Centrilobular Injury Following Hypoxia in Isolated, Perfused Rat Liver

Lemasters, John J.; Ji, Sungchul; Thurman, Ronald G.

doi:10.1126/science.7256265

Cited by 153 publications

(57 citation statements)

References 19 publications

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“…29,33 Exposure to hypoxia alone is sufficient to cause hepatic parenchymal cell injury in isolated, perfused livers. 34,35 Interestingly, the severity of lesions caused by LPS is enhanced by exposing rats to a hypoxic atmosphere. 36 Indeed, enhanced hepatic expression of hypoxia-regulated genes occurred in LPS/RAN-treated rats 10 , and two markers of hypoxia were observed in livers of LPS/RANtreated rats (Figs.…”

Section: Discussionmentioning

confidence: 99%

Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats

et al. 2004

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Coadministration of nonhepatotoxic doses of the histamine 2-receptor antagonist ranitidine (RAN) and bacterial lipopolysaccharide (LPS) results in hepatocellular injury in rats, the onset of which occurs in 3 to 6 hours. This reaction resembles RAN idiosyncratic hepatotoxicity in humans. Early fibrin deposition occurs in livers of rats cotreated with LPS/RAN. Accordingly, we tested the hypothesis that the hemostatic system contributes to liver injury in LPS/RAN-treated rats. Rats were given either LPS (44.4 ؋ 10 6 EU/kg) or its vehicle, then RAN (30 mg/kg) or its vehicle 2 hours later. They were killed 2, 3, 6, 12, or 24 hours after RAN treatment, and liver injury was estimated from serum alanine aminotransferase activity. A modest elevation in serum hyaluronic acid, which was most pronounced in LPS/RANcotreated rats, suggested altered sinusoidal endothelial cell function. A decrease in plasma fibrinogen and increases in thrombin-antithrombin dimers and in serum concentration of plasminogen activator inhibitor-1 occurred before the onset of liver injury. Hepatic fibrin deposition was observed in livers from LPS/RAN-cotreated rats 3 and 6 hours after RAN. Liver injury was abolished by the anticoagulant heparin and was significantly attenuated by the fibrinolytic agent streptokinase. Hypoxia, one potential consequence of sinusoidal fibrin deposition, was observed in livers of LPS/RAN-treated rats. In conclusion, the results suggest that the hemostatic system is activated after LPS/RAN cotreatment and that fibrin deposition in liver is important for the genesis of hepatic parenchymal cell injury in this model. B acterial lipopolysaccharide (endotoxin, LPS) is an outer cell wall component of gram-negative bacteria and a potent inflammagen. Exposure to large doses of LPS can cause extensive damage to the liver and other organs in humans and rodents. 1 Exposure of liver to smaller amounts of LPS is commonplace and occurs through multiple means, including LPS translocation from the intestinal lumen into the portal venous blood. 2 Inflammatory responses triggered by small doses of LPS typically are noninjurious, but several studies have shown they can markedly enhance the hepatotoxicity of a variety of chemicals. 2 Moreover, idiosyncratic hepatotoxicity during drug therapy may arise from coexposure to inflammagens such as LPS. 3 Idiosyncratic liver injury occurs during treatment with numerous drugs, typically in a small fraction of people taking the drug. These responses are seemingly unrelated to dose, and the time of onset relative to beginning of drug therapy is often highly variable. One drug that causes idiosyncratic hepatotoxicity is the histamine 2 receptorantagonist, ranitidine (RAN). RAN is used therapeutically for treatment of duodenal ulcers, gastric hypersecretory diseases, and gastroesophageal reflux disease, and it is estimated to cause liver injury in less than 0.1% of people taking the drug. 4 Mechanisms of RAN idiosyncrasy are not understood, but liver injury might develop in part from a coexisting infl...

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Section: Discussionmentioning

confidence: 99%

Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats

et al. 2004

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“…Reversible injury was associated with cessation of the shedding and subsequent leakage of cytosolic enzymes, whereas irreversible injury was associated with a sustained release of endothelial enzymes. Interestingly, 45 min of warm ischemia represents the transition between reversible and irreversible ischemia in both studies (11,17). In mammalian cells PNP catalyzes the breakdown of inosine to hypoxanthine (18), the substrate for xanthine oxidase-mediated generation of free oxygen radicals.…”

Section: Discussionmentioning

confidence: 99%

Purine nucleoside phosphorylase: A new marker for free oxygen radical injury to the endothelial cell

et al. 1990

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The effect of ischemia and reperfusion on purine nucleoside phosphorylase was studied in an isolated perfused rat liver model. This enzyme is localized primarily in the cytoplasm of the endothelial and Kupffer cells; some activity is associated with the parenchymal cells. Levels of this enzyme accurately predicted the extent of ischemia and reperfusion damage to the microvascular endothelial cell of the liver. Livers from Lewis rats were subjected to 30, 45 and 60 min of warm (37° C) no flow ischemia that was followed by a standard reperfusion period lasting 45 min. Purine nucleoside phosphorylase was measured at the end of the no flow ischemia and reperfusion periods as was superoxide generation (O 2 − ). Bile production was monitored throughout the no flow ischemia and reperfusion periods. Control perfusions were carried out for 120 min. A significant rise in purine nucleoside phosphorylase levels as compared with controls was observed at the end of ischemia in all the three groups. The highest level, 203.5 ± 29.2 mU/ml, was observed after 60 min of ischemia. After the reperfusion period, levels of purine nucleoside phosphorylase decreased in the 30-and 45-min groups 58.17 ± 9.66 mU/ml and 67.5 ± 17.1 mU/ml, respectively. These levels were equal to control perfusions. In contrast, after 60 min of ischemia, levels of purine nucleoside phosphorylase decreased early in the reperfusion period and then rose to 127.8 ± 14.8 mU/ml by the end of reperfusion (p < 0.0001). Superoxide generation at the beginning of reperfusion was higher than in controls with similar values observed at the end of 30, 45 and 60 min of ischemia. During reperfusion, production of superoxide continued. Bile production was significantly lower at the end of 30 min (0.044 ± 0.026 µl/min/gm), 45 min (0.029 ± 0.022 µl/min/gm) and 60 min of ischemia (0.022 ± 0.008 µl/min/gm) when compared with bile production by control livers during the corresponding time (0.680 ± 0.195, 0.562 ± 0.133 and 0.480 ± 0.100 µl/min/gm respectively; p < 0.001). During reperfusion, rates of bile production were normal after 30 and 45 min of ischemia. In contrast, significantly lower rates of bile production, 0.046 ± 0.36 µl/min/gm (p < 0.001) occurred during reperfusion after 60 min of ischemia. Control livers during the same period produced 0.330 ± 0.056 µl/min/gm of bile. The results indicate that purine nucleoside phosphorylase levels may be a good index of oxidative injury to the liver in ischemia reperfusion and reliably predict the functional state of the organ after reperfusion.Liver transplantation is now the therapy of choice for end-stage liver disease (1). Procurement, preservation and subsequent transplantation of solid organs involve a period of ischemia followed by reperfusion. Ischemia results in the breakdown of ATP to hypoxanthine, which is the substrate for xanthine oxidase-mediated conversion to xanthine (2). During the reperfusion, this reaction produces superoxide and other reactive oxygen species, which have been implicated in the reperfusio...

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“…Oxygen inhibits 2-nitroimidazole adduct binding by reoxidizing the nitro radical anion (R-NOᠨ Ϫ 2 ) injury to liver [1]; however, using standard techniques it is not possible to measure oxygen precisely in liver at the cellular level after the first step of reductive activation (Fig. 1 C).…”

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confidence: 99%

Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state

Arteel

Thurman

Raleigh

1998

European Journal of Biochemistry

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157

125

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2-Nitroimidazoles, such as pimonidazole, are reduced in cells with low oxygen tension and are, therefore, used as hypoxia markers. However, the effect of the pyridine nucleotide redox state on pimonidazole reduction is not known. Therefore, livers from fed or fasted rats were perfused with oxygen-saturated buffer containing pimonidazole (400 µM) in the presence and absence of an inhibitor of the mitochondrial respiratory chain, potassium cyanide ; these treatments were used to modulate the mitochondrial and cytosolic pyridine nucleotide redox states. Pimonidazole-induced increases in oxygen uptake over basal values were as follows: fed, 15.1Ϯ 2.4 ; fasted, 4.2 Ϯ 0.8; fedϩ KCN, 32.1Ϯ0.9 ; fastedϩKCN, 0.2 Ϯ 0.2 µmol · g Ϫ1 · h Ϫ1 . However, if NADPH was added in excess, microsomal oxygen uptake due to oxidative metabolism of pimonidazole was independent of treatment. These results indicate that pimonidazole-stimulated O 2 uptake, due predominantly to N-oxidation and glucuronidation, is dependent on the NADPH redox state. In contrast, reduced pimonidazole adducts, detected immunochemically, accumulated in pericentral regions in liver. Increasing the NADH redox state by inhibiting the mitochondrial respiratory chain with KCN decreased protein-bound pimonidazole adducts. Concomitantly, the average O 2 tension of the liver was increased at least 30%. However, KCN had no effect on total pimonidazole adducts detected by ELISA, although both cytosolic (lactate/pyruvate) and mitochondrial (3-hydroxybutyrate/acetoacetate) NADH redox states were elevated by at least a factor of eight. These results indicate that, unlike oxidative metabolism, the pyridine nucleotide redox state does not determine the rate of reductive metabolism of pimonidazole. Instead, the cellular oxygen tension regulates this process. Therefore, even in cases where the supply of reducing equivalents is increased (e.g., ethanol metabolism), accumulation of the reduced bound product of pimonidazole is oxygen dependent in liver.

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Centrilobular Injury Following Hypoxia in Isolated, Perfused Rat Liver

Cited by 153 publications

References 19 publications

Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats

Role of hepatic fibrin in idiosyncrasy-like liver injury from lipopolysaccharide-ranitidine coexposure in rats

Purine nucleoside phosphorylase: A new marker for free oxygen radical injury to the endothelial cell

Reductive metabolism of the hypoxia marker pimonidazole is regulated by oxygen tension independent of the pyridine nucleotide redox state

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