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Hepatic ischemia-reperfusion (I/R) injury occurs in the settings of transplantation, trauma, and elective liver resection. Ischemic preconditioning has been used as a strategy to reduce inflammation and organ damage from I/R of the liver. However, the mechanisms involved in this process are poorly understood. We examined the role of the phosphatidylinositol 3 (PI3) kinase/Akt-signaling pathway during hepatic ischemic preconditioning (IPC). Prior to a prolonged warm ischemic insult, BALB/c mice were subjected to a 20-minute IPC period consisting of 10 minutes of ischemia and 10 minutes of reperfusion. Mice undergoing IPC demonstrated a significantly greater level and earlier activation of Akt in the liver compared with control animals. IPC also resulted in markedly less hepatocellular injury and improved survival compared with control animals. Akt activation associated with hepatic IPC suppressed the activity of several modulators of apoptosis, including Bad, glycogen synthase kinase beta, and caspase-3. In addition, IPC also inhibited the activities of c-Jun N-terminal kinase and nuclear factor kappaB after I/R. Pretreatment of mice with PI3 kinase inhibitors completely abolished Akt phosphorylation and the protective effects seen with IPC. In conclusion, these results indicate that the PI3 kinase/Akt pathway plays an essential role in the protective effects of IPC in hepatic I/R injury. Modulation of this pathway may be a potential strategy in clinical settings of ischemic liver injury to decrease organ damage.

Ischemia reperfusion (IR) of the liver is a multifactorial process that, at least in part, is responsible for the morbidity associated with major liver surgery under occlusion of the portal triad with the Pringle maneuver, total vascular exclusion or after liver transplantation. Surgeons are confronted with IR injury (IRI) more often than they anticipate. Although the human body has its own defense system, understanding the pathophysiology of IRI is essential for the surgeon in preventing and/or treating the reperfusion injury in common clinical practice. Several endogenous mechanisms exist to overcome IRI and a large number of pharmacological agents have also been found to confer protection against ischemic injury in the liver. They either blocked the injurious pathways directly or they subjected the liver to preconditioning. Prostaglandins (PGs) are a group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase (COX) pathway. They are short-lived, hormone-like chemicals that regulate cellular activities on a moment-to-moment basis and are produced in most tissues of the body, although the liver has emerged as the major organ participating in the synthesis, degradation and elimination of arachidonate products of systemic origin. PGs are released through the prostaglandin transporter on the cell's plasma membrane. During the last decade intensive work on the cytoprotective effects of PGs on livers suffering from IRI have been well documented. Prostaglandins confer their protective effects on IR-injured livers mainly by inhibiting the generation of reactive oxygen species, preventing leukocyte migration, reducing the synthesis or production of membrane degradation products, improving hepatic insulin and lipid metabolism, and regulating the production of inflammatory cytokines and cell adhesion molecules. Production of PGs have been found essential also soon after partial hepatectomy for hepatocyte proliferation.

Background/purpose: D-Allose, a rare sugar, is one of the potent inhibitors of ischemia/reperfusion injury of the rat liver. To investigate the potency of this powerful agent we examined its effect against ischemia/reperfusion injury and compared it to that of allopurinol and superoxide dismutase., Methods: Male Lewis rats were given water ad libitum preoperatively for 12 h and anesthetized by isoflurane inhalation anesthesia. Drugs were administered through a polyethylene catheter inserted into the portal vein for 2 h (D-allose), 10 min (allopurinol), or 5 min (superoxide dismutase) before ischemia, and the livers were then subjected to 70% ischemia, induced by crossclamping the vessels to the lateral and median lobes of the liver for 90 min. Rats were divided into four groups: group 1, pretreated with vehicle (normal saline); group 2, treated with D-allose; group 3, treated with allopurinol; and group 4, treated with superoxide dismutase. The effects of the drugs were evaluated by liver hemodynamics, neutrophil count, myeloperoxidase, liver enzymes, and histological studies., Results: D-Allose improved liver hemodynamics (P < 0.001) and postischemic animal survival (P < 0.05) significantly compared with the control group and nonsignificantly compared with the allopurinol and superoxide dismutase groups. Myeloperoxidase activity in the postischemic liver tissue was decreased significantly (P < 0.05) by D-allose compared with all other treatment and control groups. Neutrophil count was also significantly (P < 0.05) decreased in the D-allose group compared with than that in the control group, as well as the superoxide dismutase group. Only D-allose produced a statistically significant decrease in the level of liver enzymes, compared with levels in the control group., Conclusions: The moderately protective effect of D-allose, which caused no clinical side effects, is encouraging. D-Allose had the best protective effect against neutrophil-related postischemic injury of the liver tissue, followed by allopurinol and superoxide dismutase. However, a more extensive study is needed to ensure the effects as well as the mechanisms of the effect of this rare sugar., (Copyright 2004 Springer-Verlag)

The cytoprotective effect of prostaglandin E(1) (PGE(1)) 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 PGE(1). 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 PGE(1) (0.4 microg/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 PGE(1) group. The blood chemical analysis indicated that PGE(1) significantly suppressed posthepatectomy liver dysfunction. Most importantly, PGE(1) 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 PGE(1) makes extensive hepatectomy possible under ischemic conditions in cirrhotic livers.

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 endothelium 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 90 min. D-allose was infused 2 h 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. Post-reperfusion animal survival was followed for 15 days., Results: D-allose significantly improved the liver hemodynamics and post-reperfusion 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.

The effect of warm ischemia on lidocaine-metabolizing activity was examined in vivo. Total liver ischemia was produced for 1 hr in Sprague-Dawley rats by clamping the portal vein and hepatic artery at the hilum. Livers were then reperfused, and liver microsomes were prepared before and 0, 2, 6, and 24 hr, and 3, 6, and 10 days after reperfusion. Microsomal lidocaine-metabolizing activity and cytochrome P-450 content were examined. Lidocaine N-deethylase activity was decreased from 2.25 +/- 0.33 to 0.97 +/- 0.21 nmol/mg protein/min (mean +/- SD) 24 hr after reperfusion. This inhibition was prolonged, and activity gradually recovered after 10 days. The cytochrome P-450 content showed the same tendency. On the other hand, serum levels of alanine aminotransferase increased significantly 2 hr after reperfusion and returned to control levels 3 days after reperfusion. Liver blood flow recovered rapidly after unclamping and reached baseline levels within 6 hr. Our results suggest that after warm ischemia, prolonged hepatic dysfunction in drug metabolism, which cannot be detected by evaluating serum enzymes or liver blood flow, exists at the microsomal level.

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 microg/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.

The effect of antithrombin III (AT III) supplementation on energy status, microcirculation, cytoprotection, and prostacyclin (PGI2) production during and after a period of warm ischemia of the rat liver was investigated. AT III supplementation (250 units/kg) stimulate prostaglandin I2 (PGI2) production from 1 hour after administration, with maximal production observed at 3 hours. Ischemia was induced by occluding the hepatoduodenal ligament for 30 minutes, and experiments were continued for 60 minutes after reperfusion. The rats received AT III (250 units/kg IC) 30 minutes before induction of liver ischemia (AT III group). In the AT III group, recovery of the beta-ATP/inorganic phosphate ratio measured by 31P nuclear magnetic resonance showed significant improvement (p < 0.01), and the recovery of tissue blood flow markedly improved (p < 0.01) compared to the saline-treated group (control group). Leakages of aspartame aminotransferase, alanine aminotransferase, and lactate dehydrogenase were mitigated in the AT III group (p < 0. 05). Ultrastructural alterations of sinusoidal endothelial cells were markedly reduced in the AT III group. The PGI2 level at the end of reperfusion was significantly elevated (p < 0.01) in the AT III group compared to the control group. The results of this study indicated that pretreatment with AT III significantly improved the energy status and microcirculation, as well as histologic damage, after liver ischemia and reperfusion. One of the fundamental effects of AT III might be mediated through the production of prostacyclin.

We investigated the role of adhesion molecules in the early phase of reperfusion following cold ischemia. Livers of male Lewis rats were preserved for 0 h (group A) or 24 h in University of Wisconsin (UW) solution without additives (group B) or in UW solution with anti-ICAM-1 antibody (group C) or anti-E-selectin-1, SLe(x) and SLe(a) antibodies (group D). The livers were then reperfused with diluted rat whole blood (DWB; groups A and B). DWB containing anti-ICAM-1 and LFA-1 antibodies (group C) or DWB containing anti-L-selectin, SLe(x) and SLe(a) antibodies (group D). The reperfusion was performed at 37 degrees C for 1 h at 5 cm H2O of perfusion pressure. During reperfusion, hepatic microcirculation was assessed by monitoring portal and peripheral tissue blood flow. Bile production was significantly reduced in group B livers compared with those in group A. Anti-ICAM-1 and LFA-1 antibodies failed to improve hepatic microcirculation, whereas anti-LECAM-1, SLe(x) and SLe(a) antibodies significantly improved the microcirculation. Bile production in group C and D livers was comparable to that in group B livers. Preservation for 24 h significantly increased the release of TNF-alpha from 0.207 to 43.7 pg/g per hour during reperfusion. Monoclonal antibodies to the adhesion molecules did not suppress the release of TNF-alpha in groups C and D. Histological examination demonstrated a lack of leukocyte infiltration or thrombus in hetapic microvessels. The extent of hepatocyte necrosis did not differ among groups B, C, and D. We conclude that the microcirculatory disturbance in the early phase of reperfusion occurs as a result of the tethering of leukocytes through the interaction of the selectin family and their ligands, and that the ICAM-1-LFA-1 pathway is not involved in this step. The lack of improvement in bile production with antibodies to the selectin family and their ligands strongly suggests that other mechanisms participate in the deterioration of hepatic function.

To find out the mechanism of action of Dallose researchers tried to trace whether D-allose has an effect on the inhibition of neutrophil adherence to endothelial cells after reperfusion. Researchers administered D-allose or vehicle intraperitoneally to a rat model of 70% partial ischemia for 90 min followed by reperfusion. The effect of D-allose on the expression of adhesion molecule, ICAM-1 was analyzed by immunohistochemistry in the liver tissues taken 3 h after reperfusion. Liver enzymes from hepatic venous blood were estimated. Histological examination was performed in the injured liver.