The effects of intraportal administration of prostaglandin E1 on liver ischemia and hepatectomy in rats

The effects of intraportal administration of prostaglandin E₁ (PGE₁) on portal venous flow, hepatic arterial flow, peripheral tissue blood flow, and systemic arterial flow before and after 60 min total liver ischemia followed by 70% partial hepatectomy in rats were investigated. Total liver ischemia was induced by occluding the hepatoduodenal ligament for 60 min. PGE₁ at a dose of 0.5 μg/kg/min was infused intraportally for 15 min before inducing hepatic ischemia (preischemic period) and for 60 min after ischemia (postischemic reperfusion period) in the treatment group. Normal saline was infused in the control group. Seventy percent partial hepatectomy was performed during ischemia. Serum biochemical analysis and liver tissue histology were carried out 1, 3, and 24 h, and 1 and 24 h after reperfusion respectively. One-week survival of the PGE₁ group was improved to 70% compared to that of the control group of 30%. Postischemia reperfusion values of portal and peripheral tissue blood flows in the PGE₁ group were 6.33 ± 0.600 ml/min and 27.2 ± 23.5 (arbitrary), and were significantly different from those of the control group of 4.34 ± 0.400 ml/min and 23.5 ± 5.54 (arbitrary), respectively. There was no significant difference in hepatic arterial flow between the two groups. Serum alkaline phosphatase decreased significantly in the prostaglandin group. Histological examination revealed a significant portal venous congestion in the control group 1 and 24 h after reperfusion. The extent of the sinusoidal congestion was also severe in the control group 24 h after reperfusion. It was concluded that PGE₁ has a protective effect against liver damage when the liver was injured by warm ischemia and reperfusion followed by partial resection. Received for publication on May 30, 1997; accepted on July 27, 1998     

Pretreatment with intravenous fish oil reduces hepatic ischemia reperfusion injury in a murine model

Background

Ischemia reperfusion injury is a barrier to liver surgery and transplantation, particularly for steatotic livers. The purpose of this study was to determine if pretreatment with a single dose of intravenous fish oil decreases hepatic ischemia reperfusion injury and improves recovery of injured livers.

Enhanced hepatic portal blood flow induced by prostaglandin E1 following liver transplantation in pigs

Portal venous blood flow (PVF), hepatic arterial blood flow (HAF), and systemic arterial pressure (SAP) were examined after prostaglandin E₁ (PGE₁) was injected into the vena cava superior (VCS) of liver-transplanted pigs. The injection of PGE₁ at 0.2 g/kg/min for 2 min on the day of transplantation and 3 days later produced an increase in PVF without causing any change in HAF or SAP, the response in PVF being dose-dependent. However, no reliable change in PVF, HAF, or SAP was seen when the same dose of PGE₁ was administered 7 days after transplantation. Furthermore, no significant difference was noted among the values for PVF and total hepatic blood flow (THF) during the experimented days, although the HAF value had increased markedly 3 days after transplantation. These findings suggest that PGE₁ is effective in increasing PVF in the liver transplanted condition; however, the hepatic circulatory improvement attributed to this agent would be limited to the first few days following transplantation.     

Effects of adenosine monophosphate-activated kinase in the ventral horn of rabbit spinal cord after transient ischemia

Objective

To investigate the effect compound C, an adenosine monophosphate-activated kinase (AMPK) inhibitor, has on motor neurons of rabbit spinal cord after ischemia/reperfusion.

Design

Compound C (30 mg/kg) was administered intraperitoneally to rabbits 30 minutes before ischemia and the animals were sacrificed at 15 minutes after ischemia/reperfusion to measure lactate levels and at 72 hours after ischemia/reperfusion for morphological study.

Results

The administration of compound C did not produce any significant changes in physiological parameters such as pH, arterial blood gas (PaCO₂ and PaO₂), and blood glucose in rabbit either at 10 minutes before ischemia or at 10 minutes after reperfusion. However, the administration of compound C did significantly ameliorate lactate acidosis at 15 minutes after reperfusion. In addition, the administration of compound C significantly improved the neurological scores of the rabbits and reduced the neuronal death seen in the ventral horn of their spinal cords at 72 hours after ischemia/reperfusion.

Conclusions

Inhibition of AMPK can ameliorate the ischemia-induced neuronal death in the spinal cord via the reduction of early lactate acidosis.     

Intracellular oxygenation and cytochrome oxidase C activity in ischemic preconditioning of steatotic rabbit liver

Background

Mild to moderate steatotic livers are used as marginal donors in liver transplantation. Very little is known about the mechanisms of ischemia reperfusion (IR) injury (IRI) in fatty liver. This study aimed to establish whether cytochrome oxidase C (COX) activity is compromised by IRI in fatty liver and whether ischemic preconditioning (IPC) can protect COX activity.

Methods

New Zealand rabbits were fed on a high-cholesterol diet for 8 weeks to induce moderate hepatic steatosis. Three groups were tested. The IR group underwent 60 minutes of ischemia, followed by 7 hours of reperfusion. The IPC group (IPC + IR) underwent 5 minutes of ischemia, followed by 10 minutes of reperfusion and then 60 minutes of ischemia and 7 hours of reperfusion. The control group (sham) underwent the same surgical procedure, but ischemia was not induced. Deoxyhemoglobin, oxyhemoglobin, and change in the redox state of COX was continuously monitored in vivo by near-infrared spectroscopy. COX and citrate synthase (CS) activity assays were carried out on liver biopsy specimens in vitro. Bile was collected continuously during the procedure and analyzed using proton nuclear magnetic resonance spectroscopy.

Results

The IR group had decreased COX activity and tissue oxygenation represented by deoxyhemoglobin, oxyhemoglobin, COX, and elevated redox ratios of lactate/pyruvate and β-hydroxybutarate/acetoacetate in vivo and a decrease in COX and CS activity in vitro. The IPC + IR group showed higher levels of all measured parameters in vivo and showed a smaller decrease in COX and CS activity in vitro.

Conclusion

This study shows that IRI affects COX activity in fatty livers. This is attenuated by IPC.     

Protective effects of D-allose against ischemia reperfusion injury of the rat liver

Background/Purpose. d-Allose, a rare sugar, has been reported to inhibit segmented neutrophil production without causing any significant detrimental clinical effects. Our previous study demonstrated the immunosuppressive effect of d-allose in a rat model of liver transplantation. Neutrophils are closely involved in the process of hepatic ischemia/reperfusion (I/R) injury. One possible mechanism is the adherence of neutrophils to the hepatic sinusoidal endithelium following microcirculatory failure. Methods. The present study investigated the effects of d-allose on the involvement of neutrophils, with particular emphasis to the microcirculation in a model of hepatic I/R. Ischemia was induced by occluding the hepatoduodenal ligament for 90min. d-Allose was infused 2h before ischemia. Normal saline was infused in the control group. Liver tissue blood flow (LTBF) and portal venous flow (PVF) were measured before and after ischemia. Myeloperoxidase (MPO) and ATP were measured at, before inducing ischemia, at the end of ischemia, and at the end of 2-h reperfusion. Liver enzyme analysis and histology were done at the end of reperfusion. Postreperfusion animal survival was followed for 15 days. Results. d-Allose significantly improved the liver hemodynamics and postreperfusion animal survival, with a significant decrease in liver tissue MPO, liver enzymes, and the number of neutrophils. ATP level was improved significantly in the d-allose group. Histology revealed significant sinusoidal congestion and tissue necrosis after 2-h reperfusion in the control group. Conclusions. d-Allose exerted its protective effects against liver damage incurred when the liver was injured by warm ischemia and reperfusion mainly by the suppression of activated neutrophils.     

Use of the Liver Tissue Oxygenation Index as a Noninvasive Parameter of Intestinal Ischemia in Rabbits

Objective The tissue oxygenation index (TOI), measured by spatially resolved spectroscopy (SRS), reflects the ratio between oxygenated and deoxygenated tissue hemoglobin. We investigated whether liver TOI is a noninvasive parameter for early detection of intestinal ischemia. Methods In seven adult New Zealand rabbits the superior mesenteric artery (SMA) and vein were exposed by laparotomy. The SRS probe was attached at the skin above the liver to calculate the TOI. The bowel (SbO₂) and peripheral (SpO₂) oxygen saturation were continuously measured. The SMA was occluded, creating small bowel ischemia for 90 minutes. Then reperfusion was started for 1 hour. The median TOI and interquartile range (IQR) of the TOI were calculated. A paired Wilcoxon test was used to evaluate changes in the liver TOI and SpO₂ during ischemia and reperfusion. Results The median TOI was 54.3% (IQR 8) at the start of ischemia, 54.9% (IQR 9) after 30 minutes, 51% (IQR 11) after 60 minutes, and 50.3% (IQR 10) after 90 minutes. The median TOI values were 46.3% (IQR 5) after 30 minutes of reperfusion and 41.2% (IQR 5) after 60 minutes. The decrease in TOI became significant (p < 0.05) after 90 minutes of ischemia. The SpO₂ was stable during the experiment. Discussion A significant decrease in liver TOI was seen after 90 minutes of occlusion of the SMA and is likely to be the consequence of bowel ischemia. The further decrease after reperfusion might reflect reperfusion injury. Liver TOI may be a new tool for noninvasive early detection of intestinal ischemia and reperfusion. Further study is needed to confirm these findings.     

Effects of adenosine monophosphate-activated kinase in the ventral horn of rabbit spinal cord after transient ischemia

Abstract

Objective

To investigate the effect compound C, an adenosine monophosphate-activated kinase (AMPK) inhibitor, has on motor neurons of rabbit spinal cord after ischemia/reperfusion.

Design

Compound C (30 mg/kg) was administered intraperitoneally to rabbits 30 minutes before ischemia and the animals were sacrificed at 15 minutes after ischemia/reperfusion to measure lactate levels and at 72 hours after ischemia/reperfusion for morphological study.

Results

The administration of compound C did not produce any significant changes in physiological parameters such as pH, arterial blood gas (PaCO₂ and PaO₂), and blood glucose in rabbit either at 10 minutes before ischemia or at 10 minutes after reperfusion. However, the administration of compound C did significantly ameliorate lactate acidosis at 15 minutes after reperfusion. In addition, the administration of compound C significantly improved the neurological scores of the rabbits and reduced the neuronal death seen in the ventral horn of their spinal cords at 72 hours after ischemia/reperfusion.

Conclusions

Inhibition of AMPK can ameliorate the ischemia-induced neuronal death in the spinal cord via the reduction of early lactate acidosis.     

Magnetic Resonance Diffusion Tensor Imaging Characterize the Hepatic Ischemia-Reperfusion Injury in an Animal Study

BackgroundHepatic ischemia-reperfusion (I/R) injury is the main cause of morbidity and mortality after hepatectomy; thus, new methods for reducing I/R injury are required. The aim of this study is to evaluate changes in the average apparent diffusion coefficient (ADC_avg) and fractional anisotropy (FA) in rabbits with partial hepatic I/R injury with magnetic resonance diffusion tensor imaging (DTI).MethodsThe left lobe of the rabbit liver underwent 60 minutes of ischemia followed by 0.5, 2, 6, 12, 24, and 48 hours of reperfusion. T₂-weighted images (T₂WI), T₁-weighted images (T₁WI), DTI, and contrast-enhanced T₁WI were performed; 6 b values were used for DTI on 6 diffusion directions. The serum levels of transaminases and liver histopathology findings were examined.ResultsIn the early stage of I/R (0.5 hour), ADC_avg decreased significantly and increased sharply to 2 hours, then increased from 6 hours to 48 hours of reperfusion, except for a transient decrease (24 hours). Meanwhile, FA showed almost the opposite trend, drastically increasing during the first 0.5 hour and then slightly decreasing until 48 hours of reperfusion, except for an obvious decrease in the 2-hours group. The serum levels of liver markers and the pathologic scores were sharply increased in the I/R group after reperfusion and correlated with DTI of hepatic tissue after I/R.ConclusionsDiffusion tensor imaging is feasible for imaging I/R-induced liver damage and can discriminate isotropic properties of the liver after I/R injury with objective changes in the ADC_avg and FA. Diffusion tensor imaging can be a promising novel approach for use in clinical management after liver surgery.     

Effects of tetrandrine on ischemia/reperfusion injury in mouse liver

Objective

Hepatic ischemia/reperfusion injury (IRI) may cause acute inflammatory damage, producing significant organ dysfunction, an important problem for liver transplantation. Previous studies have demonstrated that Tetrandrine (Tet), a component of traditional Chinese herbal medicine, shows protective effects to scavenge active oxygen radicals and inhibit lipid peroxidation. In this study, we examined whether Tet has a protective effect on mouse hepatic IRI.

Materials and Methods

Male C57BL/6 mice were divided into sham, ischemic, and Tet-treated groups; 90 minutes of warm ischemia was performed on the left liver lobe. Tet (20 mg/kg) was injected intraperitoneally at 1 hour before ischemia with a second intravenous dose was injected just before reperfusion. Blood and liver samples were collected at 6 hours after reperfusion. We analyzed the hepatocellular injury, oxidative stress, neutrophil recruitment, and tumor necrosis factor-alpha (TNF-α) generation associated with hepatic IRI.

Results

Undergoing 90 minutes of ischemia and 6 hours reperfusion caused dramatic injuries in mouse livers. Administration of Tet (20 mg/kg) reduced serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH); decreased liver edema, TNF-α, myeloperoxidase (MPO) and malondialdehyde (MDA) contents; and ameliorated the down-regulation of superoxide dismutase (SOD) activity.

Conclusion

Tet showed protective effects on mouse hepatic IRI.     

Protective effects of trifluoperazine on the microcirculation of cold-stored livers

Previous studies have shown a protective effect of trifluoperazine (TFP), a calmodulin inhibitor, upon the microcirculation of cold-stored kidneys. The present study points to similar beneficial effects of TFP on the microcirculation of cold-stored livers; 25 canine livers were preserved for 24 hr with Euro-Collins' solution (EC) (n = 8), University of Wisconsin solution (UW) (n = 7), or UW + TFP (n = 10). The stored livers underwent heterotopic transplantation (HLTX); hepatic-artery and portal-vein pressure and flow were monitored; oxygen consumption and extraction were measured before HLTX and at 15-min intervals after reperfusion, for 1 hr. Mean hepatic-artery and portal-vein flow (HAF & PVF) prior to donor hepatectomy were 172 and 530 cc/min, respectively. Poor HAF and PVF occurred in EC-HLTX (mean 35, 175 cc/min, respectively). The damaged EC-flushed livers could not compensate to the decreased hepatic blood flow by increased oxygen extraction (oxygen consumption and extraction, 8.7 vol.% and 48%, respectively). Light and electron microscopy showed severe liver necrosis and periportal hemorrhages. Improved hepatic-artery and portal-vein flows were seen in UW HLTX (105 and 254 cc/min), and oxygen consumption and extraction were 16.4 vol.% and 66%, respectively. Liver biopsy taken just before reperfusion revealed well-preserved liver architecture. Liver biopsy obtained 1 hr after reperfusion revealed marked edema of the portal triad, sinusoid congestion, and hemorrhage. Electron-microscopy biopsies obtained during reperfusion at 15-min intervals revealed severe vasospasm of the terminal hepatic arterioles and progressive damage to the liver microcirculation. The addition of TFP to the UW-flush solution resulted in excellent protection of the liver microcirculation. Marked increase in hepatic-artery and portal-vein blood flow was noted after reperfusion (mean 167 and 421 cc/min, respectively (P 0.02 vs. UW: P 0.001 vs. EC). The recovery of metabolic activity was evident by the high oxygen consumption and extraction (25.8 vol.% and 80%, respectively). And serial liver biopsies obtained after reperfusion have shown excellent protection of liver architecture and the absence of hepatic arteriolar vasospasm. Taken together, these data suggest that the addition of TFP to the UW solution protects the liver microcirculation by rendering the hepatic microcirculation insensitive to vasospastic stimuli during reperfusion, thus permitting better metabolic recovery after transplantation.     

Intermittent Ischemic Preconditioning Protects Against Hepatic Ischemia-Reperfusion Injury and Extensive Hepatectomy in Steatotic Rat Liver

ABSTRACT

Background: Hepatic steatosis causes severe liver damage and has deleterious effects when associated with ischemia-reperfusion mechanisms. Ischemic preconditioning (IPC) protects lean liver against prolonged ischemia by improving micro-circulation and reducing lipid peroxidation. We investigated the effect of intermittent IPC on liver ischemia-reperfusion injury (IRI) and extensive hepatectomy in severe hepatic steatosis. Methods: Severe hepatic steatosis was performed by 12–14 weeks of choline-free diet in 108 Wistar rats. We induced 30-minute ischemia-reperfusion manipulations and extensive hepatectomy with or without prior IPC in steatotic livers and after 6 and 24 hours of reperfusion blood transaminases, and IL6, TNFα, NO and Lactate in blood and liver tissue were measured. Results: Steatotic rats subjected to hepatic ischemia-reperfusion alone after extensive hepatectomy, showed severe liver damage with significantly increased values of AST, ALT, TNFα and Lactate and significantly reduced IL6 and NO, while no one rat survived for more than 29 hours. On the contrary, steatotic rats subjected to intermittent IPC, 24 hours before ischemia-reperfusion, presented increased 30-day survival (67%), lower values of AST, ALT, TNFα and Lactate, and increased IL6 and NO levels. Simple and intermittent IPC manipulations, 1 hour before the IRI and extended hepatectomy, did not prolong survival more than 57 and 98 hours, respectively. Simple IPC, 24 hours before IRI and extended hepatectomy had the lowest possible survival (16.7%).Conclusions: Hepatic steatosis and IRI after major liver surgery largely affect morbidity and mortality. Intermittent IPC, 24 hours before IRI and extensive hepatectomy, presents higher 30-day survival and improved liver function parameters.     

Vascular occlusion in hepatic resections in cirrhotic rat livers: An experimental study in rats

The aim of this study was to evaluate the tolerance of normothermic liver ischemia with different degrees of hepatic function in cirrhotic rats. Liver cirrhosis was induced by administering carbon tetrachloride (CCl₄) in water solution to male Wistar rats. Hepatic function was graded using the plasma levels of antithrombin III, albumin, and bilirubin and the presence of ascites. Rats were distributed in four groups: noncirrhotic (control group), compensated cirrhosis (group A), decompensated cirrhosis (group B), and decompensated cirrhosis with ascites (group C). Groups A, B, and C were significantly different in all four parameters studied (P < .003). Subtotal liver ischemia was performed for periods of 0, 30, 45, 60, and 75 minutes. At the end of the procedure, the nonischemic lobes were resected. Postoperative evolution of alanine aminotransferase, aspartate aminotransferase, and bilirubin levels was also recorded. Survival rates after the same periods of ischemia were statistically different (P < .05): control group, 7 of 7 after 45 minutes (100%), 7 of 7 after 60 minutes (100%), and 4 of 9 after 75 minutes (44%); group A, 7 of 7 after 45 minutes (100%) and 1 of 7 after 60 minutes (14%); group B, 7 of 7 after 0 minutes (100%), 5 of 7 after 30 minutes (71%), and 1 of 7 after 45 minutes (14%); and group C, 0 of 5 after 0 minutes (0%) and 1 of 7 after 30 minutes (14%). No differences were found in the postoperative course of transaminases. However, bilirubin levels found 24 hours and 7 days after ischemia were significantly greater in cirrhotic rats, and this was directly related to the degree of hepatic insufficiency (P < .001). Histological examination of the livers exposed to CCl4 showed features of liver cirrhosis with ductal proliferation. The ischemia time tolerated by cirrhotic rat livers is shorter than the time tolerated by normal rats. Tolerance to hilar vascular occlusion depends on the degree of hepatic insufficiency. Rats with decompensated cirrhosis and ascites do not tolerate any surgical procedure. (Liver Transpl Surg 1997 Nov;3(6):617-23)     

Effect of neferine on liver ischemia-reperfusion injury in rats

Introduction

Liver ischemia/reperfusion leads to the formation of reactive oxygen species (ROS) that cause liver injury, a critical clinical problem during liver surgery and transplantation. The aim of the present study was to investigate the hepatoprotective and antioxidant effects of neferine against liver ischemia/reperfusion injury in rats.

Materials and Methods

Wistar rats were randomly divided into 4 groups (n = 8): sham group; model group, and neferine high and low groups (50 and 25 mg/kg, respectively). After either saline or neferine was orally administered for 5 days rat livers were subjected to 30 minutes of ischemia followed by 6 hours of reperfusion. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and hydroxyl radical levels were measured in serum. The liver was removed to assay malondialdehyde (MDA) and carbonyl contents, superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities, as well as to evaluate histopathologic changes.

Results

Neferine significantly prevented AST and ALT elevations, reduced hydroxyl radical release, inhibited SOD and GPx activities, and decreased MDA and carbonyl contents. At the same time, neferine attenuated the histopathologic changes.

Conclusion

Neferine protected against liver ischemia/reperfusion in rats through antioxidant mechanisms. However, further studies are needed to verify whether the hepatoprotection of neferine is correlated with anti-inflammatory and anti-apoptotic effects.     

Large-for-size liver transplantation: a flowmetry study in pigs

Background

Ischemia–reperfusion injury is partly responsible for morbidity in pediatric liver transplantation. Large-for-size (LFS) liver transplantation has not been fully studied in the pediatric population, and the effects of reperfusion injury may be underestimated.

Materials and methods

Thirteen Landrace–Large white pigs weighing 23 kg (range, 17–38 kg) underwent orthotopic liver transplantation. They were divided into two groups according to the size of the donor body: LFS and control (CTRL). After transplantation, the abdominal cavity of the recipient was kept open and portal venous flow (PVF) was measured after 1 h. The ratio of recipient PVF (PVFr) to donor PVF was used to establish correlations with ischemia and reperfusion parameters. Liver biopsies were taken 1 h after transplantation to assess ischemia and reperfusion and to quantify the gene expression of endothelial nitric oxide synthase, interleukin 6, BAX, and BCL.

Results

Recipient weight, total ischemia time, and warm ischemia time were similar between groups. Among hemodynamic and metabolic analyses, pH, central arteriovenous PCO₂ difference, and AST were statistically worse in the LFS group than in the CTRL group. The same was found with endothelial nitric oxide synthase (0.41 ± 0.18 versus 1.56 ± 0.78; P = 0.02) and interleukin 6 (4.66 ± 4.61 versus 16.21 ± 8.25; P = 0.02). In the LFS group, a significant decay in the PVFr was observed in comparison with the CTRL group (0.93 ± 0.08 and 0.52 ± 0.11, respectively; P < 0.001).

Conclusions

The implantation of a graft was responsible for poor hemodynamic status of the recipient 1 h after transplantation. Furthermore, the LFS group demonstrated markers of ischemia and reperfusion that were worse when compared with the CTRL group and exhibited a more significant decrease in PVF from donor to recipient.     

Novel short-term hypothermic oxygenated perfusion (HOPE) system prevents injury in rat liver graft from non-heart beating donor

OBJECTIVE: To assess a machine perfusion system in rescuing liver grafts from non-heart-beating donors (NHBD). SUMMARY BACKGROUND DATA: The introduction of extracorporeal liver perfusion systems in the clinical routine depends on feasibility. Conceivably, perfusion could be performed during recipient preparation. We investigated whether a novel rat liver machine perfusion applied after in situ ischemia and cold storage can rescue NHBD liver grafts. METHODS: We induced cardiac arrest in male Brown Norway rats by phrenotomy and ligation of the subcardial aorta. We studied 2 experimental groups: 45 minutes of warm in situ ischemia + 5 hours cold storage versus 45 minutes of warm in situ ischemia + 5 hours cold storage followed by 1 hour hypothermic oxygenated extracorporeal perfusion (HOPE). In both groups, livers were reperfused in a closed sanguineous isolated liver perfusion device for 3 hours at 37 degrees C. To test the benefit of HOPE on survival, we performed orthotopic liver transplantation in both experimental groups. RESULTS: After cold storage and reperfusion, NHBD livers showed necrosis of hepatocytes, increased release of AST, and decreased bile flow. HOPE improved NHBD livers significantly with a reduction of necrosis, less AST release, and increased bile flow. ATP was severely depleted in cold-stored NHBD livers but restored in livers treated by HOPE. After orthotopic liver transplantation, grafts treated by HOPE demonstrated a significant extension on animal survival. CONCLUSIONS: We demonstrate a beneficial effect of HOPE by preventing reperfusion injury in a clinically relevant NHBD model.     

Donor pretreatment with gadolinium chloride improves early graft function and survival after porcine liver transplantation

Kupffer cell depletion by gadolinium chloride (GdCl₃) in rat livers has previously been proven to minimize hepatic ischemia/reperfusion injury after experimental liver transplantation (LTX). In the current study, we evaluated the effects of donor pretreatment with GdCl₃ on hepatic ischemia/reperfusion injury, macro- and microcirculation, and endotoxin clearance of the liver in a porcine model of experimental LTX. Two groups of 12 pigs were treated either with intravenous NaCl (0.9%; control) or GdCl₃ (20 mg/kg). Twenty-four hours after pretreatment, hepatic macrocirculation was quantified by Doppler flowmetry and liver parenchymous microcirculation by implanted thermodiffusion electrodes. The liver grafts were transplanted after 4–6 h of cold ischemia in University of Wisconsin (UW) solution. At 1 and 24 h after LTX, the perfusion values were re-evaluated and histology, biochemical (aspartate aminotransferase, AST) and functional parameters (partial thromboplastin time, prothrombin time, and bilirubin) were analyzed. Furthermore, endotoxin clearance of the liver was evaluated at all time points. In GdCl₃-treated animals 80% of the Kupffer cells were destroyed, and 24 h after LTX ischemia/reperfusion injury in treated grafts was significantly lower in comparison to controls, as shown by histology, AST levels (741±490 U/l in controls vs 379±159 U/l in treated grafts, P<0.05), survival (67% vs 92%), and enhanced macro- (total transhepatic blood flow [THBF]=112±22 ml/min per 100 g in controls vs 157±45 ml/min per 100 g in treated grafts, P0.05) and microcirculation (thermodiffusion [TD]=73±9 ml/min per 100 g in controls vs 90±16 ml/min per 100 g in treated grafts, P0.05). Despite destruction of the macrophage system in the liver, the transhepatic endotoxin gradient of treated livers was enhanced before and 1 h after transplantation (58% in controls vs 85% in treated grafts, P<0.05). Destruction of Kupffer cells of donors by pretreatment with GdCl₃ in pigs is effective in preventing liver graft dys- and nonfunction after LTX. Pretreatment with GdCl₃ does not diminish but increase hepatic endotoxin clearance.     

Coagulation profile following liver resection: Does liver cirrhosis affect thromboelastography?

Background

Thromboelastography has called into question the coagulopathy seen following partial hepatectomy. However the coagulation profile in cirrhotic livers has not been studied. Our objective was to determine the coagulation profile following partial hepatectomy in normal and cirrhotic livers.

Sympathetic Nerves Do Not Affect Experimental Ischemia-Reperfusion Injury of Rat Liver

Background

We investigated whether sympathetic, noradrenergic nerves participate in experimental acute ischemia-reperfusion injury of the rat liver.

Methods

Female Wistar rats (200-250 g body weight) were anesthetized with pentobarbital. After tracheotomy, we cannulated a carotid artery and jugular vein. The rats were divided in 2 groups (n = 8 per group). The control group received NaCl IV and the test group received the sympatholytic agent, guanethidine (3 mg/kg, IV). After 30 minutes of drug equilibration, laparotomy was performed to arrange the liver for temporary occlusion (by a ligature) of its vascular supply, corresponding with 70% reduction in hepatic blood flow. The rats were then allowed 60 minutes of equilibration. Thereafter, regional ischemia was induced for 30 minutes. The animals were then monitored for 2 hours of reperfusion. Blood samples for alanine aminotransferase (ALT) estimation (as a measure of injury to the parenchyma) were drawn immediately before ischemia, as well as 60 and 120 minutes after reperfusion. Readings of mean arterial pressure were taken during these times.

Results

After 2 hours of reperfusion, there were no significant differences between the groups with regard to ALT or mean arterial pressure.

Conclusion

Sympathetic, noradrenergic nerves did not affect experimental ischemia-reperfusion injury of rat liver in the current model.     

The serum interleukin 8 level reflects hepatic mitochondrial redox state in hyperthermochemohypoxic isolated liver perfusion with use of a venovenous bypass

BACKGROUND: We have recently developed a simple method of hyperthermochemohypoxic isolated liver perfusion (HILP) as a regional therapy for unrecognized liver micrometastases. However, little is known about the influence of HILP on cytokine production and liver function. We investigated the influence of HILP on interleukin 8 (IL-8) production and the hepatic mitochondrial function and assessed the relationship between these 2 parameters. We also measured the serum tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 beta (IL-1 beta) levels to examine the involvement of HILP-induced cytokines in the tumor response. METHODS: Sixteen patients with metastatic liver tumors were randomly assigned to undergo hepatectomy with HILP (group A, n = 9) or hepatectomy alone (group B, n = 7). The isolated liver was perfused for 30 minutes with Ringer's lactate solution containing chemotherapeutic agents warmed to 42 degrees C to 43 degrees C without oxygenation. RESULTS: The serum IL-8 levels in group A were markedly increased, with peaks at 3 hours after reperfusion, which was significantly higher than levels in group B (P < .01). In group A the arterial ketone body ratio, which reflects the hepatic mitochondrial redox state, decreased during perfusion and was gradually restored to the preperfusion level 1 hour after reperfusion. However, in group B it decreased during hepatectomy but rapidly recovered 5 minutes after hepatectomy. There was a significant negative correlation between the peak serum IL-8 level and the initial velocity of arterial ketone body ratio recovery for the first 5 minutes after reperfusion r = -0.83, P < .001). The serum TNF-alpha and IL-1 beta were temporarily detected only in 3 of 9 patients in group A. CONCLUSIONS: We have shown that HILP resulted in augmented IL-8 release but not TNF-alpha and IL-1 beta and that the serum IL-8 level reflects the hepatic mitochondrial redox state. These findings suggest that IL-8 production may be associated with hepatic mitochondrial impairment during ischemia. This work may contribute to new therapeutic strategies not only for hepatic ischemia reperfusion injury but also for metastatic liver tumors.