No abstract

Dysregulation of Ca2+ has long been implicated to be important in cell injury. A Ca2+-linked process important in necrosis and apoptosis (or necrapoptosis) is the mitochondrial permeability transition (MPT). In the MPT, large conductance permeability transition (PT) pores open that make the mitochondrial inner membrane abruptly permeable to solutes up to 1500 Da. The importance of Ca2+ in MPT induction varies with circumstance. Ca2+ overload is sufficient to induce the MPT. By contrast after ischemia-reperfusion to cardiac myocytes, Ca2+ overload is the consequence of bioenergetic failure after the MPT rather than its cause. In other models, such as cytotoxicity from Reye-related agents and storage-reperfusion injury to liver grafts, Ca2+ appears to be permissive to MPT onset. Lastly in oxidative stress, increased mitochondrial Ca2+ and ROS generation act synergistically to product the MPT and cell death. Thus, the exact role of Ca2+ for inducing the MPT and cell death depends on the particular biologic setting.

Bacterial infections frequently occur early after liver transplantation. We recently reported significant progress with a synbiotic composition, consisting of one lactic acid bacteria (LAB) and one fiber, which reduced the infection rate from 48% (with selective bowel decontamination) to 13%. Now, our aim is to study if a combination of different LAB and fibers would further improve outcome.A prospective randomized double-blind trial was undertaken in 66 liver transplant recipients. All patients received enteral nutrition immediately postoperatively. Comparison was made between one group (A) receiving a composition of four LAB and four fibers and another group (B) receiving the fibers only. The treatment started the day before surgery and continued for 14 days. Thirty-day infection rate, length of hospital stay, duration of antibiotic therapy, noninfectious complications and side effects of enteral nutrition were recorded.The incidence of post-operative bacterial infections was significantly reduced; being 48% with only fibers and 3% with LAB and fibers. In addition, the duration of antibiotic therapy was significantly shorter in the latter group. In both groups, mainly mild or moderate infections occurred. Fibers and LAB were well tolerated.Early enteral nutrition supplemented with a mixture of LAB and fibers reduces bacterial infection rates following liver transplantation. Treatment with only fibers led to a low incidence of severe infections.

Early enteral nutrition supplemented with a mixture of LAB and fibers reduces bacterial infection rates and antibiotic therapy following PPPD.

Small rodents are the most used experimental models in liver surgical research. Hepatic resections in rodents are commonly performed to study liver regeneration, acute liver failure, hepatic metastasis, hepatic function, 'small-for-size' transplantation and metabolic response to injury. Most resections require only basic skills, are fast, reliable and highly reproducible. The partial hepatectomy technique in rodents can be improved by microsurgical techniques, which permit individualized dissection and ligature of the vascular and biliary branches with minimal operative morbidity and mortality. This is particularly relevant for murine models of liver resection. However, it requires advanced microsurgical skills. Here, we review the models, surgical techniques, results and limitations of partial liver resections in rodent models. We also reported for the first time segmentectomies of the median lobe in rodent models.

Graft failure after liver transplantation may involve mitochondrial dysfunction. We examined whether prevention of mitochondrial injury would improve graft function. Orthotopic rat liver transplantation was performed after 18 hours' cold storage in University of Wisconsin solution and treatment with vehicle, minocycline, tetracycline, or N-methyl-4-isoleucine cyclosporin (NIM811) of explants and recipients. Serum alanine aminotransferase (ALT), necrosis, and apoptosis were assessed 6 hours after implantation. Mitochondrial polarization and cell viability were assessed by intravital microscopy. Respiration and the mitochondrial permeability transition (MPT) were assessed in isolated rat liver mitochondria. After transplantation with vehicle or tetracycline, ALT increased to 5242 U/L and 4373 U/L, respectively. Minocycline and NIM811 treatment decreased ALT to 2374 U/L and 2159 U/L, respectively (P < 0.01). Necrosis and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) also decreased from 21.4% and 21 cells/field, respectively, after vehicle to 10.1% and 6 cells/field after minocycline and to 8.7% and 5.2 cells/field after NIM811 (P < 0.05). Additionally, minocycline decreased caspase-3 activity in graft homogenates (P < 0.05). Long-term graft survival was 27% and 33%, respectively, after vehicle and tetracycline treatment, which increased to 60% and 70% after minocycline and NIM811 (P < 0.05). In isolated mitochondria, minocycline and NIM811 but not tetracycline blocked the MPT. Minocycline blocked the MPT by decreasing mitochondrial Ca 2؉ uptake, whereas NIM811 blocks by interaction with cyclophilin D. Intravital microscopy showed that minocycline and NIM811 preserved mitochondrial polarization and cell viability after transplantation (P < 0.05). Conclusion: Minocycline and NIM811 attenuated graft injury after rat liver transplantation and improved graft survival. Minocycline and/or NIM811 might be useful clinically in hepatic surgery and transplantation. (HEPATOLOGY 2008;47:236-246.)

Right lobe living donor liver transplantation (LD-LTx) is currently performed at an increasing number of transplant centers. Donor selection, donor safety, donor recovery, and postdonation psychological impairment are essential criteria to determine whether and under which conditions LD-LTx is justifiable. Before commencing the LD-LTx program, approval was obtained from the local ethics committee. Potential donors underwent a comprehensive multistep evaluation protocol to exclude any conditions that could lead to an increased operative risk. Each donation was approved by the local Living Donation Commission. Follow-up investigations were performed after 6 and 12 months. Liver regeneration was assessed by computed tomography scan and magnetic resonance imaging scan derived volumetries. Quality of life (QOL) was investigated according to the Anamnestic Comparative Self-Assessment Scale (ACSA) before donation, and 6 and 12 months after donation. As of December 2001,43 right lobe living donations have been performed at the Charit& Campus Virchow, Berlin. None of the donors died or has suffered life-threatening or persisting complications. All patients recovered completely. Complications occured in 8 donors (18%). The incidence of perioperative surgical complications was g%, comprising temporary biliary leakages (n = 3; 6.8%) as well as postoperative bleeding (n = 1). Liver volume regeneration approximated 72% 2 15% of predonation volume by 6 months and 85% k 18% (mean 2 SD) by 12 months. There was no evidence of significant psychological impairment after donation. QOL increased after donation compared with the preoperative state (P < .OS). In our experience, LDLTx has proven to be a practicable and safe procedure. However, there is a considerable risk of postoperative complications. The donor selection process plays a pivotal role in preventing complications. The discussion of potential risks, especially potential life-threatening risks, must be an integral part of informed consent. (Liver Transpl2002;8:829-83%)

Zhong Z, Ramshesh VK, Rehman H, Currin RT, Sridharan V, Theruvath TP, Kim I, Wright GL, Lemasters JJ. Activation of the oxygen-sensing signal cascade prevents mitochondrial injury after mouse liver ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol 295: G823-G832, 2008. First published September 4, 2008 doi:10.1152/ajpgi.90287.2008.-The mitochondrial permeability transition (MPT) plays an important role in hepatocyte death caused by ischemia-reperfusion (IR). This study investigated whether activation of the cellular oxygen-sensing signal cascade by prolyl hydroxylase inhibitors (PHI) protects against the MPT after hepatic IR. Ethyl 3,4-dihyroxybenzoate (EDHB, 100 mg/kg ip), a PHI, increased mouse hepatic hypoxia-inducible factor-1␣ and heme oxygenase-1 (HO-1). EDHB-treated and untreated mice were subjected to 1 h of warm ischemia to ϳ70% of the liver followed by reperfusion. Mitochondrial polarization, cell death, and the MPT were assessed by intravital confocal/multiphoton microscopy of rhodamine 123, propidium iodide, and calcein. EDHB largely blunted alanine aminotransferase (ALT) release and necrosis after reperfusion. In vehicle-treated mice at 2 h after reperfusion, viable cells with depolarized mitochondria were 72%, and dead cells were 2%, indicating that depolarization preceded necrosis. Mitochondrial voids excluding calcein disappeared, indicating MPT onset in vivo. NIM811, a specific inhibitor of the MPT, blocked mitochondrial depolarization after IR, further confirming that mitochondrial depolarization was due to MPT onset. EDHB decreased mitochondrial depolarization to 16% and prevented the MPT. Tin protoporphyrin (10 mol/kg sc), an HO-1 inhibitor, partially abrogated protection by EDHB against ALT release, necrosis, and mitochondrial depolarization. In conclusion, IR causes the MPT and mitochondrial dysfunction, leading to hepatocellular death. PHI prevents MPT onset and liver damage through an effect mediated partially by HO-1. ethyl 3,4-dihyroxybenzoate; heme oxygenase; hepatic ischemia-reperfusion; mitochondrial permeability transition; prolyl hydroxylase inhibitor ISCHEMIA-REPERFUSION (IR) injury to the liver occurs in trauma, hemorrhagic and cardiac shock, vascular diseases, and hepatic surgery, including tumor resection and liver transplantation. A variety of pathophysiological processes likely contribute to development of IR injury. Reactive oxygen species (ROS) play a critical role in the injury caused by IR (18,36,57). ROS not only directly damage cell membranes, DNA, and protein; they also trigger formation of toxic cytokines and increase adhesion molecules leading to inflammatory responses, tissue damage, and multiple organ failure (1,10,17,41). Recently, growing evidence supports an important role of the mitochondrial permeability transition (MPT) in cell injury after IR (24,25,45,58). The mitochondrial membrane potential collapses when the MPT occurs, leading to failure of ATP synthesis, release of cytochrome c, and cell death (24,25,55). ROS cause opening of MPT pores (22...