 48 hours of preservation, there were no grafts that survived in the HTK group; however, the SS-II group had a high survival rate. After 24 hours of preservation, SS-II decreased the oxidative damage, myocardial apoptosis, and the infiltration of macrophages and neutrophils in the cardiac grafts in the early phase and suppressed the development of myocardial fibrosis in long-term grafts compared with HTK., Conclusions: The SS-II prolongs the acceptable cold storage time and protects the myocardium from I/R injury via inhibiting oxidative stress-associated damage. We believe that this novel preservation solution may be simple and safe for use in the clinical transplantation field.

Background: The fatty liver could increase the risk of serious acute ischemia reperfusion (I/R) injury, and hepatic steatosis is indeed a major risk factor for hepatic failure after grafting a fatty liver., Materials & Methods: Fatty liver models of methionine- and choline-deficient high-fat mice were subjected to I/R injury with or without 5-aminolevulinic acid (5-ALA)/sodium ferrous citrate (SFC) treatment. Levels of hepatic enzymes, lipid peroxidation and apoptosis, inflammatory cytokines and heme oxygenase (HO)-1, and the carbon monoxide (CO) in the liver, and reactive oxygen species (ROS), inflammatory cytokines and members of the signaling pathway in isolated Kupffer were assessed., Results: Alanine aminotransferase and aspartate aminotransferase levels, the number of necrotic areas, thiobarbituric acid reactive substance content, TUNEL-positive cells, infiltrated macrophages, and the inflammatory cytokine expression after I/R injury were dramatically decreased, whereas the endogenous CO concentrations and the HO-1 expression were significantly increased by 5-ALA/SFC treatment. The expression of toll-like receptors 2 and 4, NF-κB and inflammatory cytokines and ROS production in Kupffer cells were significantly decreased with 5-ALA/SFC treatment., Conclusion: 5-ALA/SFC significantly attenuates the injury level in the fatty liver after I/R injury., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe(2+)), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe(2+) 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe(2+) increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe(2+) treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe(2+) group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe(2+)-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe(2+) can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.

During aortic surgery, interruption of spinal cord blood flow might cause spinal cord ischemia-reperfusion injury (IRI). The incidence of spinal cord IRI after aortic surgery is up to 28%, and patients with spinal cord IRI might suffer from postoperative paraplegia or paraparesis. Spinal cord IRI includes two phases. The immediate spinal cord injury is related to acute ischemia. And the delayed spinal cord injury involves both ischemic cellular death and reperfusion injury. Inflammation is a subsequent event of spinal cord ischemia and possibly a major contributor to spinal cord IRI. However, the development of inflammatory mediators is incompletely demonstrated. And treatments available for inflammation in spinal cord IRI are insufficient. Improved understanding about spinal cord IRI and the development of inflammatory cells and cytokines in this process will provide novel therapeutic strategies for spinal cord IRI. Inflammatory cytokines (e.g., TNF- α and IL-1) may play an important role in spinal cord IRI. For treatment of several intractable autoimmune diseases (e.g., rheumatoid arthritis), where inflammatory cytokines are involved in disease progression, anti-inflammatory cytokine antagonist is now available. Hence, there is great potential of anti-inflammatory cytokine antagonist for therapeutic use of spinal cord IRI. We here review the mediators and several possibilities of treatment in spinal cord IRI.

Background/purpose: Apoptosis resulting from disruption of the normal cell-matrix relationship (anoikis) during islet isolation, and the reactive oxygen and nitrogen species generated following hypoxia/reoxygenation (H/R) can lead to a loss of islet tissue in culture and the reduced survival of transplanted pancreatic islets. The aim of this study was to investigate the effect of (-)-epigallocatechin-3-gallate (EGCG), a well-known antiapoptotic agent, on inhibiting anoikis and H/R injury in an in vitro islet culture system., Methods: Islets were isolated from F344 rats and cultured under normal or H/R condition with/without EGCG., Results: EGCG inhibited apoptosis and lactate-dehydrogenase leakage from anoikis and H/R in a dose-dependent manner. Further, EGCG prevent increases in 8-hydroxy-2'-deoxyguanosine content and inhibited the decline of insulin secretory function induced by H/R., Conclusions: These results suggest that the addition of EGCG to an islet culture system may improve the survival rate of isolated islets and reduce the loss of functional islet mass that compromises the stable reversal of diabetes after islet transplantation.

Hou J, Cai S, Kitajima Y, Fujino M, Ito H, Takahashi K, Abe F, Tanaka T, Ding Q, Li XK. 5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury. Am J Physiol Renal Physiol 305: F1149-F1157, 2013. First published July 31, 2013; doi:10.1152/ajprenal.00275.2013.--Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe2+), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe2+ 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe2+ increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe2+ treatments significantly decreased the tubular damage and number of apoptotic cells. IRIinduced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe2+ group. Furthermore, mRNA expression of HO-1, TNF-β, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-β and interferon-γ were decreased in the 5-ALA/Fe2+ pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/ Fe2+ can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO. [ABSTRACT FROM AUTHOR]