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     

Cyclic AMP- and ATP-mediated stimulation of DNA synthesis following partial hepatectomy by prostaglandin-E1 in D-galactosamine injured liver

D-galactosamine (D-gal) damaged rats were infused with Prostaglandin E1 (PGE1) through a peripheral vein for 40 min. before and after partial hepatectomy. DNA synthesis following 68% partial hepatectomy was severely inhibited by the pretreatment of D-galactosamine. PGE1 infusion (0.5, 1.0 microgram/kg/min) enhanced the DNA synthesis inhibited by D-gal 600 mg/kg significantly (p less than 0.01). After 20 min. of PGE1 infusion cyclic AMP levels of liver tissue was increased as compared with saline infusion in D-gal (600 mg/kg)-damaged rat (p less than 0.05). Also 20 min. and 3 hour after partial hepatectomy. ATP levels of liver tissue was enhanced in PGE1 treated group (p less than 0.05). However the doses of PGE1 infused in this investigation could not increase the hepatic tissue blood flow measured by hydrogen gas clearance method. These results suggest that PGE1 enhance DNA synthesis of injured liver after partial hepatectomy by the mechanism which PGE1 stimulate cyclic AMP production and increase ATP level in hepatic tissue.     

Continuous infusion of N-acetylcysteine reduces liver warm ischaemia-reperfusion injury

BACKGROUND: N-acetylcysteine (NAC) may modulate the initial phase (less than 2 h) of liver warm ischaemia-reperfusion (IR) injury but its effect on the late phase remains unclear. The present study investigated the role of NAC during the early and late phases in a rabbit lobar IR model. METHODS: Liver ischaemia was induced by inflow occlusion to the median and left liver lobes for 60 min, followed by 7 h of reperfusion. In the NAC group (n = 6), NAC was administered intravenously at 150 mg per kg over the 15 min before reperfusion and maintained at 10 mg per kg per h during reperfusion. In the IR group (n = 6), 20 ml 5 per cent dextrose was infused over the 15 min before reperfusion and continued at a rate of 10 ml/h. Animals in a sham operation group (n = 6) underwent laparotomy but no liver ischaemia. All animals were killed at the end of the experiment. RESULTS: Intracellular tissue oxygenation was improved after the second hour of reperfusion in animals treated with NAC compared with that in the IR group (P = 0.023). Hepatic microcirculation improved after 5 h of reperfusion (P = 0.036) and liver injury was reduced after 5 h, as indicated by alanine aminotransferase activity (P = 0.007) and indocyanine green clearance (uptake, P = 0.001; excretion, P = 0.032). CONCLUSION: The main protective effect of NAC becomes apparent 5 h after hepatic ischaemic injury.     

Effect of Short-term Administration of Prostaglandin E<Subscript>1 </Subscript>on Viability after Ischemia/Reperfusion Injury with Extended Hepatectomy in Cirrhotic Rat Liver

The cytoprotective effect of prostaglandin E₁ (PGE₁) has been demonstrated experimentally and clinically against hepatic ischemia and reperfusion injury and against the effects of partial hepatectomy in both individual and combined models of noncirrhotic livers. Cirrhotic livers are more vulnerable to ischemia/reperfusion injury during hepatectomy than are noncirrhotic livers, and postoperative malfunctioning complicates life with multiple organ failure. Cirrhotic livers with tumors have mostly been treated conservatively because extended hepatectomy with induced ischemia during surgery is impossible. The purpose of our study was to document postoperative surgical adaptation in inoperable cases with improved survival after extended hepatectomy in a rat model of cirrhosis treated by PGE₁. Cirrhosis was induced by intraperitoneal injections of 1% dimethylnitrosamine. The liver was subjected to 15 minutes of total ischemia by occluding the hepatoduodenal ligament. Hepatectomy was performed during ischemia. Pretreatment with PGE₁ (0.4 g/kg/min) (or without it in the controls) was given for 15 minutes by intravenous infusion prior to inducing ischemia and during reperfusion. Portal venous flow (PVF) and liver tissue blood flow (LTBF) were measured during reperfusion. At the end of 60 minutes of reperfusion, venous blood was collected for liver function tests. The animals were followed up regarding survival for 48 hours. The PVF and LTBF were significantly improved in the PGE₁ group. The blood chemical analysis indicated that PGE₁ significantly suppressed posthepatectomy liver dysfunction. Most importantly, PGE₁ treatment markedly improved the survival rate, from 42% in the controls to 75% in the test animals at 24 hours after hepatectomy and from 17% in the controls to 58% in the test animals at 48 hours. We concluded that short-term administration of PGE₁ makes extensive hepatectomy possible under ischemic conditions in cirrhotic livers.     

Effects of hepatic blood inflow occlusion on liver regeneration following partial hepatectomy in an experimental model of cirrhosis

BACKGROUND: Hepatic blood inflow occlusion during hepatectomy may influence postoperative liver regeneration. The aim of this study was to investigate the influence of hepatic blood inflow occlusion on liver regeneration following partial hepatectomy in thioacetamide-induced cirrhotic rats. METHODS: Forty-three cirrhotic Wistar-Furth rats were randomly assigned to three groups. Rats in group 1 underwent 64 per cent hepatectomy alone, those in group 2 were subjected to 15 min hepatic blood inflow occlusion followed by 64 per cent hepatectomy, and animals in group 3 were subjected to 30 min inflow occlusion followed by 64 per cent hepatectomy. Liver function, 5-bromo-2'-deoxyuridine (BrdU) labelling index and percentage of initial liver weight on days 1, 2 and 7 posthepatectomy were assessed. RESULTS: Rats in groups 1 and 2 had a significantly higher serum albumin level and a markedly lower alanine aminotransferase level than animals in group 3 on day 1 posthepatectomy (P < 0.05). There was no significant difference in the serum level of total bilirubin of the three groups on days 1, 2 and 7. The BrdU labelling index was significantly higher in groups 1 and 2 than in group 3 animals on day 1 posthepatectomy (P < 0.01 and P < 0.05 respectively). Percentages of initial liver weight were similar in groups 1, 2 and 3 on days 1, 2 and 7 after hepatectomy. CONCLUSION: Hepatic blood inflow occlusion for up to 30 min suppressed DNA synthesis and hepatocyte proliferation at an early posthepatectomy stage and consequently delayed recovery of liver function in cirrhotic rats. However, it did not affect restoration of liver mass or survival after 64 per cent hepatectomy.     

Effects of exogenous prostaglandin E1 in hepatectomized patients

The efficacy of prostaglandin E1 (PGE1) in preventing hepatic failure after hepatectomy was investigated prospectively in eight PGE1-treated patients and in seven untreated controls. The patients in the PGE1-treated group received PGE1 (0.03 μg/kg per min) intravenously for 72 h beginning at the initiation of surgery. The cardiac index increased markedly and the systemic vascular resistance decreased markedly during PGE1 treatment, while no significant changes were observed in the control group. The platelet count in the PGE1-treated group decreased slightly, while that in the control group decreased significantly during the first 3 postoperative days. The percent change of alanine aminotranferase in the PGE1-treated group was less than that in the control group. These findings suggest that the administration of exogenous PGE1 following hepatectomy increases hepatic blood flow and suppresses platelet aggregation, and therefore may be cytoprotective to the remnant liver. Thus, PGE1 may be effective in preventing hepatic failure after hepatectomy.     

Impact of endothelin-1 on microcirculatory disturbance after partial hepatectomy under ischemia/reperfusion in thioacetamide-induced cirrhotic rats

BACKGROUND: Endothelin (ET)-1 contributes to hepatic ischemia and reperfusion (HIR) injury in normal liver. This study was conducted to clarify the role of ET-1 in HIR injury in cirrhotic state. MATERIALS AND METHODS: Using thioacetamide-induced cirrhotic rats with spontaneous portosystemic shunt, we determined the changes in plasma aspartate aminotransferase (AST) levels, plasma and hepatic ET-1 values, 7-day survival rates, and hepatic oxygen saturation (SO(2)) by time-resolved spectroscopy as an indicator of hepatic microcirculation under intermittent or continuous total hepatic ischemia with subsequent partial hepatectomy. RESULTS: Hepatic ET-1 levels in cirrhotic rats were significantly higher than those in noncirrhotic rats. Plasma and hepatic ET-1 levels at 1, 3 and 6 h of reperfusion after intermittent hepatic ischemia were significantly lower than those after continuous hepatic ischemia. In cirrhotic animals subjected to intermittent hepatic ischemia, the elevation of plasma AST levels at 1, 3 and 6 h of reperfusion and the decline in hepatic SO(2) at the end of 60-min hepatic ischemia and after reperfusion were significantly suppressed when compared with those subjected to continuous hepatic ischemia. Pretreatment with a nonselective endothelin receptor antagonist in continuous hepatic ischemia significantly ameliorated plasma AST levels and hepatic SO(2) values with less hepatic sinusoidal congestion, resulting in an improvement in the 7-day survival rate. CONCLUSIONS: Continuous hepatic ischemia in the cirrhotic liver has disadvantages relating to microcirculatory derangement with more ET-1 production in partial hepatectomy. In liver surgery, pharmacological regulation of ET-1 production may lead to attenuation of reperfusion injuries for ischemically damaged cirrhotic liver.     

Lack of protection of ischaemic preconditioning in the rat model of major hepatectomy with ischaemia reperfusion injury

OBJECTIVE: To investigate the effects of ischaemic preconditioning (IP) on residual liver regeneration after major hepatectomy without portal blood bypass in rats, and to verify whether it can protect the residual liver from ischaemia reperfusion (IR) injury. METHODS: Ninety rats were randomized into three groups: Group PH, rats were subjected to 70% hepatectomy alone; Group IR, rats were subjected to 30 minutes of total hepatic ischaemia, and 70% hepatectomy was performed just before reperfusion; Group IP, rats were pretreated with IP (5/10 minutes). During the preoperative period and at 0.5, 6, 12, 24 and 48 hours after the operation, serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities were measured using an autoanalyser. Serum hyaluronic acid (HA) was measured by radioimmunoassay. Regenerated liver weight (RLW) of the rats was measured and the expressions of Ki-67 and cyclin D1 were determined by immunohistochemistry in remnant liver tissue. RESULTS: There were no significant differences in serum AST and ALT levels in all the groups before the operation. After partial hepatectomy, AST and ALT levels increased rapidly. From 0.5 to 24 hours after operation, serum AST and ALT levels were significantly higher in IP group rats than in PH and IR rats (p < 0.05). There were no significant differences in serum HA levels in all the groups before the operation. After partial hepatectomy, HA levels increased rapidly, reaching peak values at 12 hours. In the early stage (during 12 hours) after the operation, HA level was significantly higher in IP rats than in PH and IR rats (p < 0.05). The RLW of the rats rapidly increased after partial hepatectomy, and significantly decreased in IP rats compared with PH and IR rats (p < 0.05). Cyclin D1 and Ki-67 expression in all groups before the operation were low and were not significantly different. After partial hepatectomy, they rapidly increased. The expression of Ki-67 and cyclin D1 reached a peak at 24 hours after the operation in PH rats, and they were significantly higher compared with IR and IP rats (p < 0.05). In groups IR and IP, the expression of cyclin D1 and Ki-67 reached peak values at 48 hours. A significant decrease (p < 0.05) was observed after 24 and 48 hours of reperfusion in group IP compared with groups PH and IR. CONCLUSION: IP impairs residual liver regeneration after major hepatectomy without portal blood bypass in rats, and protection from IR injury disappears. IP-induced hyperperfusion may be the cause of reduced liver regeneration.     

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.     

Improvement of morphological changes after 70% hepatectomy with portocaval shunt: preclinical study in porcine model

BACKGROUND: After extensive hepatectomy, excessive portal venous flow (PVF) and elevated portal venous pressure (PVP) may lead to postoperative liver damage. We have evaluated the use of portocaval shunt (PCS) to control PVF and PVP following partial hepatectomy (PH) to reduce the postoperative liver damage. METHOD: Twenty-four pigs were divided into two Groups: Group C (n = 10) underwent 70% PH alone and Group S (n = 14) underwent 70% PH with PCS. The changes in PVF, PVP, serum liver function tests, and histology were evaluated. RESULTS: PVP and PVF per unit of remnant liver weight and serum total bilirubin levels in Group S were significantly lower than those in Group C postoperatively (P < 0.05). Histology showed that there were significant differences in hepatocyte ballooning, necrosis, and neutrophil aggregation between the two groups (P < 0.05). In particular, hepatic necrosis was observed in zone 3 of Group C as centrilobular necrosis. These results suggest that hepatic and sinusoidal damage after 70% PH were more severe in Group C than in Group S, with the latter group maintaining an almost normal ultrastructural appearance. Hepatocyte apoptotic index differed significantly between the two groups (P < 0.0001). CONCLUSION: After 70% PH, extensive centrolobular necrosis and neutrophil aggregation were present and may have caused liver damage, manifested as hyperbilirubinemia and coagulopathy. The delayed liver regeneration with PCS may reduce the postoperative liver damages rather than the rapid liver hypertrophy. The diversion of PVF with PCS to maintain adequate PVP is a very effective procedure for avoiding the postoperative liver failure after extensive hepatectomy.     

ISCHAEMIC PRECONDITIONING OF THE LIVER: A PRELIMINARY STUDY

Background: A phenomenon of ‘preconditioning’ exists for the heart, but has not been described for the liver. This study was undertaken to determine whether a brief episode of ischaemia (3 or 5 min) followed by a short reperfusion time (5 or 10 min) would precondition the liver to reduce subsequent injury from prolonged ischaemia (30 to 90 min). Methods: Male Wistar rats were allocated into five control (no preconditioning) and five preconditioned groups, each having a liver resection. The preconditioning times were 3 rnin ischaemia followed by 5 rnin reperfusion with a prolonged ischaemia of 60 or 90 min for the first two groups, and 5 min ischaemia followed by 10 rnin reperfusion with prolonged ischaemia times of 30 or 45 min for the other three groups. Results: Of rats resected with 3–5–60 rnin time sequence designed to assess survival, 9/10 died. However 9/10 died also in the matching control group with 60 rnin ischaemia. With a 5–10–45 rnin sequence, 9/10 survived more than 24 h in the preconditioned group and 1/10 in the non-preconditioned controls. With a 5–10–30+ sequence designed to measure liver function tests, the prothrombin time was significantly improved; bilirubin, serum alkaline phosphatase and the alanine aminotransferase improved but these did not reach significance. Conclusion: A brief episode of ischaemia followed by an episode of reperfusion before a prolonged period of ischaemia ameliorated the effects of ischaemia-reperfusion injury in a rat liver resection model. If hepatic preconditioning is confirmed in humans, ischaemic preconditioning will have an important role for all liver surgery.     

肝缺血再灌注后肝内血流动力学的变化

目的探讨肝脏缺血再灌注（I／R）后肝内分流（IHSF）和功能性肝血流（FHBF）的变化。方法健康雄性SD大鼠l2只，作右侧颈动脉、颈静脉插管；开腹后，经回结肠静脉作门静脉插管，分别用以输血、输液、给药、留样、检测等。大鼠经部分肝I／R制模后，随机分为2组（每组6只）：（1）正常对照组（对照组），术中只分离肝周围韧带，不作肝门阻断及再灌注。（2）缺血再灌注组（1／R组，实验组），进行45min的肝门阻断及60min的再灌注。然后两组均经门静脉输注D一山梨醇（10mmol／L，0．2mL／min），2min后同时取颈动脉、门静脉、肝静脉血各1mL。测定门静脉血流量（PVF）、肝动脉血流量（HAF）。计算肝脏山梨醇摄取率、FHBF和IHSF。结果两组PVF，HAF及总肝血流量（THBF）无明显统计学差异；与对照组比较，I／R组肝脏山梨醇摄取率和FHBF减少，IHSF增加（P〈0．01）。结论肝I／R后，肝内血流动力学变化表现为肝内门一体分流开放，功能性肝血流减少。     

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.     

Beneficial effect of deletion variant of hepatocyte growth factor for impaired hepatic regeneration in the ischemically damaged liver

This study was conducted to determine the influence of hepatic ischemia and reperfusion (HIR) injury on liver regeneration and the effect of the deletion variant of hepatocyte growth factor (dHGF) under these conditions. Male Sprague-Dawley rats were subjected to 60 minutes of total hepatic ischemia, and two-thirds hepatectomy was performed just before reperfusion. Animals received intravenous administration of either vehicle buffer (vehicle control group) or dHGF (1 mg/kg) (HGF group) at the end of the period of hepatic ischemia and again 6 hours after reperfusion. At 8 hours after hepatectomy, plasma HGF levels in the vehicle control group were significantly lower than those in the nonischemic controls. Plasma aspartate transaminase levels in the vehicle control group reached 3,462 +/- 1,039 IU/L, but levels in the HGF group were significantly inhibited to 1,849 +/- 605 IU/L. The relative liver weight in the vehicle control group was significantly greater than in the HGF group, a finding that was implicated in focal liver necrosis with sinusoidal congestion. Less histological damage was observed in the HGF group. Twenty-four hours after hepatectomy, an increase in the relative liver weight in nonischemic controls and in the HGF group was higher than that in vehicle control group, and the 5-bromo-2?deoxyuridine (BrdU) labeling index in the HGF group was 23% versus 18% in the nonischemic controls. Administration of dHGF significantly improved the 7-day survival to 82% versus 40% in the vehicle control group. dHGF has potential benefit as a pharmacological agent to ameliorate impairment of the hepatic microcirculation and to potentiate a regeneration response in the ischemically damaged liver after hepatectomy and/or liver transplantation.     

Reevaluation of protective effects of alprostadil on hepatic function in patients undergoing hepatectomy

BACKGROUND: The protective effect of alprostadil (PGE1), used during hepatectomy, on hepatic function has not been clearly proven. We reevaluated this effect by measuring serum alpha-glutathione S-transferase (aGST), which detects liver injury sensitively. METHOD: Thirty hepatocellular carcinoma patients scheduled for hepatectomy were randomly assigned to control (n=12) and PGE1 (n=10) groups. In the latter group, PGE1 was administered intravenously at a rate of 0.05 microg x kg(-1) x min(-1) during surgery. For measuring alphaGST, arterial blood samples were obtained before anesthesia, following laparotomy, and immediately, 2, 4, and 6 hrs after liver resection. RESULTS: The alphaGST concentrations after liver resection were significantly higher, while mean arterial pressures were significantly lower in the PGE1 group. CONCLUSIONS: Our findings suggest that PGE1 medication during hepatectomy cannot protect hepatic function during and after liver resection.     

MCI-186 (edaravone), a free radical scavenger, attenuates hepatic warm ischemia–reperfusion injury in rats

Hepatic warm ischemia-reperfusion injury (IRI) during hepatectomy and liver transplantation is a major cause of liver dysfunction in which the pathologic role of free radicals is a major concern. To assess the effect of MCI-186 (edaravone) on hepatic IRI, male Wistar rats were subjected to partial hepatic ischemia for 60 min after pretreatment with vehicle (group C) or MCI-186 (group M), or after both MCI-186 pretreatment and additional administration of MCI-186 12 h after reperfusion (group MX). Groups M and MX showed significantly lower levels of serum alanine aminotransferase and hepatic lipid peroxidation than group C, and also significantly lower expression levels of mRNA for cytokines, chemokines and intercellular adhesion molecule-1. There were fewer tissue monocytes and neutrophils in groups M and MX than in group C. These effects were more marked in group MX than in group M. Our findings suggest that treatment with MCI-186 attenuates hepatic IRI in this rat in vivo model.     

The effect of intraportal prostaglandin E1 on adhesion molecule expression, inflammatory modulator function, and histology in canine hepatic ischemia/reperfusion injury

BACKGROUND: Prostaglandin E1 (PGE1) is known to protect the liver from I/R, however, the mechanism of cytoprotection is not well understood. This study investigates the effect of intraportal infusion of PGE1 in a warm liver ischemia/reperfusion (I/R) model on cytokines, adhesion molecules and liver structure. MATERIALS AND METHODS: Twenty dogs underwent laparotomy under general anesthesia. PGE1 (0.02 microg\kg\min) was perfused through the portal vein in the PGE1 group (n = 10), or a similar volume of Ringer's solution in the control group (n = 10) for 15 min. Liver ischemia was induced by hepatic artery and portal vein occlusion and PGE1 was infused via the portal vein for 60 min. The occlusion was released and PGE1 infusion recommenced for 30 min. Blood and liver biopsies were sampled at baseline, 60 min ischemia, and 30 min reperfusion and assessed for transaminases, cytokines, adhesion molecules, and electron microscopy. RESULTS: PGE1 infusion significantly reduced transaminases TNF-alpha, sICAM-1, sP-selectin, and sE-selectin on ischemia and reperfusion. PGE1 reduced hepatocytic degeneration, portal and central ICAM-1 expression, central and sinusoidal VCAM-1 expression, portal and central P-selectin expression, and portal and sinusoidal E-selectin expression on reperfusion. CONCLUSION: Intraportal PGE1 infusion reduced I/R injury and was associated with down-regulation of ICAM-1, VCAM-1, P-selectin, and E-selectin on reperfusion.     

Protective effect of diltiazem on hepatic ischemia-reperfusion injury in rats by improving liver tissue blood flow

BACKGROUND: Cytosolic calcium ions are known to play an important role in ischemia-reperfusion (IR) injury. However, the protective effect of calcium channel blockers remains controversial in liver IR injury. Moreover, calcium channel blockers improve hepatic IR injury not due to blocking an increase in hepatic calcium concentration. Therefore, we hypothesized that calcium antagonists protected a liver from IR injury by a vasodilatory action rather than by the inhibition of an increase in Ca2+ within parenchymal cells. This study evaluated the effects of diltiazem, a calcium channel blocker, on liver energy metabolism and blood flow after IR injury. METHODS: Twenty-seven rats underwent hepatic ischemia for 30 minutes followed by 60 minutes of reperfusion. The animals were allocated into group C (without drug); group D5 (diltiazem, 5 microg/kg per min); or group D10 (diltiazem, 10 microg/kg per min). Diltiazem was infused before laparotomy and then throughout the experiment. RESULTS: After 60 minutes of reperfusion, liver tissue blood flow and ATP concentrations were significantly higher in group D10 than the other animals (both, P < .05). Changes in ATP values strongly correlated those observed in blood flow (R = 0.80, P < .001). CONCLUSION: Diltiazem improved ATP-generating capacity during reperfusion by improving liver tissue blood flow. An improvement in hepatic tissue perfusion may be a therapeutic strategy for liver IR injury.     

Beneficial effects of prostaglandin E(1) incorporated in lipid microspheres on liver injury and regeneration after 90% partial hepatectomy in rats

The aim of this study was to assess how the administration of prostaglandin E(1) incorporated in lipid microspheres (Lipo PGE(1)) affects liver injury and regeneration after massive hepatectomy in rats. Two hundred and eight male Wistar rats underwent 90% partial hepatectomy. Lipo PGE(1) of 1, 10 or 30 microg/kg were administered intraperitoneally at 6 h prior to and 0 and 6 h after hepatectomy. Postoperative increases in serum GOT, total bilirubin, IL-6 and plasma endotoxin levels were significantly suppressed by Lipo PGE(1). The depressed phagocytic index and arterial ketone body ratio and hepatic DNA synthesis after 90% partial hepatectomy were significantly enhanced by Lipo PGE(1), which resulted in the improvement of survival. Lipo PGE(1) might bring about a protective effect on liver injury and an enhancement of liver regeneration after massive hepatectomy.     

Beneficial effects of arterialization of the portal vein on extended hepatectomy

BACKGROUND: Extended hepatectomy may result in postoperative liver failure. The aim of this study was to evaluate the effects of arterialization of the portal vein on oxygen supply, hepatic energy metabolism and liver regeneration after extended hepatectomy. METHODS: Portal haemodynamics were evaluated 0 or 10 days after arterialization of the portal vein in three experimental groups: 85 per cent partial hepatectomy, 85 per cent partial hepatectomy 10 days after arterialization of the portal vein and 85 per cent partial hepatectomy 10 days after ligation of the hepatic artery. Survival rates, weight of the regenerating liver, levels of adenine nucleotides and hepatic energy charge were assessed. RESULTS: Arterialization of the portal vein caused a significant increase in partial pressure of oxygen and oxygen saturation. Portal blood flow 10 days after arterialization was significantly increased. Survival rate and weight of the regenerating liver in the group with arterialization of the portal vein were significantly higher than those in the other two groups. The group with arterialization of the portal vein showed the highest levels of adenosine 5'-triphosphate. CONCLUSION: The increase in portal blood flow and oxygen supply produced by arterialization of the portal vein has beneficial effects on hepatic energy metabolism and liver regeneration, and leads to improved survival after experimental extended hepatectomy.