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Posthepatectomy liver failure (PHLF) may occur after extended partial hepatectomy (PH). If malignancy is widespread in the liver, the size of PH and hence the size of the future liver remnant (FLR) may limit curability. We aimed to characterize differences in protein expression between different sizes of FLRs and identify proteins specific to the regenerative process of minimal-size FLR (MSFLR), with special focus on postoperative day (POD) 1 when PHLF is present. A total of 104 male Wistar rats were subjected to 30, 70, or 90% PH (MSFLR in rats), sham operation, or no operation. Blood and liver tissue were harvested at POD1, 3, and 5 ( n = 8 per group). Protein expression was assessed by proteomic profiling by unsupervised two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) liquid chromatography tandem mass spectrometry (LC-MS/MS), followed by supervised selected reaction monitoring (SRM)-MS/MS. In all, 1,035 protein spots were detected, 54 of which were significantly differentially expressed between groups and identifiable. During PHLF after PH(90%) at POD1, urea cycle and related proteins showed significant perturbations, including the urea cycle flux-regulating enzyme of carbamoyl phosphate synthase-1, ornithine transcarbamylase, and arginase-1, as well as the ornithine aminotransferase and propionyl-CoA carboxylase alpha chain. Plasma-ammonia increased significantly at POD1 after PH(90%), followed by a prompt decrease. At the protein level, we found perturbations of urea cycle and related enzymes in the MSFLR during PHLF. Our results suggest that these perturbations may augment urea cycle function, which may be pivotal for increased ammonia elimination after extensive PHs and potential PHLF.NEW & NOTEWORTHY Posthepatectomy liver failure (PHLF) is associated with high mortality. In a rat model of 90% hepatectomy, PHLF is present. Our results on liver tissue proteomics suggest that the ability of the liver remnant to sufficiently eliminate ammonia may be brought about by perturbation related to urea cycle proteins and that enhancing the urea cycle capacity may play a key role in surviving PHLF.

BACKGROUND: The upper limit for the size of hepatectomy is approximately 90% in rats. The aim of the study was to assess quantitatively using stereological methods the impact on liver function, regeneration rate (RR), and hepatocyte proliferation of varying hepatectomy size in a rat model.MATERIALS AND METHODS: A total of 104 male Wistar rats were subjected to 30%, 70%, or 90% partial hepatectomy, sham operation, or no operation. Euthanization and harvesting of liver tissue and blood took place at postoperative days 1, 3, and 5 (n = 8 per group). Liver-specific biochemistry and RR were evaluated. Hepatocyte proliferation was estimated by immunohistochemical staining for Ki-67 antigen using unbiased stereological principles.RESULTS: Liver RR in the 90% group increased by a 6.6 fold during the 5 postoperative days compared with only a minor increase in both the 70% and 30% partial hepatectomy groups. The highest number of Ki-67-positive hepatocytes was observed in the 70% group at postoperative day 1 and for the 90% group at postoperative day 3. Prothrombin-proconvertin ratio was significantly lower in the 90% group 1 d after surgery compared with all other groups, however, nearly normalized at postoperative day 5.CONCLUSIONS: We show that liver RR and the number of proliferating hepatocytes increase, whereas the initial hepatic synthetic capacity decreases with increasing hepatectomy size.

Aim The Pringle maneuver is a way to reduce blood loss during liver surgery. However, this may result in ischemia/reperfusion injury in the development of which Kupffer cells play a central role. Corticosteroids are known to have anti-inflammatory effects. Our aim was to investigate whether a conjugate of dexamethasone and antibody against the CD163 macrophage cell surface receptor could reduce ischemia/reperfusion injury in the rat liver. Methods Thirty-six male Wistar rats were used for the experiments. Animals were randomly divided into four groups of eight receiving anti-CD163-dexamethasone, high dose dexamethasone, low dose dexamethasone or placebo intravenously 18 h before laparotomy with subsequent 60 min of liver ischemia. After reperfusion for 24 h the animals had their liver removed. Bloods were drawn 30 min and 24 h post ischemia induction. Liver cell apoptosis and necrosis were analyzed by stereological quantification. Results After 24 h' reperfusion, the fraction of cell in non-necrotic tissues exhibiting apoptotic profiles was significantly lower in the high dose dexamethasone (p = 0.03) and anti-CD163-dex (p = 0.03) groups compared with the low dose dexamethasone and placebo groups. There was no difference in necrotic cell volume between groups. After 30 min of reperfusion, levels of haptoglobin were significantly higher in the anti-CD163-dex and high dose dexamethasone groups. Alanine aminotransferase and alkaline phosphatase were significantly higher in the high dose dexamethasone group compared to controls after 24 h' reperfusion. Conclusions We show that pharmacological preconditioning with anti-CD163-dex and high dose dexamethasone reduces the number of apoptotic cells following ischemia/reperfusion injury., Highlights • We investigated the effect of pharmacologic preconditioning with HDD, LDD and anti-CD163-dex on ischemia/reperfusion injury. • Liver cell apoptosis and necrosis were analyzed by stereological quantification. • Anti-CD163-dex and high dose dexamethasone reduces the number of apoptotic cells following ischemia/reperfusion injury.

AIM To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH). METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post- PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration. RESULTS The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05). CONCLUSION NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.

Extended hepatectomies may result in posthepatectomy liver failure, a condition with a high mortality. The main purpose of the present study was to investigate and compare the gene expression profiles in rats subjected to increasing size of partial hepatectomy (PH). Thirty Wistar rats were subjected to 30%, 70%, or 90% PH, sham operation, or no operation. Twenty-four hours following resection, liver tissue was harvested and genome-wide expression analysis was performed. Cluster analysis revealed two main groupings, one containing the PH(90%) and one containing the remaining groups [baseline, sham, PH(30%), and PH(70%)]. Categorization of specific affected molecular pathways in the PH(90%) group revealed a downregulation of cellular homeostatic function degradation and biosynthesis, whereas proliferation, cell growth, and cellular stress and injury were upregulated in the PH(90%) group. After PH(90%), the main upregulated pathways were mTOR and ILK. The main activated upstream regulators were hepatocyte growth factor and transforming growth factor. With decreasing size of the future liver remnant, the liver tended to prioritize expression of genes involved in cell proliferation and differentiation at the expense of genes involved in metabolism and body homeostasis. This prioritizing may be an essential molecular explanation for posthepatectomy liver failure.

Circulating liver enzymes such as alanine transaminase are often used as markers of hepatocellular damage. Ischaemia/reperfusion (I/R) injury is an inevitable consequence of prolonged liver ischaemia. The aim of this study was to examine the correlation between liver enzymes and volume of liver cell necrosis after ischaemia/reperfusion injuries, using design-unbiased stereological methods. Forty-seven male Wistar rats were subjected to 1 h of partial liver ischaemia, followed by either 4 or 24 h of reperfusion. Within each group, one-third of animals were subjected to ischaemic preconditioning and one-third to ischaemic postconditioning. At the end of reperfusion, blood and liver samples were collected for analysis. The volume of necrotic liver tissue was subsequently correlated to circulating markers of I/R injury. Correlation between histological findings and circulating markers was performed using Pearson's correlation coefficient. Alanine transferase peaked after 4 h of reperfusion; however, at this time-point, only mild necrosis was observed, with a Pearson's correlation coefficient of 0.663 (P = 0.001). After 24 h of reperfusion, alanine aminotransferase was found to be highly correlated to the degree of hepatocellular necrosis R = 0.836 (P = 0.000). Furthermore, alkaline phosphatase (R = 0.806) and α-2-macroglobulin (R = 0.655) levels were also correlated with the degree of necrosis. We show for the first time that there is a close correlation between the volume of hepatocellular necrosis and alanine aminotransferase levels in a model of I/R injury. This is especially apparent after 24 h of reperfusion. Similarly, increased levels of alkaline phosphatase and α-2-macroglobulin are correlated to the volume of liver necrosis.

The aim was to develop a method for quantification of hepatobiliary uptake and secretion of conjugated bile acids using PET and the (11)C-labeled conjugated bile acid analog [N-methyl-(11)C]cholylsarcosine ((11)C-CSar).METHODS: Six pigs (13 experiments) underwent dynamic (11)C-CSar PET of the liver with measurements of hepatic blood perfusion and (11)C-CSar concentrations in arterial, portal and hepatic venous blood. In three pigs (seven experiments) bile was collected from a catheter in the common hepatic duct (CHD). PET data were analyzed by a two-tissue compartmental model with calculation of rate constants for transport of (11)C-CSar between blood, hepatocytes and intra- and extra-hepatic bile ducts. PET results were validated against invasive blood and bile measurements.RESULTS: Directly measured secretion rate of (11)C-CSar into bile was equal to removal rate from blood at steady state. Hepatocytes accordingly did not accumulate bile acids but simply facilitated transport of bile acids from blood into bile against a measured concentration gradient of 4,000 from blood to bile. In experiments with catheter in CHD, rate constant for secretion of (11)C-CSar from hepatocytes into bile was 25% of that in experiments without a catheter (P < 0.05) which we interpreted as mild cholestasis caused by the catheter. The catheter caused an increased backflux of (11)C-CSar from hepatocytes to blood and hepatic blood flow was 25% higher than in experiment without catheter. The capacity of the overall transport of (11)C-CSar from blood into bile, as quantified by intrinsic clearance, was significantly lower in experiments with catheter than in pigs without catheter (P < 0.001). PET and blood measurements correlated significantly (P < 0.05).CONCLUSION: In vivo kinetics of hepatobiliary secretion of conjugated bile acids can now be determined by dynamic (11)C-CSar PET.

Introduction Surgical resection is the gold standard in treatment of hepatic malignancies, giving the patient the best chance to be cured. The liver has a unique capacity to regenerate. However, an inflammatory response occurs during resection, in part mediated by Kupffer cells, that influences the speed of regeneration. The aim of this study was to investigate the effect of a Kupffer cell targeted anti-inflammatory treatment on liver regeneration in rats. Methods Two sets of animals, each including four groups of eight rats, were included. Paired groups from each set received treatment with placebo, low dose dexamethasone, high dose dexamethasone or low dose anti-CD163 dexamethasone. Subsequently, the rats underwent 70% partial hepatectomy. The two sets were evaluated on postoperative day 2 or 5, respectively. Blood was drawn for circulating markers of inflammation and liver cell damage; liver tissue was sampled for analysis of regeneration rate and proliferation index. Results The high dose dexamethasone group had significantly lower body and liver weight than the placebo and anti-CD163-dex groups. There were no differences in liver regeneration rates between groups. Hepatocyte proliferation was completed faster in the placebo group, although this was not significant. The anti-CD163-dex group showed increased blood levels of albumin and alanine aminotransferase and a diminished inflammatory response in terms of significantly reduced haptoglobin, α2-macroglobulin and Interleukine-6. Conclusion Low dose dexamethasone targeted to Kupffer cells does not affect histological liver cell regeneration after 70% hepatectomy in rats, but reduces the inflammatory response judged by circulating markers of inflammation., Highlights • Use of anti-CD163-dexamethasone is an attractive strategy for anti-inflammatory treatment. • In the present study the impact of anti-CD163 dexamethasone on liver regeneration in rats was studied. • We show that low dose anti-CD163 dexamethasone has no negative effect on liver regeneration after 70% hepatectomy in rats. Characters should then be down to 122.

BACKGROUND: Sorafenib, a multikinase inhibitor, has been shown to halt the growth of hepatocellular carcinoma. The aim of the present study was to investigate the effect of Sorafenib on liver regeneration in healthy rats.METHODS: In two substudies we examined the effect of pre- or post-operative treatment with Sorafenib (15 mg/kg/d). Wistar rats (n = 120) received either Sorafenib (S) or placebo (P). After 70% partial hepatectomy, the rats were euthanized on postoperative days 2, 4, or 8. Body weight and liver weight were recorded and regeneration rate (RR) calculated. Hepatocyte proliferation was estimated by immunohistochemistry for Ki-67 antigen using unbiased stereological methods.RESULTS: Eleven animals (9%) died after surgery. In the preoperative substudy, lower body weight gains during the gavage period in the S group were found. No difference between groups S and P regarding liver weight gain, liver RRs, and hepatocyte proliferation on postoperative days 2 and 4 were found. In the postoperative substudy, significantly lower values of liver weight gain, liver RRs, and hepatocyte proliferation were found in the S group.CONCLUSIONS: In our rat model, Sorafenib did not increase posthepatectomy mortality. Postoperative treatment significantly impaired liver regeneration. Preoperative treatment impaired body weight during the gavage period, but was without effect on liver regeneration.

Transarterial chemoembolization (TACE) is used as palliative treatment of hepatocellular carcinoma (HCC). Most publications are from HCC patient populations where viral hepatitis is the primary cause of liver disease. In the Nordic countries, most patients have either alcohol-induced cirrhosis or are noncirrhotic. The aim of this single-center study was to evaluate patient characteristics, survival, and side effects of TACE in a Danish referral center for HCC treatment.Fifty-nine consecutive patients with HCC, treated with TACE, either chemoembolization with drug-eluting beads or conventional-TACE with Lipiodol, were included in the study. Their medical records were retrospectively reviewed, computed tomography images analyzed, and biochemical markers recorded. The primary endpoint was overall survival. Analyses were by intention to treat.Thirty-five patients (59 %) had HCC on a background of liver cirrhosis most often caused by alcohol (60 % of cirrhotics or 35 % overall). Before the first chemoembolization, the patients had a median Child-Pugh score of 6 (5-7) and a median MELD score of 10 (6-21). Median survival after chemoembolization was 18.9 months (13.1-24.7). TACE patients were hospitalized for an average of 3 days (2-30). Prolonged stay was most often due to side effects-eg. pain (31 %), fever (14 %), nausea (10 %), and infection (10 %). Thirty-three patients (56 %) did not have any side effects.In this cohort, we observed an acceptable survival following TACE without significant side effects.

Background Rodent models have been used to evaluate aspects of liver regeneration. The aim of the present study was to investigate the natural history of liver regeneration in healthy rats. Methods A 70% partial hepatectomy was performed in 64 rats. The animals were randomised into 8 groups and evaluated on postoperative days one to eight. Hepatocyte proliferation was evaluated by immunohistochemistry using unbiased stereological principles. Results The mean rat body weight was 238 g (211–287). The mean weight of the resected liver was 6.3 g (5.2–7.3) and the estimated mean total liver weight was 8.9 g (7.4–10.4). Both liver weight analysis and regeneration rate showed an ascending curve, with a maximum slope on postoperative days 1–4, reaching a steady state on days 5–8. Hepatocyte proliferation (positive Ki-67 cell profiles pr. mm 2 ) was high (250 cell profiles/mm 2 ) on postoperative days 1–3 and tapered off on day 5. Conclusion Seventy percent partial hepatectomy in healthy rats induces a rapid regenerative response and PODs 2, 4 and 8 seems optimal for assessing hepatic growth in future studies.

Background Sorafenib is a multikinase inhibitor with antiangiogenic and antiproliferative properties, approved for the treatment of hepatocellular carcinoma. The effect of Sorafenib on liver regeneration in healthy rats was investigated. Methods Sixty Wistar rats received either Sorafenib (group S; 15 mg/kg) or placebo for 14 days prior to resection and until sacrifice. After a 70% partial hepatectomy, the rats were euthanized on post-operative days (POD) 2, 4 or 8. Hepatocyte proliferation was estimated by immunohistochemistry for Ki-67 antigen using stereological methods on sections prepared by systematic uniform random sampling. Results Seven animals (12%) died after surgery. Death rates were similar in treated rats and controls. At hepatectomy, the body weight was significantly lower in group S rats. The liver weight and regeneration rates were lower in group S rats on PODs 2, 4 and 8. Hepatocyte proliferation was significantly lower in group S animals on PODs 2 and 4. Alanine aminotransferase ALAT was significantly higher in the Sorafenib-treated group on PODs 2, 4 and 8. Alkaline phosphatase ALP and bilirubin levels were similar in the two groups, although bilirubin was elevated in group S rats on POD 8. Conclusion In this rat model, Sorafenib did not increase post-hepatectomy mortality, but was associated with a significant impaired liver weight gain, regeneration rates and hepatocyte proliferation.

BACKGROUND: Although wound healing is a simple regenerative process that is critical after surgery, it has been shown to be impaired under psychological stress. The liver has a unique capacity to regenerate through highly complex mechanisms. The aim of this study was to investigate the effects of chronic stress, which may induce a depression-like state, on the complex process of liver regeneration in rats.METHODS: Twenty rats were included in this study. The animals received either a standard housing protocol or were subjected to a Chronic Mild Stress (CMS) stress paradigm. All rats underwent a 70 % partial hepatectomy (PHx). The animals were evaluated on postoperative day 2 or 4. Blood samples were collected to examine circulating markers of inflammation and liver cell damage. Additionally, liver tissues were sampled to evaluate liver weight and regeneration rate.RESULTS: None of the animals died during the study. There were no differences between in body weight, liver weight, liver regeneration rate or biochemical markers at any time during the study.CONCLUSION: The results of this study indicate that stress and the induction of depression-like state do not affect the process of liver regeneration after 70 % hepatectomy in rats.

Background: Multi-detector computed tomography (MDCT) has dramatically improved in recent years. In a previous study we suggested that diagnostic laparoscopy (DL) and laparoscopic ultrasonography (LUS) no longer should be mandatory in the work-up of patients with colorectal (CRC) liver metastases. The aim of the present study was to evaluate the clinical and economic consequences of such a strategy. Material/Methods: Seventy consecutive patients considered to have resectable liver metastases after MDCT were analysed. A pre-operative treatment strategy was in each case planned according to the result of the MDCT-scan. Patients considered to have incurable disease during operation were recorded, as were cases where the operative strategy had to be altered. For evaluating the economic and clinical consequences of adding a preoperative LUS, procedural and marginal cost effectiveness was calculated. Results: Seventy patients underwent laparotomy. Three patients (4%) were considered incurable peroperatively and in 15 cases (21%) the strategy had to be altered. The average cost for a successful LUS was EUR 2 394 and the marginal costs for supplementing every MDCT with a LUS were EUR 59 849. Conclusions: MDCT is sufficient and cost effective as the only preoperative work-up in patients with colorectal liver metastases.

Background: Many suggestions of how and when to assess the regenerated liver in animal models have been proposed. The aim of the present study was to evaluate the natural history of liver regeneration in healthy rats, regarding size, weight and functional capacity. The study was meant as a precursor for further interventional studies in healthy and cirrhotic animals.Material and Methods: Partial hepatectomy (PHx) of 70% was performed on 64 rats. After PHx the animals were randomised into 8 groups for evaluation. The animals in each group were evaluated on same postoperative day (POD) from POD 1 to 8. Results: At PHx the animals had a mean body weight of 238.4 g (211.4;286.5). Mean weight of resected liver was 6.25 g (5.2;7.3) and an estimated total liver weight of 8.9 g. Liver weight analysis showed an ascending curve, with max slope POD 1-3, reaching a steady state of ca 9 g on day 5-8. When correlated to body weight, through regeneration rate, a similar pattern was seen, with a RR of 100% reached day 5-8.Interleukin-6 (Il-6) peaked POD 1 and was falling to undetectable levels day 4. Alfa-2-Macroglobulin (α-2-M) levels were high POD 1-3 before falling to low levels. Tumor-necrosis-factor-alpha (Tnf-α) was undetectable throughout the period. At the moment functional capacity of the regenerating liver, is analysed by the enzymatic method BTR (Ratio of Branched-Chain Amino Acids to Tyrosine) Stereological aspects are looked into regarding KI-67 analysis and blood vessel density estimation, as is more serological markers (Alanin-amino-transferase, Bilirubin, Alkaline-phosfatase and Hepatocyte-growth-factor).Conclusion: Liver regeneration, regarding size and weight, were at top speed day 1-3. Full liver regeneration reached a plateau after 5-8 days, and should after this point be considered practically at end.Liver regeneration should in further studies be evaluated on postoperative day 1, 3 and 8.

Background: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is used to accelerate growth of the future liver remnant. We investigated alternative methods for increasing the future liver remnant. Methods: A total of 152 rats were randomized as follows: (1) sham; (2) portal vein ligation; (3) portal vein ligation/surgical split (ALPPS); (4) portal vein ligation/split of the liver with a radiofrequency ablation needle; (5) portal vein ligation/radiofrequency ablation of the deportalized liver (portal vein ligation/radiofrequency ablation necrosis in the deportalized liver); (6) portal vein ligation/radiofrequency ablation of the future liver remnant (portal vein ligation/radiofrequency ablation-future liver remnant); and (7) controls. Animals were evaluated on postoperative days 2 and 4. Bodyweight, liver parameters, hepatic regeneration rate, proinflammatory cytokines, hepatocyte proliferation, and gene expression were measured. Results: Hepatic regeneration rate indicated a steady increase in all intervention groups compared with sham rats (P < .001). At postoperative day 2, the hepatic regeneration rate was significantly higher in the portal vein ligation/radiofrequency ablation necrosis in the deportalized liver group than in the portal vein ligation group (P = .039). On postoperative day 4, we found significant differences between the portal vein ligation group and the ALPPS (P = .015), portal vein ligation/split of the liver with a radiofrequency ablation needle (P = .010), and portal vein ligation/radiofrequency ablation necrosis in the deportalized liver (P = .046) groups. Hepatocyte proliferation was significantly higher at all times compared with sham rats. On postoperative day 4, we found a significantly higher proliferation in groups 3, 4, 5, and 6 compared to portal vein ligation. Gene analysis revealed upregulation of genes involved in cellular proliferation and downregulation of genes involved in cellular homeostasis in all intervention groups. Between the intervention groups, gene expression was nearly identical. Biochemical markers and proinflammatory cytokines were comparable between groups. Conclusion: The surplus liver regeneration after ALPPS is probably mediated through parenchymal damage and subsequent release of growth stimulators, which again upregulates genes involved in cellular regeneration and downregulates genes involved in cellular homeostasis. We also demonstrate that growth of the future liver remnant, comparable to that seen after ALPPS, could be achieved by radiofrequency ablation treatment of the deportalized liver, that is, a procedure in which the initial step in humans can be performed percutaneously.

INTRODUCTION: The aim of this study was to investigate a single-electrode radio frequency ablation (RFA) needle as an instrument for liver resections with special emphasis on operation time, time of liver ischaemia, intra-operative blood loss and post-operative complications.MATERIAL AND METHODS: A total of 40 consecutive patients having a liver transection performed by an RFA single electrode from 1 September 2011 to 28 February 2012 were included in the study. Data concerning type of liver resection, liver parenchyma transection time, intraoperative bleeding and transfusions were prospectively recorded and registered. Furthermore, complications were recorded with special emphasis on bile fistulas and abscesses.RESULTS: In all, 20 females and 20 males had a liver resection performed by a single RFA electrode. The mean bleeding was 520 ml ± 469 ml, and the mean liver parenchyma transection time was 52 min. ± 22 min. Three patients, all of whom underwent major resections, received blood transfusions. Five patients developed bile fistulas and two abscesses. There were no re-operations for bleeding and no 30-day mortality.CONCLUSION: A single electrode RFA needle is a suitable tool for liver parenchyma transection with regard to operation time and intraoperative bleeding, but the frequency of bile leakage seems to be unacceptably high in cases of hemi-hepatectomies.FUNDING: The authors have no conflicts of interest or financial support to declare.TRIAL REGISTRATION: not relevant.

Background: Ischemic pre- and postconditioning protects the liver against ischemia/reperfusion injuries. The aim of the present study was to examine how ischemic pre- and postconditioning affects gene expression of hypoxia inducible factor 1a (HIF-1a), vascular endothelial growth factor A (VEGF-A) and transforming growth factor b (TGFb) in liver tissue. Methods: 28 rats were randomized into five groups: control; ischemia/reperfusion; ischemic preconditioning (IPC); ischemic postconditioning (IPO); combined IPC and IPO. IPC consisted of 10 min of ischemia and 10 min of reperfusion. IPO consisted of three cycles of 30 sec. reperfusion and 30 sec. of ischemia. Results: HIF-1a mRNA expression was significantly increased after liver ischemia compared to controls (p = 0.010). HIF-1a mRNA expression was significantly lower in groups subjected to IPC or combined IPC and IPO when compared to the ischemia/reperfusion group (p = 0.002). VEGF-A mRNA expression increased in the ischemia/ reperfusion or combined IPC and IPO groups when compared to the control group (p < 0.05). Conclusion: Ischemic conditioning seems to prevent HIF-1a mRNA induction in the rat liver after ischemia and reperfusion. This suggests that the protective effects of ischemic conditioning do not involve the HIF-1 system. On the other hand, the magnitude of the HIF-1a response might be a marker for the degree of I/R injuries after liver ischemia. Further studies are needed to clarify this issue. Background