Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the effect of two doses of allopurinol (ALL) (100 and 50 mg/kg) administered i.v. on liver function after 1 h of normothermic ischemia. ALL given in a concentration of 100 mg/kg significantly improved bile output after 1 and 24 h of reperfusion. Hepatocyte injury reflected by alanine aminotransferase (ALT) and lactic dehydrogenase (LDH) in plasma was also significantly reduced at 24 h, but not at 1 h of reperfusion compared with controls. ALL administered at a concentration of 50 mg/kg had some protective effect. Significant correlation between circulating liver enzymes and bile output at 24 h after reperfusion indicates an important pathophysiologic link between hepatocyte function and injury in this time window.
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PMID:Allopurinol dose is important for attenuation of liver dysfunction after normothermic ischemia: correlation between bile flow and liver enzymes in circulation. 785 48

The potential role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of reperfusion injury was investigated in male Fischer rats subjected to 45 min of hepatic ischemia and 24 h of reperfusion. ICAM-1 mRNA levels increased during ischemia in the ischemic liver lobes; however, during reperfusion mRNA levels increased in both the ischemic and nonischemic lobes. Immunohistochemical evaluation indicated ICAM-1 expression only on sinusoidal lining cells in controls; ischemia-reperfusion enhanced ICAM-1 expression in the sinusoids and induced some expression on hepatocytes. The monoclonal anti-ICAM-1 antibody 1A29, but not an immunoglobulin G control antibody, administered at 1 h and 8 h of reperfusion (2 mg/kg) significantly attenuated liver injury as indicated by 51% lower plasma alanine aminotransferase activities and 32-36% less hepatic necrosis at 24 h without affecting reactive oxygen formation by Kupffer cells and hepatic neutrophils. Although 1A29 reduced neutrophil extravasation in a glycogen peritonitis by 60%, the antibody had no significant effect on hepatic neutrophil infiltration during reperfusion. These data suggest that ICAM-1 plays a significant role during the neutrophil-dependent injury phase after hepatic ischemia and reperfusion and therefore blocking this adhesion molecule may have therapeutic potential against postischemic acute liver failure.
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PMID:Intercellular adhesion molecule 1 (ICAM-1) expression and its role in neutrophil-induced ischemia-reperfusion injury in rat liver. 788 6

Alteration of calcium metabolism in cells has been thought to be one of the main factors in ischemia-reperfusion injury. Serial changes in the tissue calcium content of the liver and the correlation between calcium level and liver injury were investigated. Experimental dogs were divided into two groups and subjected to hepatic ischemia of different duration: 60 min in Group A and 120 min in Group B, followed by reperfusion. Serum alanine aminotransferase, as an indicator of liver injury, was more elevated in Group B than in Group A. There was no change in hepatic calcium content during ischemia in either group. Immediately after reperfusion, there was no change in hepatic calcium level in Group A, whereas in Group B it was markedly elevated. The peak value occurred 30 min after reperfusion and gradually decreased thereafter, but did not return to pre-ischemic levels during the observation time. Plasma calcium concentrations in hepatic venous blood were markedly decreased in Group B 30 min and 60 min after reperfusion. These results suggest that calcium accumulation in the liver during the early reperfusion period may be one of the mediators of hepatic injury. To elucidate the mechanisms for elevation of calcium in hepatic tissue, serum malondialdehyde, a product of lipid peroxidation, was measured in hepatic venous blood. No elevation of serum malondialdehyde was observed in either group, indicating that the increases in calcium may not be due to oxidative stress. Serum mitochondrial aspartate aminotransferase and electron microscopic findings were used as indicators of mitochondrial injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Changes in calcium content of the liver during hepatic ischemia-reperfusion in dogs. 789 Aug 88

Alanine transport and the role of alanine amino-transferase in the synthesis and consumption of glutamate were investigated in the preparation of rat brain synaptosomes. Alanine was accumulated rapidly via both the high- and low-affinity uptake systems. The high-affinity transport was dependent on the sodium concentration gradient and membrane electrical potential, which suggests a cotransport with Na+. Rapid accumulation of the Na(+)-alanine complex by synaptosomes stimulated activity of the Na+/K+ pump and increased energy utilization; this, in turn, activated the ATP-producing pathways, glycolysis and oxidative phosphorylation. Accumulation of Na+ also caused a small depolarization of the plasma membrane, a rise in [Ca2+]i, and a release of glutamate. Intra-synaptosomal metabolism of alanine via alanine amino-transferase, as estimated from measurements of N fluxes from labeled precursors, was much slower than the rate of alanine uptake, even in the presence of added oxoacids. The velocity of [15N]alanine formation from [15N]glutamine was seven to eight times higher than the rate of [15N]-glutamate generation from [15N]alanine. It is concluded that (a) overloading of nerve endings with alanine could be deleterious to neuronal function because it increases release of glutamate; (b) the activity of synaptosomal alanine aminotransferase is much slower than that of glutaminase and hence unlikely to play a major role in maintaining [glutamate] during neuronal activity; and (c) alanine amino-transferase might serve as a source of glutamate during recovery from ischemia/hypoxia when the alanine concentration rises and that of glutamate falls.
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PMID:Cerebral alanine transport and alanine aminotransferase reaction: alanine as a source of neuronal glutamate. 790 47

To clarify the in vivo relevance of leukocyte-endothelial cell interactions in the manifestation of hepatic ischemia-reperfusion (I/R) injury, we studied leukocyte flow behavior in sinusoids and postsinusoidal venules of postischemic hepatic tissue in rats using intravital microscopy. Reperfusion following either 20 min (n = 9) or 60 min (n = 9) of left hepatic lobar ischemia resulted in a significant increase of the number of stagnant leukocytes in sinusoids and adherent cells in postsinusoidal venules compared with sham-operated controls (n = 10). Transmission electron microscopy revealed the extravasation of leukocytes from both sinusoids (into the space of Disse) and postsinusoidal venules. In parallel, hepatic I/R was associated with increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and reduced bile flow. Linear regression estimates revealed significant (P < 0.01) correlations between serum ALT (r = 0.76) and AST (r = 0.65) activities, bile flow (r = -0.62), and the number of adherent leukocytes in postsinusoidal venules. In contrast, parameters of hepatocellular integrity and function did not directly correlate with the number of stagnant leukocytes in liver sinusoids. We conclude that hepatic I/R induces accumulation, adherence, and extravasation of leukocytes in both hepatic sinusoids and postsinusoidal venules. However, the adherence of leukocytes to the endothelial lining of venules, rather than of sinusoids, may determine the manifestation of hepatocellular damage and liver dysfunction.
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PMID:Impact of leukocyte-endothelial cell interaction in hepatic ischemia-reperfusion injury. 797 40

Plasma levels of glutathione disulfide (GSSG) as an indicator of a vascular oxidant stress, tumor necrosis factor-alpha (TNF-alpha) formation, and liver injury (alanine aminotransferase activity, histology) were monitored in male Fischer rats after 30 min of hepatic ischemia followed by up to 4 hr of reperfusion. The injection of 1 mg/kg Salmonella enteritidis endotoxin at 30 min of reflow potentiated the postischemic oxidant stress and liver injury. TNF-alpha levels increased from 10 +/- 7 pg/ml (baseline) to 3,553 +/- 738 pg/ml after ischemia-reperfusion followed by endotoxin, or to 3,670 +/- 508 pg/ml after endotoxin alone. Depletion of serum complement before ischemia attenuated the endotoxin-mediated increase of reactive oxygen formation by 70% but did not affect TNF-alpha levels. Complement activation with cobra venom factor (CVF) during reperfusion had an effect similar to that of endotoxin on the oxidant stress and liver injury. CVF did not increase TNF-alpha formation during reperfusion. Kupffer cells and neutrophils isolated from the postischemic liver 2.5 hr after endotoxin injection generated 600% and 400% more superoxide, respectively, than cells isolated from control livers. The results demonstrate a substantial priming of hepatic phagocytes for reactive oxygen production but not TNF-alpha formation, even after short periods of hepatic ischemia, and the vulnerability of the postischemic liver to severe endotoxin-induced injury. Activated complement seems to be mainly responsible for the effects. These results may explain the high risk for hepatic failure after extensive liver resection and hypovolemic shock.
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PMID:Priming of phagocytes for reactive oxygen production during hepatic ischemia-reperfusion potentiates the susceptibility for endotoxin-induced liver injury. 798 73

Hepatic ischemia-reperfusion (I/R) is characterized by circulatory and metabolic derangements, liver dysfunction, and tissue damage. However, little is known about the causative role of I/R-induced microcirculatory disturbance on the manifestation of postischemic reperfusion injury. Therefore, the intention of the study was to assess changes of hepatic microvascular perfusion (intravital fluorescence microscopy) as related to hepatic morphology (light/electron microscopy), hepatocellular integrity (serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities), and excretory function (bile flow). Sprague-Dawley rats were subjected to 20 minutes (group B, n = 9) and 60 minutes (group C, n = 9) of left hepatic lobar ischemia followed by 60 minutes of reperfusion. Sham-operated animals without ischemia served as controls (group A, n = 10). Lobar ischemia for 20 minutes followed by reperfusion resulted in a significant reduction of sinusoidal perfusion rate (93.9 +/- 1.4%; P < 0.05) and a decrease in erythrocyte flux (90.0 +/- 5.6%) when compared with controls (99.4 +/- 0.2 and 97.9 +/- 2.7%). This was accompanied by a significant increase of serum AST and ALT activities (P < 0.05) and a reduction of bile flow (P < 0.05). Prolongation of lobar ischemia (group C, 60 minutes) aggravated postischemic reperfusion injury (sinusoidal perfusion rate: 87.4 +/- 2.9%; erythrocyte flux: 62.1 +/- 8.4%) and was paralleled by severed hepatocellular damage. Electron microscopy of postischemic tissue demonstrated alteration of nonparenchymal cells (swelling of sinusoidal lining cells and widening of Disse's space) and substantial parenchymal cell damage (swelling of mitochondria, disarrangement of rough endoplasmatic reticulum, vacuolization, complete cytoplasmic degeneration). Initial postischemic increase in serum AST and ALT activities and reduction of bile flow directly correlated with the extent of microcirculatory failure (P < 0.01), ie, impairment of sinusoidal perfusion and decrease of erythrocyte flux, indicating the decisive role of microvascular perfusion failure for the manifestation of hepatic tissue damage and liver dysfunction.
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PMID:Hepatic microcirculatory perfusion failure is a determinant of liver dysfunction in warm ischemia-reperfusion. 799 45

Leukocytes, in particular polymorphonuclear neutrophils (PMNs), are believed to play a central role in ischemia-reperfusion (I/R)-induced tissue injury. Changes in endothelial cells occurring during ischemia promote PMN binding to these cells during reperfusion, which primers PMN synthesis of oxygen radicals and release of cytotoxic proteins. These events lead to vascular damage and subsequent tissue injury. Recently we have shown that doxycycline (Dc), a member of the tetracycline family of antibiotics, inhibits PMN superoxide (O2) synthesis and degranulation in vitro. It also suppresses PMN-mediated RBC, fibroblast, and endothelial cytotoxicity, properties of the drug that may make it of use to protect tissues from I/R-induced injury. In this study we demonstrate that Dc administration either prior to clamping of the portal circulation, or 1 h after the reperfusion, significantly suppressed liver damage as assessed by serum levels of a marker of hepatic injury, alanine aminotransferase (s-ALT). The reduction in s-ALT was not a result of reduced reflow in the Dc-treated rats as indicated by Evans' blue perfusion data. The findings suggest that Dc and possibly other tetracyclines may be of value in protecting tissues and organs from I/R-mediated damage even if the drug is given after the ischemic event has occurred.
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PMID:Doxycycline suppression of ischemia-reperfusion-induced hepatic injury. 807 Sep 3

Glycine has been shown to protect renal tubule cells and hepatocytes from ischemia, ATP depletion, and cold storage injury. Glycine may be a useful additive to organ preservation solutions or suppress reperfusion injury by infusion into recipients of liver transplantation. In this study, the effects of glycine on survival and postoperative liver injury were studied in the rat and dog orthotopic transplant model. Rat livers preserved for 30 hr in the University of Wisconsin (UW) solution were 50% viable (3 of 6 survivors for 7 days). When glutathione was replaced by 10 mM glycine, survival increased to 100% (6 of 6). There was a significant reduction in hepatocellular injury at the end of preservation (lactate dehydrogenase [LDH] in the pretransplant flush-out of the liver was lower in the glycine group) and after transplantation (serum LDH concentration 6 hr after transplant was lower in the glycine group). In the dog, omission of glutathione from the UW solution resulted in 33% survival (48-hr preservation model) versus 100% survival with glutathione. Replacing glutathione in the UW solution by glycine did not improve survival (33% after 48 hr of preservation). However, when glycine was given to recipients of livers preserved in the UW solution for 24 or 48 hr, there was a decrease in the degree of hepatocellular injury. After 48 hr of preservation, peak aspartate aminotransferase, alanine aminotransferase, and LDH were reduced by about 45-55% when glycine was given to the recipient. Although the differences, with and without glycine treatment of the recipients, did not reach statistical significance, there was a noticeable reduction in hepatocellular injury with glycine. There was 100% survival of dogs in the groups that received livers preserved with the UW solution plus or minus glycine infusion. Hepatamine, a parenteral nutrition solution containing glycine and other amino acids increased hepatocellular injury (higher concentrations of aspartate aminotransferase, alanine transferase, and LDH versus control 48-hr preserved livers), although all dogs survived. This study shows that glycine is cytoprotective when administered to recipients of livers preserved for 24 or 48 hr and suppresses hepatocellular injury, as reflected in a reduction in the concentration of serum enzymes. However, the differences, with and without glycine, were, at best, marginal and further studies are needed to determine whether glycine would make a significant improvement in liver preservation and prevent primary nonfunction.
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PMID:Effect of glycine in dog and rat liver transplantation. 821 99

The purposes of this study were to clarify the role of neutrophilic proteases in the pathogenesis of hepatic ischemia/reperfusion injury and to determine whether urinary trypsin inhibitor (UTI) pretreatment attenuated liver ischemia/reperfusion injury in rats. Livers from male Sprague-Dawley rats were subjected to 90 min of no-flow warm ischemia followed by 120 min of reperfusion. Rats were divided into a UTI group and a control group. In the control group, 120-min reperfusion of the liver produced a significant increase in myeloperoxidase activity, a significant decrease in ATP and energy charge, and a marked increase in the serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase levels. In the UTI group, the myeloperoxidase activity was significantly attenuated (P < 0.01), ATP and energy charge were significantly improved (P < 0.01 and P < 0.05, respectively), and the elevation in serum aspartate aminotransferase, alanine aminotransferase, and lactic dehydrogenase was also markedly suppressed (P < 0.05, P < 0.01, and P < 0.05, respectively) compared with the control group. Sections through the livers of control rats showed severe hepatocyte necrosis with neutrophil infiltration. In the UTI group, there was slight congestion and hepatocyte necrosis. The survival rate after 90-min liver ischemia was significantly improved compared with that in the control group (P < 0.05). The results of this study suggest that pretreatment with UTI significantly attenuates liver reperfusion injury, perhaps by inhibiting neutrophil proteases.
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PMID:Effect of protease inhibitor on ischemia/reperfusion injury of the rat liver. 827 98


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