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)

Triple therapy with S-adenosylmethionine (SAM) (given to the donor animal, included in University of Wisconsin solution [UW], and added to the reperfusing medium) has been shown to reduce the sequential cold and warm ischemia/reperfusion injuries characteristic of the liver transplantation procedure. To clarify the actions of SAM during different stages of ischemia/ reperfusion, we have compared its benefit in five dosage regimens, using perfused rat livers after sequential periods of 24 hr cold and 20 min rewarming ischemia. When added only to UW, the presence of SAM throughout ischemia improved hepatic blood flow by 26% after 15 min of reperfusion versus no treatment (2.32+/-0.18 vs. 1.84+/-0.11 ml/min/g liver, P<0.05). SAM also improved blood flow by 23% during the 3-hr perfusion overall (P<0.05). Oxygen consumption and the release of purine nucleoside phosphorylase (PNP) were decreased (both P<0.05). When added to both UW and the perfusate, SAM additionally increased bile production at 15 min (7.14+/-1.21 vs. 2.31+/-0.74 mg/h/g liver, P<0.01). By pretreating the liver donor with SAM in vivo, and including it in the preservation and reperfusing media, it was possible to prolong and amplify the benefits on blood flow (P<0.001) and bile production (P<0.05) and to sustain glucose uptake (P<0.01). An acute exposure to SAM, when used in saline to flush UW from the graft before reperfusion, increased blood flow at 15 min (by 68%) and over a 3-hr period (both P<0.001), but no indices of metabolic activity were improved. Oxygen consumption and PNP release were both decreased (P<0.05). When added to the perfusate (present throughout reperfusion), SAM increased blood flow at 15 min (58%) and over a 3-hr period (P<0.01 in both cases). Net glucose uptake was increased (P<0.05), whereas oxygen consumption (P<0.001) and PNP release fell (P<0.05). Actions of SAM achieved acutely and over the intermediate- and long-term all seem to underlie its benefits in reducing ischemia/reperfusion injuries.
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PMID:Treatment of experimental ischemia/reperfusion injury with S-adenyosylmethionine: evidence that donor pretreatment complements other regimens. 904 41

Pretransplant rinse solutions have been shown to reduce reperfusion injury in cold-stored liver grafts, especially at the nonparenchymal level in sinusoidal endothelial cells (SEC). In this study, different rinse temperatures were tested in a rat liver preservation model. Livers were washed out in situ via the portal vein with cold (4 degrees C) University of Wisconsin (UW) solution, and after hepatectomy (t0), were stored for 8, 16, or 24 h of cold ischemia time (CIT). After storage, livers were flushed with UW solution at either 4 degrees C, 20 degrees C, or 37 degrees C and reperfused for 90 min (37 degrees C). Control livers were reperfused at t0 without preflush. Levels of hyaluronic acid (HA), purine nucleoside phosphorylase (PNP), AST, and LDH were measured in the reperfusion medium. Bile production was monitored during reperfusion. At the end of reperfusion, liver biopsies were taken for enzyme hystochemistry (5'-nucleotidase and LDH). After 8-h CIT and a flush at 4 degrees C, a release of endogenous HA (-7%) was observed, whereas uptake of exogenous HA occurred after the 20 degrees C flush (2%, P = NS) and after the 37 degrees C flush (24%, p < 0.001). HA release occurred at all three preflush temperatures after the 16-h CIT but was significantly lower when flushed at 37 degrees C (-10%) that at 4 degrees C and 20 degrees C (-64% and -17%, respectively, p = 0.05). After the 24-h CIT, the release of endogenous HA increased in the 4 degrees C and 20 degrees C preflush groups, but not in the 37 degrees C group. Levels of PNP and AST increased until the 24-h CIT in all groups but were significantly lower after preflush at 37 degrees C. Release of LDH did not increase with increasing periods of cold storage in any of the flush series. Compared to control livers, mean bile production during reperfusion was significantly decreased following preflush at 4 degrees C or 37 degrees C after all periods of CIT. No differences in mean bile production could be demonstrated in the three preflush groups after any period of CIT. LDH activity in liver tissue was best preserved after the 8 and 16-h CIT in combination with the 37 degrees C preflush, indicating less hepatocellular damage. In conclusion, in cold stored rat livers flushed at 37 degrees C before reperfusion, SEC and hepatocellular damage is attenuated.
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PMID:Warm flush at 37 degrees C following cold storage attenuates reperfusion injury in preserved rat livers. 950 53

Interleukin-1 (IL-1) and tumor necrosis factor (TNF) are cytokines commonly associated with inflammatory conditions such as hepatic injury after ischemia-reperfusion. FR167653 has been characterized as a potent suppressant of IL-1beta and TNF-alpha production. In this study, we evaluated the effect of FR167653 in an extended liver resection with ischemia in a dog model. The right portal pedicle was clamped for 60 minutes, while the left portal branch was patent to avoid portal congestion. Following reperfusion, 75% of the liver (including the right central, quadrate, left central, left lateral, and papillary lobes) were resected. Animals were divided into two groups: a control group (n = 10), and a FR-treated group (n = 6) in which FR167653 was administered via the portal vein. Hepatic venous blood was collected to measure alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), purine nucleoside phosphorylase (PNP), and hyaluronic acid (HA) levels, and IL-1beta expression was also measured by reverse-transcriptase polymerase chain reaction (RT-PCR). ALT, AST, LDH, PNP, and HA levels after reperfusion were significantly lower (P < .05) in the FR-treated group than in the control group, and the FR-treated group showed inhibited IL-1beta expression. Liver tissue blood flow, measured by a laser Doppler flow meter, was kept higher in the FR-treated group than in the control group. Histologically, tissue damage was mild in the FR-treated group. The 2-day survival rate was statistically better (P < .05) in the FR-treated group than in the control group. We conclude that FR167653 provides a protective effect for liver parenchyma and sinusoidal endothelial cells in extended liver resection with ischemia.
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PMID:The effects of FR167653 in extended liver resection with ischemia in dogs. 969 12

The aim of our studies was to investigate hormonal prevention of hepatic preservation damage by the atrial natriuretic peptide (ANP) and the mechanisms involved. Isolated perfusion of rat livers was performed in a nonrecirculating fashion. Twenty minutes of preischemic perfusion was performed with or without different concentrations of ANP, followed by 24-hour storage in cold University of Wisconsin (UW) solution. Two hundred nanomoles of ANP prevented hepatocellular damage during a 2-hour reperfusion period as indicated by a marked attenuation of the sinusoidal efflux of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP), and by reduced Trypan blue uptake. Furthermore, postischemic bile flow as an indicator of liver function was significantly improved by about 60% with 200 nmol/L ANP. No protection was conveyed by 20 nmol/L ANP nor by pretreatment with 200 nmol/L ANP for only 10 minutes. The effects of ANP seemed to be mediated by the guanylate cyclase-coupled A (GC-A) receptor and cyclic guanosine monophosphate (cGMP): whereas expression of both GC-A and GC-B receptors as well as of the GC-C receptor was found, cGMP did protect from ischemia-reperfusion damage, but selective ligands of the B and C receptor did not. To begin to determine the mechanisms of ANP-mediated protection, different parameters were investigated: ANP had no effect on portal pressure as an indicator of hepatic circulation, nor on intracellular energy depletion determined by adenosine nucleotide concentration. However, the marked augmentation of nuclear factor kappaB (NF-kappaB) binding activity during reperfusion was prevented in ANP-pretreated livers. In conclusion, pretreatment with ANP protects the rat liver from cold ischemia-reperfusion damage. This effect is mediated via the GC-A receptor and cGMP, and may be linked to an influence of ANP on NF-kappaB activation. Thus, ANP signaling via the GC-A receptor should be considered as a new pharmacological target to prevent preservation injury of the liver.
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PMID:The guanylate cyclase-coupled natriuretic peptide receptor: a new target for prevention of cold ischemia-reperfusion damage of the rat liver. 979 16

Activated neutrophils play an important role in reperfusion injury following hepatic ischemia. Neutrophil elastase is a powerful proteolytic enzyme. We investigated the possibility that ONO-5046. Na, which is a new recombinant-specific neutrophil elastase inhibitor, can reduce ischemia and reperfusion injury in the canine liver. Adult mongrel dogs (n = 19) were used in this experimental study. Seventy-five percent of the liver was resected after 60 min of vascular occlusion. The animals were divided into two groups. The ONO group (n = 8) was given ONO-5046. Na dissolved in saline starting 30 min prior to clamping the hepatic inflow and continuing for 4 h after reperfusion at a rate of 10 mg/kg/h. The nontreatment group (n = 11) received a saline solution for the same period. ALT and LDH levels were significantly lower (P < 0.05) in the ONO group than in the nontreatment group after reperfusion. Purine nucleoside phosphorylase and hyaluronic acid levels, which are markers of endothelial damage, were significantly lower (P < 0.05) in the ONO group than in the nontreatment group after reperfusion. Histologically, widely spread hepatocyte necrosis was found in dogs in the nontreatment group that died prematurely. Neutrophil infiltration of the sinusoids was less evident in the ONO group than in the nontreatment group. Neutrophil elastase inhibitor may prevent injuries of both endothelial and parenchymal cells in extended hepatectomy with vascular occlusion.
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PMID:The effect of neutrophil elastase inhibitor in hepatectomy with ischemia in dogs. 992 45

The generation of reactive oxygen species (ROS) by activated Kupffer cells contributes to liver injury following liver preservation, shock, or endotoxemia. Pharmacological interventions to protect liver cells against this inflammatory response of Kupffer cells have not yet been established. Atrial natriuretic peptide (ANP) protects the liver against ischemia-reperfusion injury, suggesting a possible modulation of Kupffer cell-mediated cytotoxicity. Therefore, we investigated the mechanism of cytoprotection by ANP during Kupffer cell activation in perfused rat livers of male Sprague-Dawley rats. Activation of Kupffer cells by zymosan (150 microgram/ml) resulted in considerable cell damage, as assessed by the sinusoidal release of lactate dehydrogenase and purine nucleoside phosphorylase. Cell damage was almost completely prevented by superoxide dismutase (50 U/ml) and catalase (150 U/ml), indicating ROS-related liver injury. ANP (200 nM) reduced Kupffer cell-induced injury via the guanylyl cyclase-coupled A receptor (GCA receptor) and cGMP: mRNA expression of the GCA receptor was found in hepatocytes, endothelial cells, and Kupffer cells, and the cGMP analog 8-bromo-cGMP (8-BrcGMP; 50 microM) was as potent as ANP in protecting from zymosan-induced cell damage. ANP and 8-BrcGMP significantly attenuated the prolonged increase of hepatic vascular resistance when Kupffer cell activation occurred. Furthermore, both compounds reduced oxidative cell damage following infusion of H2O2 (500 microM). In contrast, superoxide anion formation of isolated Kupffer cells was not affected by ANP and only moderately reduced by 8-BrcGMP. In conclusion, ANP protects the liver against Kupffer cell-related oxidant stress. This hormonal protection is mediated via the GCA receptor and cGMP, suggesting that the cGMP receptor plays a critical role in controlling oxidative cell damage. Thus ANP signaling should be considered as a new pharmacological target for protecting liver cells against the inflammatory response of activated Kupffer cells without eliminating the vital host defense function of these cells.
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PMID:Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide. 1033 4

The mechanisms by which heparin protects the liver during induced episodes of liver ischemia-reperfusion are poorly understood. Previous work in a swine model demonstrated that serum levels of glycohydrolases and lipid peroxide peaked within 3 h after 45 minutes of hepatic ischemia followed by reperfusion. Serum levels of lactate dehydrogenase and aspartate aminotransferase peaked 20-24 h later. The aim of this study was to evaluate the effect of heparin on these two-phases of enzyme release, using a pig model of hepatic ischemia-reperfusion injury. Twenty male swine were divided into control (n = 8) and heparin (n = 12) groups. In the heparin group, heparin was administered prior to and concurrent with ischemia-reperfusion. Following 45 min of hepatic ischemia, the levels of beta-galactosidase, beta-glucosidase, acid phosphatase, purine nucleoside phosphorylase, lipid peroxides, lactate dehydrogenase, and aspartate aminotransferase in serum were monitored for up to 166 h and compared to pre-ischemic and control levels. With heparin infusion, the peak levels of beta-galactosidase, beta-glucosidase, and the lipid peroxide were reduced to 50-60% of the control levels. Acid phosphatase and purine nucleoside phosphorylase activities in serum were reduced to 25% and 60%, respectively. The peak concentrations of lactate dehydrogenase and aspartate aminotransferase were reduced to about 25% of the control level. In addition, the serum enzymes of control pigs did not return to pre-ischemic levels until 2 weeks after hepatic ischemia, while they normalized in less than 1 week in the heparin-treated animals. Systemic heparinization had different protective effects on the first and secondary phases of liver injury. These differences may reflect heparin protection of different types of liver cells. The protection of the parenchymal cells may be the combined result of reduced sinusoidal cell injury and the anticoagulant properties of heparin.
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PMID:Differential effects of heparin on the early and late phases of hepatic ischemia and reperfusion injury in the pig. 1044 94

The release of liver enzymes is typically used to assess tissue damage following ischemia-reperfusion. The present study was designed to determine the impact of ischemia-reperfusion on liver function and compare these findings with enzyme release. Isolated, perfused rat livers were subjected to low flow ischemia followed by reperfusion. Alterations in liver function were determined by comparing rates of oxygen consumption, gluconeogenesis, ureagenesis, and ketogenesis before and after ischemia. Lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP) activities in effluent perfusate were used as markers of parenchymal and endothelial cell injury, respectively. Trypan blue staining was used to localize necrosis. Total glutathione (GSH + GSSG) and oxidized glutathione (GSSG) were measured in the perfusate as indicators of intracellular oxidative stress. LDH activity was increased 2-fold during reperfusion compared to livers kept normoxic for the same time period whereas PNP activity was elevated 5-fold under comparable conditions. Rates of oxygen consumption, gluconeogenesis, and ureagenesis were unchanged after ischemia, but ketogenesis was decreased 40% following 90 min ischemia. During reperfusion, the efflux rates of total glutathione and GSSG were unchanged from pre-ischemic values. Significant midzonal staining of hepatocyte nuclei was observed following ischemia-reperfusion, whereas normoxic livers had only scattered staining of individual cells. Reperfusion of ischemic liver caused release of hepatic enzymes and midzonal cell death, however, several major liver functions were unaffected under these experimental conditions. These data indicate that there were negligible changes in liver function in this model of ischemia and reperfusion despite substantial enzyme release from the liver and midzonal cell death.
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PMID:Effect of low flow ischemia-reperfusion injury on liver function. 1072 50

The objective of this study was to determine whether Kupffer cells contribute to parenchymal and endothelial cell damage induced by ischemia-reperfusion in perfused rat livers. Parenchymal and endothelial cell injury were determined by measuring activities of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP), respectively, in the effluent perfusate of livers subjected to 60 min of low flow ischemia followed by 30 min of reperfusion. Upon reperfusion, LDH and PNP activities increased significantly within the first 10 min of reperfusion and remained elevated over control values throughout the duration of reperfusion. Pretreatment with gadolinium chloride, an inhibitor of Kupffer cell function, significantly decreased LDH and PNP efflux during reperfusion by approximately 60% and 50%, respectively. When Kupffer cells were stimulated by vitamin A pretreatment, PNP efflux was doubled during reperfusion. Vitamin E pretreatment attenuated LDH and PNP release by approximately 70% during reperfusion compared to enzyme release in untreated livers. Moreover, the water-soluble antioxidants superoxide dismutase and desferrioxamine reduced reperfusion injury, whereas catalase had no effect on enzyme release. These results demonstrate that superoxide anions released from Kupffer cells are involved in oxidative damage to endothelial cells as well as hepatocytes during the early stages of hepatic reperfusion.
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PMID:Antioxidants and gadolinium chloride attenuate hepatic parenchymal and endothelial cell injury induced by low flow ischemia and reperfusion in perfused rat livers. 1079 15

We investigated whether S-adenosylmethionine (SAM) treatment improved ischemic injury using perfused rat liver after sequential periods of 24 h cold and 20 min re-warming ischemia. SAM (100 micromol/L) was added to University of Wisconsin (UW) solution and Ringers lactate solution. After cold and sequential warm ischemia, releases of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP) markedly increased during reperfusion. The increase in PNP was significantly reduced by SAM treatment. While the concentration of reduced glutathione (GSH) in ischemic livers significantly decreased, the concentration of glutathione disulfide (GSSG) increased. This decrease in GSH and increase in GSSG were suppressed by SAM treatment. Lipid peroxidation was elevated in cold and warm ischemic and reperfused livers, but this elevation was also prevented by SAM treatment. Hepatic ATP levels were decreased in the ischemic and reperfused livers to 42% of the control levels. However, treatment with SAM resulted in significantly higher ATP levels and preserved the concentration of AMP in ischemic livers. Our findings suggest that SAM prevents oxidative stress and lipid peroxidation and helps preserve hepatic energy metabolism.
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PMID:Effect of S-adenosylmethionine on hepatic injury from sequential cold and warm ischemia. 1105 30


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