Oxygen free radicals and glutathione in hepatic ischemia/reperfusion injury

Stein, Hubert; Oosthuizen, M. M. J.; Hinder, Ronald A.; Lamprechts, Hugo

doi:10.1016/0022-4804(91)90209-5

Cited by 79 publications

(33 citation statements)

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“…Likewise, the antioxidants Trolox (Aldrich Chemical Co.) and DMSO, which abrogated the changes in glutathione status, completely protected endothelial cells in this system. Decreased GSH levels have been shown in the intact liver during ischemia-reperfusion by some 17,18 but not other workers 30,31 ; the differences may be explained by the critical importance of GSH for sinusoidal endothelial cells, in which levels are several orders of magnitude less than those of hepatocytes. 32 Studies with toxins such as cyclophosphamide have shown that intracelluar GSH is an important defense against druginduced toxicity, and that toxicity to sinusoidal endothelial cells is preceded by a profound reduction in GSH levels.…”

Section: Discussionmentioning

confidence: 85%

“…Endogenous levels of reduced glutathione (GSH) are critically important in protection against injury from ROS during ischemia-reperfusion injury in the intact liver 17,18 as well as in other tissues. 19,20 Using production of oxidized glutathione (GSSG) as a marker of oxidative stress, Jaeschke noted substantial increases in plasma GSSG with minimal-toinsignificant increases in hepatic tissue and biliary GSSG 4 ; this constellation of changes was indicative of significant oxidative stress in the intravascular, but not in the intracellular, compartment.…”

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confidence: 99%

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Role of oxidative stress in hypoxia-reoxygenation injury to cultured rat hepatic sinusoidal endothelial cells

2000

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To characterize the role of oxidative stress in cultured rat sinusoidal endothelial cells, we studied the production of superoxide after reoxygenation, the relationship of reduced glutathione (GSH) levels to cell injury, and the protective efficacy of antioxidants. Hypoxia (pO 2 1-2 mm Hg) was achieved by culturing cells under 95% N 2 5% CO 2 for 4 hours. Reoxygenation was then reestablished, and viability was determined at 24 hours by trypan blue exclusion; putative protective agents were added at the time of reoxygenation (4 hours). As previously reported, reoxygenation after 4 hours hypoxia accentuated sinusoidal cell death fourfold compared with hypoxic or normoxic controls (P F .0001). Superoxide was not produced on reoxygenation, and superoxide dismutase provided no protection against reoxygenation injury. Cellular levels of GSH fell to 37 ؎ 4% of normoxic controls (P F .0001) following reoxygenation. These changes were essentially abrogated by Trolox (Aldrich Chemical Co., Milwaukee, WI) and dimethyl sulfoxide, both of which also completely protected against reoxygenation injury. When cellular GSH levels were lowered by addition of diethylmaleate (which conjugates GSH), this reduced the viability of endothelial cells cultured under normoxic conditions and greatly augmented reoxygenation injury. Conversely, addition of exogenous GSH partially protected endothelial cells against hypoxia-reoxygenation injury. Desferrioxamine also protected against reoxygenation injury, but catalase was only partly protective. It is concluded that sinusoidal endothelial cells undergo significant intracellular oxidative stress following reoxygenation, and their viability is critically dependent on GSH levels. Reactive oxygen species are likely mediators of oxidative stress in hepatic sinusoidal endothelial cells. (HEPATOLOGY 2000;31:160-165.)In the intact liver, oxidative stress appears to be part of the mechanism for ischemia-reperfusion injury and is related to the generation of reactive oxygen species (ROS) 1-4 and possibly nitric oxide. 5 However, the role of individual cell types in the production of these potentially cytotoxic mediators remains uncertain. Conversely, sinusoidal endothelial cells appear to be a major target of ischemia-reperfusion (or hypoxia-reoxygenation) injury. [6][7][8] The resultant endothelial injury disrupts the microcirculation, reducing blood flow and enhancing further tissue necrosis. Neutrophils adhere to damaged endothelial cells and their resultant activation is likely to be one source of ROS. In the present studies, we have explored the possibility that sinusoidal endothelial cells could themselves generate oxidative stress.Earlier in vitro studies on the effects of hypoxia-reoxygenation on endothelial cells have usually been performed on cultures of endothelial cells derived from large blood vessels, such as the pulmonary artery and umbilical vein. 9,10 From this work, it is apparent that nonhepatic endothelial cells are susceptible to hypoxia-reoxygenation injury through the generation of...

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Section: Discussionmentioning

confidence: 85%

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confidence: 99%

Role of oxidative stress in hypoxia-reoxygenation injury to cultured rat hepatic sinusoidal endothelial cells

2000

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“…Hepatic GSH production decreases during normothermic ischemia, and discharge of ROS during reperfusion phase causes rapid consumption of GSH 19,20 . These two mechanisms cause decreases in both intracellular and extracellular GSH levels, which causes oxidation and degration of important structures in the cell such as proteins, lipids, or double strand structure of DNA 20 . Therefore, the tissue GSH level has been accepted as a marker for oxidative stress injury.…”

Section: Results Of Histopathological Analysismentioning

confidence: 99%

Grape seed protects cholestatic rats liver from ischemia/reperfusion injury

et al. 2016

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PURPOSE:To determine the effect of grape-seed extract against ischemia/reperfusion injury in cholestatic liver. METHODS:Eighteen Wistar albino rats were divided into three groups. In control and study groups, cholestasis was provided by bile duct ligation. Seven days later, the rats were subjected to 30 min hepatic ischemia, followed by 60 min of reperfusion. Oral administration of 50 mg/kg/day grape-seed extract was started 15 days before bile duct ligation and continued to the second operation in the study group. Serum, plasma and liver samples were taken. Laboratory analysis, tissue gluthation, malondialdehyde, myeloperoxidase levels and histopathological examination were performed.RESULTS: Significant decrease in liver gluthation level and significant increase in malondialdehyde level and myeloperoxidase activity were observed after ischemia/reperfusion in cholestatic rats. Serum and plasma levels for laboratory analysis were also significantly higher in cholestatic I/R group. Hepatic necrosis and fibrosis were detected in histopathological examination. Oral grape-seed extract administiration reversed all these parameters and histopathological findings except serum bilirubin levels. CONCLUSION:Oral grape-seed extract treatment can improve liver functions and attenuate the inflammation and oxidative stress in cholestatic ischemia/reperfusion injury.

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“…5 Those pathological features would limit the suitability of those strains antioxidants such as glutathione. 20,21 A completely different explanation for the liver's longevity may be the ability of for this type of experiment.…”

Section: Materials and Methods Transplantation Did Not Differ Signifimentioning

confidence: 99%

Assessment of the longevity of the liver using a rat transplant model

Sakai

1997

Hepatology

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been suggested that the liver's enormous functional reserve, To assess the longevity of the liver, arterialized, orits regenerative capacity, and its abundant, dual blood supply thotopic liver grafts were performed using syngeneic are important factors in its ability to maintain its youthful male BN/BiRij rats. Young (5-month-old) livers were properties as its host becomes senescent.3 transplanted into 5-month-old recipients (group I, n Å The livers of most strains of rats are similar to humans in 27), and old (28-month-old) livers were transplanted into the sense that they are not targets of age-related disease and 5-month-old rats (group II, n Å 28). Recipient survival they continue to function well in senescent animals. 5 The after transplantation was similar in both groups. The aging and survival characteristics of various strains of rats average age of the livers at the time of death was 16.7have been defined. 6,7 When rats reach the age of 24 to 28 months in group I and 39.1 months in group II. Four of months, they are considered old 8 and they correspond in age the livers in group II survived for more than 4 years to humans in the sixth to seventh decades of life. Using synge-(48.1 to 52.4 months). Early deaths (less than 1 year) after neic rats, we transplanted old livers into young rats and studtransplantation were most commonly caused by biliary ied their function, histology, and longevity. We postulated obstruction and cholangitis in both groups. Late deaths that the old livers would survive for extended periods after (more than 1 year) after grafting were mainly from heart transplantation because of the innate youthful characterisfailure or tumors. None of the animals died of liver failtics of the liver. ure or liver disease. Weight gain in the rats, total serum protein levels, and alanine transaminase levels after MATERIALS AND METHODS transplantation did not differ significantly between theMale BN/BiRij rats from the National Institute of Aging two groups. There was a trend for the histological fea- (Bethesda, Maryland) were used in the experiments, which were tures of aging of the liver-fibrosis, bile duct proliferaapproved by the Institutional Animal Care Committee, University tion, and pigment deposition-to become more prevaof Western Ontario. Young (5-month-old) recipient rats were randomlent as the livers became very old (mean age, 46 months). ized to receive either young livers from 5-month-old donors (group Nevertheless, typical aging changes, as individual find-I, n Å 28) or old livers from rats that were 28 months old (group II, ings, were absent in nearly half of the oldest organs. The n Å 27). alterations in morphology had no apparent effect on the dissection. The liver was skeletonized and a polyethylene tube was inserted into the end of the divided common duct. The hepatic artery was dissected from the celiac trunk ligating the gastroduodenal, gasThe biological process of aging causes alterations in the tric, and splenic branches. The aorta distal to the celiac origin was structure of...

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Oxygen free radicals and glutathione in hepatic ischemia/reperfusion injury

Cited by 79 publications

References 8 publications

Role of oxidative stress in hypoxia-reoxygenation injury to cultured rat hepatic sinusoidal endothelial cells

Role of oxidative stress in hypoxia-reoxygenation injury to cultured rat hepatic sinusoidal endothelial cells

Grape seed protects cholestatic rats liver from ischemia/reperfusion injury

Assessment of the longevity of the liver using a rat transplant model

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