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We describe four solid-organ transplant recipients with donor-derived West Nile virus (WNV) infection (encephalitis 3, asymptomatic 1) from a common donor residing in a region of increased WNV activity. All four transplant recipients had molecular evidence of WNV infection in their serum and/or cerebrospinal fluid (CSF) by reverse transcription polymerase chain reaction (RT-PCR) testing. Serum from the organ donor was positive for WNV IgM but negative for WNV RNA, whereas his lymph node and spleen tissues tested positive for WNV by RT-PCR. Combination therapy included intravenous immunoglobulin (4 cases), interferon (3 cases), fresh frozen plasma with WNV IgG (2 cases), and ribavirin (1 case). Two of the four transplant recipients survived.Review of the 20 published cases of organ-derived WNV infection found that this infection is associated with a high incidence of neuroinvasive disease (70%) and severe morbidity and mortality (30%). Median time to onset of symptomatic WNV infection was 13 days after transplantation (range 5-37 days). Initial unexplained fever unresponsive to antibiotic therapy followed by rapid onset of neurologic deficits was the most common clinical presentation. Confirmation of infection was made by testing serum and CSF for both WNV RNA by RT-PCR and WNV IgM by serological assays. Treatment usually included supportive care, reduction of immunosuppression, and frequent intravenous immunoglobulin. The often negative results for WNV by current RT-PCR and serological assays and the absence of clinical signs of acute infection in donors contribute to the sporadic occurrence of donor-derived WNV infection. Potential organ donors should be assessed for unexplained fever and neurological symptoms, particularly if they reside in areas of increased WNV activity.

Cyclooxygenase-2 (COX-2) is a mediator of hepatic ischemia and reperfusion injury (IRI). While both global COX-2 deletion and pharmacologic COX-2 inhibition ameliorate liver IRI, the clinical use of COX-2 inhibitors has been linked to increased risks of heart attack and stroke. Therefore, a better understanding of the role of COX-2 in different cell types may lead to improved therapeutic strategies for hepatic IRI. Macrophages of myeloid origin are currently considered to be important sources of the COX-2 in damaged livers. Here, we used a Cox-2flox conditional knockout mouse (COX-2-M/-M) to examine the function of COX-2 expression in myeloid cells during liver IRI. COX-2-M/-M mice and their WT control littermates were subjected to partial liver ischemia followed by reperfusion. COX-2-M/-M macrophages did not express COX-2 upon lipopolysaccharide stimulation and COX-2-M/-M livers showed reduced levels of COX-2 protein post-IRI. Nevertheless, selective deletion of myeloid cell-derived COX-2 failed to ameliorate liver IRI; serum transaminases and histology were comparable in both COX-2-M/-M and WT mice. COX-2-M/-M livers, like WT livers, developed extensive necrosis, vascular congestion, leukocyte infiltration and matrix metalloproteinase-9 (MMP-9) expression post-reperfusion. In addition, myeloid COX-2 deletion led to a transient increase in IL-6 levels after hepatic reperfusion, when compared to controls. Administration of celecoxib, a selective COX-2 inhibitor, resulted in significantly improved liver function and histology in both COX-2-M/-M and WT mice post-reperfusion, providing evidence that COX-2-mediated liver IRI is caused by COX-2 derived from a source(s) other than myeloid cells. In conclusion, these results support the view that myeloid COX-2, including myeloid-macrophage COX-2, is not responsible for the hepatic IRI phenotype.

Background & Aims: Organ shortage has led to the use of steatotic livers in transplantation, despite their elevated susceptibility to ischemia/reperfusion injury (IRI). Matrix metalloproteinase-9 (MMP-9), an inducible gelatinase, is emerging as a central mediator of leukocyte traffic into inflamed tissues. However, its role in steatotic hepatic IRI has yet to be demonstrated., Methods: We examined the function of MMP-9 in mice fed with a high-fat diet (HFD), which developed approximately 50% hepatic steatosis, predominantly macrovesicular, prior to partial hepatic IRI., Results: The inability of MMP-9(-/-) deficient steatotic mice to express MMP-9 significantly protected these mice from liver IRI. Compared to fatty controls, MMP-9(-/-) steatotic livers showed significantly reduced leukocyte infiltration, proinflammatory cytokine expression, and liver necrosis. Loss of MMP-9 activity preserved platelet endothelial cell adhesion molecule-1 (PECAM-1) expression, a modulator of vascular integrity at the endothelial cell-cell junctions in steatotic livers after IRI. Using in vitro approaches, we show that targeted inhibition of MMP-9 sheltered the extracellular portion of PECAM-1 from proteolytic processing, and disrupted leukocyte migration across this junctional molecule. Moreover, the evaluation of distinct parameters of regeneration, proliferating cell nuclear antigen (PCNA) and histone H3 phosphorylation (pH3), provided evidence that hepatocyte progression into S phase and mitosis was notably enhanced in MMP-9(-/-) steatotic livers after IRI., Conclusions: MMP-9 activity disrupts vascular integrity at least partially through a PECAM-1 dependent mechanism and interferes with regeneration of steatotic livers after IRI. Our novel findings establish MMP-9 as an important mediator of steatotic liver IRI., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Importance: While orthotopic liver transplantation (OLT) is a durable life-saving treatment for patients with irreversible liver disease, the waiting list mortality rate for children younger than 6 years is 4 times higher than for children aged 11 to 17 years and adults owing to scarce availability of size-appropriate grafts for transplantation., Objective: To compare long-term outcomes for children (aged ≤18 years) undergoing OLT using grafts from donation after circulatory death (DCD) and donation after brain death (DBD)., Design, Setting, and Participants: Retrospective study using case-control matched groups at a university transplant center. All patients aged 18 years and younger who underwent OLT using DCD organs between February 1, 1990, and November 30, 2010, at the University of California, Los Angeles, were matched in a 1 to 3 ratio with patients who received primary OLT from DBD donors within a 12-month period. Other matching criteria included recipient age, weight, cause of liver disease, and acuity of illness. Outcomes after OLT were compared for DCD (n = 7) and DBD (n = 21) donors. The median follow-up was 4.5 years., Main Outcomes and Measures: The primary outcome measure was graft failure-free survival; the secondary end point was the development of ischemic cholangiopathy., Results: Comparing DCD and DBD groups, recipient median age (28.4 vs 20.1 months, respectively; P = .80), weight (12.0 vs 11.6 kg, respectively; P = .87), Model for End-Stage Liver Disease/Pediatric End-Stage Liver Disease score (19 vs 11, respectively; P = .48), and donor age (24.0 vs 13.1 months, respectively; P = .72) were similar. For the DCD donors, the median donor warm ischemia duration was 24 minutes. Liver test results were similar for both groups at 1 week and 3, 6, and 12 months following OLT. Ten-year patient and graft survival rates for both DCD and DBD were 100%. Neither ischemic cholangiopathy nor vascular complications occurred in the DCD group. Biliary anastomotic strictures occurred in 1 DCD patient and 3 DBD patients., Conclusions and Relevance: Our study showed excellent long-term outcomes with liver transplantation in children using DCD organs. Use of liver grafts procured after circulatory death is an effective approach to expand the donor pool and remains an untapped resource for children with end-stage liver disease.

Background & Aims: The Keap1-Nrf2 signaling pathway regulates host cell defense responses against oxidative stress and maintains the cellular redox balance., Methods: We investigated the function/molecular mechanisms by which Keap1-Nrf2 complex may influence liver ischemia/reperfusion injury (IRI) in a mouse model of hepatic cold storage (20h at 4°C) followed by orthotopic liver transplantation (OLT)., Results: The Keap1 hepatocyte-specific knockout (HKO) in the donor liver ameliorated post-transplant IRI, evidenced by improved hepatocellular function and OLT outcomes (Keap1 HKO→Keap1 HKO; 100% survival), as compared with controls (WT→WT; 50% survival; p<0.01). By contrast, donor liver Nrf2 deficiency exacerbated IRI in transplant recipients (Nrf2 KO→Nrf2 KO; 40% survival). Ablation of Keap1 signaling reduced macrophage/neutrophil trafficking, pro-inflammatory cytokine programs, and hepatocellular necrosis/apoptosis, while simultaneously promoting anti-apoptotic functions in OLTs. At the molecular level, Keap1 HKO increased Nrf2 levels, stimulated Akt phosphorylation, and enhanced expression of anti-oxidant Trx1, HIF-1α, and HO-1. Pretreatment of liver donors with PI3K inhibitor (LY294002) disrupted Akt/HIF-1A signaling and recreated hepatocellular damage in otherwise IR-resistant Keap1 HKO transplants. In parallel in vitro studies, hydrogen peroxide-stressed Keap1-deficient hepatocytes were characterized by enhanced expression of Nrf2, Trx1, and Akt phosphorylation, in association with decreased release of lactate dehydrogenase (LDH) in cell culture supernatants., Conclusions: Keap1-Nrf2 complex prevents oxidative injury in IR-stressed OLTs through Keap1 signaling, which negatively regulates Nrf2 pathway. Activation of Nrf2 induces Trx1 and promotes PI3K/Akt, crucial for HIF-1α activity. HIF-1α-mediated overexpression of HO-1/Cyclin D1 facilitates cytoprotection by limiting hepatic inflammatory responses, and hepatocellular necrosis/apoptosis in a PI3K-dependent manner., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To analyze a 28-year single-center experience with orthotopic liver transplantation (OLT) for patients with irreversible liver failure., Background: The implementation of the model for end-stage liver disease (MELD) in 2002 represented a fundamental shift in liver donor allocation to recipients with the highest acuity, raising concerns about posttransplant outcome and morbidity., Methods: Outcomes and factors affecting survival were analyzed in 5347 consecutive OLTs performed in 3752 adults and 822 children between 1984 and 2012, including comparisons of recipient and donor characteristics, graft and patient outcomes, and postoperative morbidity before (n = 3218) and after (n = 2129) implementation of the MELD allocation system. Independent predictors of survival were identified., Results: Overall, 1-, 5-, 10-, and 20-year patient and graft survival estimates were 82%, 70%, 63%, 52%, and 73%, 61%, 54%, 43%, respectively. Recipient survival was best in children with biliary atresia and worst in adults with malignancy. Post-MELD era recipients were older (54 vs 49, P < 0.001), more likely to be hospitalized (50% vs 47%, P = 0.026) and receiving pretransplant renal replacement therapy (34% vs 12%, P < 0.001), and had significantly greater laboratory MELD scores (28 vs 19, P < 0.001), longer wait-list times (270 days vs 186 days, P < 0.001), and pretransplant hospital stays (10 days vs 8 days, P < 0.001). Despite increased acuity, post-MELD era recipients achieved superior 1-, 5-, and 10-year patient survival (82%, 70%, and 65% vs 77%, 66%, and 58%, P < 0.001) and graft survival (78%, 66%, and 61% vs 69%, 58%, and 51%, P < 0.001) compared with pre-MELD recipients. Of 17 recipient and donor variables, era of transplantation, etiology of liver disease, recipient and donor age, prior transplantation, MELD score, hospitalization at time of OLT, and cold and warm ischemia time were independent predictors of survival., Conclusions: We present the world's largest reported single-institution experience with OLT. Despite increasing acuity in post-MELD era recipients, patient and graft survival continues to improve, justifying the "sickest first" allocation approach.

Hepatic ischemia/reperfusion injury (IRI), an exogenous, antigen-independent, local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The nervous system maintains extensive crosstalk with the immune system through neuropeptide and peptide hormone networks. This study examined the function and therapeutic potential of the vasoactive intestinal peptide (VIP) neuropeptide in a murine model of liver warm ischemia (90 minutes) followed by reperfusion. Liver ischemia/reperfusion (IR) triggered an induction of gene expression of intrinsic VIP; this peaked at 24 hours of reperfusion and coincided with a hepatic self-healing phase. Treatment with the VIP neuropeptide protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture and was associated with elevated intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling. The hepatocellular protection rendered by VIP was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and increased hepatic interleukin-10 (IL-10) expression. Strikingly, PKA inhibition restored liver damage in otherwise IR-resistant VIP-treated mice. In vitro, VIP not only diminished macrophage tumor necrosis factor α/IL-6/IL-12 expression in a PKA-dependent manner but also prevented necrosis/apoptosis in primary mouse hepatocyte cultures. In conclusion, our findings document the importance of VIP neuropeptide-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to managing liver IRI in transplant patients., (© 2013 American Association for the Study of Liver Diseases.)

Background/introduction: Undifferentiated embryonal liver sarcoma (UELS) makes up 9% to 15% of all malignant liver tumors in children. UELS is characteristically diagnosed between the ages of 6 and 10 years and presents with abdominal pain, vomiting, and an abdominal mass. There is currently no standardized treatment for UELS except attempt at complete surgical resection. There have been only about 150 cases of UELS reported in the literature all with historically poor overall survival of <37.5% at 5 years. This report is one of the largest single-institution reports of UELS consisting of 5 patients over 2 decades. The purpose of this study is to characterize presentation and to report treatment success in UELS in children, adolescents, and young adults and the use of liver transplantation and, lastly, to suggest a use of positron emission tomography/computed tomography (PET/CT) in monitoring of this disease process., Methods: We conducted an Institutional Review Board-approved retrospective chart review. Data were collected from UELS patients younger than 21 years seen at the University of California Los Angeles over the past 20 years (January 2001 to September 2011). Descriptive analysis was conducted including multiple parameters of patient demographics, tumor characteristics, treatment modalities, and morbidity and mortality., Results: Five patients with UELS were identified. Patients initially presented with fever, abdominal pain, or nausea. Ages ranged from 10 to 19 years old (median age 13 y old), and there was a 4:1 male-to-female predominance. Tumor size ranged from 6 to 22 cm in largest diameter. One patient presented with metastatic disease to the lungs and heart and 1 patient recurred 2 years from diagnosis with bilateral paraspinal masses. Treatment included local control surgery with neoadjuvant and adjuvant chemotherapy with an anthracycline/alkylating agent combination. One patient with recurrent and refractory disease achieved local control with an orthotopic liver transplantation (OLT). Metastatic disease was controlled with surgery and radiation therapy. 18-Fluorodeoxyglucose PET/CT was a useful imaging tool for judging response to therapy with complete loss of metabolic activity in tumor after neoadjuvant chemotherapy in 2 representative cases. Although follow-up is short for some patients, overall survival in these 5 patients was 100% with follow-up ranging from 21 to 68 months. Disease-free survival ranged from 8 to 46 months with no patients with residual disease., Conclusions: UELS is an aggressive high-grade primary liver sarcoma with high metastatic potential. This report represents one of the largest single-institution studies of UELS. Using multimodality therapy, patients have achieved 100% overall survival even in the setting of extensive disease, metastases, and recurrence. In cases of unresectable primary tumor or recurrent and refractory disease isolated to the liver, OLT is a potential therapeutic option. We report success with adjuvant chemotherapy and complete surgical resection with OLT as an alternative in unresectable or refractory cases. We also suggest a possible utility of PET/CT in monitoring treatment response in this disease.

Unlabelled: Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), an adaptor protein for inflammasome receptors, is essential for inducing caspase-1 activation and the consequent secretion of interleukin-1β (IL-1β), which is associated with local inflammation during liver ischemia/reperfusion injury (IRI). However, little is known about the mechanisms by which the ASC/caspase-1/IL-1β axis exerts its function in hepatic IRI. This study was designed to explore the functional roles and molecular mechanisms of ASC/caspase-1/IL-1β signaling in the regulation of inflammatory responses in vitro and in vivo. With a partial lobar liver warm ischemia (90 minutes) model, ASC-deficient and wild-type mice (C57BL/6) were sacrificed at 6 hours of reperfusion. Separate animal cohorts were treated with an anti-IL-1β antibody or control immunoglobulin G (10 mg/kg/day intraperitoneally). We found that ASC deficiency inhibited caspase-1/IL-1β signaling and led to protection against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic functions, and down-regulation of high mobility group box 1 (HMGB1)-mediated, toll-like receptor 4 (TLR4)-driven inflammation. Interestingly, the treatment of ASC-deficient mice with recombinant HMGB1 re-created liver IRI. Moreover, neutralization of IL-1β ameliorated the hepatocellular damage by inhibiting nuclear factor kappa B (NF-κB)/cyclooxygenase 2 signaling in IR-stressed livers. In parallel in vitro studies, the knockout of ASC in lipopolysaccharide-stimulated bone marrow-derived macrophages depressed HMGB1 activity via the p38 mitogen-activated protein kinase pathway and led to the inhibition of TLR4/NF-κB and ultimately the depression of proinflammatory cytokine programs., Conclusion: ASC-mediated caspase-1/IL-1β signaling promotes HMGB1 to produce a TLR4-dependent inflammatory phenotype and leads to hepatocellular injury. Hence, ASC/caspase-1/IL-1β signaling mediates the inflammatory response by triggering HMGB1 induction in hepatic IRI. Our findings provide a rationale for a novel therapeutic strategy for managing liver injury due to IR., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Background: Despite recent advances in intestinal transplantation (ITx), infection (INF) and acute cellular rejection (ACR) remain major causes of patient and graft loss. Studies in other solid-organ transplantations indicate that low levels of serum immunoglobulin G (IgG) negatively impact outcomes. To date, there have been no studies on IgG after ITx., Methods: A retrospective review of an IgG measurement protocol in primary ITx recipients between 2007 and 2011 was undertaken. IgG levels were measured at the time of evaluation, transplantation, and at weekly intervals for 2 months. Hypogammaglobulinemia (HGG) was defined as IgG levels below the lower limit of the 95% confidence interval for age. Associations between HGG, INF, and ACR were tested, and the incidence and timing of INF and ACR were compared., Results: Thirty-four patients were transplanted at a mean (SD) age of 12.4 (17.2) years. Most were Latino children with gastroschisis who received multivisceral grafts. Relative to pre-ITx levels, a statistically significant decrease in IgG levels was observed after ITx (P<0.05). Twenty patients (59%) developed HGG during the post-ITx period at a mean (SD) of 9.8 days. No significant associations were identified between HGG and INF or ACR., Conclusions: This is the first study to describe serum IgG levels after ITx. A marked decrease in serum IgG levels was observed early on, in most patients. The etiology is potentially related to immunotherapy. HGG was not associated with INF or ACR, possibly related to the sample size and our practice of exogenous intravenous immunoglobulin replacement.

Unlabelled: Hepatocellular carcinoma (HCC) is the fifth most common malignancy and is the third leading cause of cancer death worldwide. Recently, the multitargeted kinase inhibitor sorafenib was shown to be the first systemic agent to improve survival in advanced HCC. Unlike other malignancies such as breast cancer, in which molecular subtypes have been clearly defined (i.e., luminal, HER2 amplified, basal, etc.) and tied to effective molecular therapeutics (hormone blockade and trastuzumab, respectively), in HCC this translational link does not exist. Molecular profiling studies of human HCC have identified unique molecular subtypes of the disease. We hypothesized that a panel of human HCC cell lines would maintain molecular characteristics of the clinical disease and could then be used as a model for novel therapeutics. Twenty human HCC cell lines were collected and RNA was analyzed using the Agilent microarray platform. Profiles from the cell lines in vitro recapitulate previously described subgroups from clinical material. Next, we evaluated whether molecular subgroup would have predictive value for response to the Src/Abl inhibitor dasatinib. The results demonstrate that sensitivity to dasatinib was associated with a progenitor subtype. Dasatinib was effective at inducing cell cycle arrest and apoptosis in "progenitor-like" cell lines but not in resistant lines., Conclusion: These findings suggest that cell line models maintain the molecular background of HCC and that subtype may be important for selecting patients for response to novel therapies. In addition, it highlights a potential role for Src family signaling in this progenitor subtype of HCC., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Background: Blood loss during liver transplantation is not incorporated into the dominant models for post-transplant survival. Our objective was to investigate blood transfusion requirement as a risk factor for mortality after liver transplantation, and to further analyze risk factors for intraoperative blood transfusion requirement and hepatectomy time., Study Design: We conducted a retrospective analysis of 233 consecutive liver transplant recipients over a span of 3 years by a single experienced surgeon. Mean follow-up was 2.5 years. Independent risk factors for patient survival after liver transplantation were identified using Cox proportion hazard regression. Independent risk factors for intraoperative blood transfusion requirement and hepatectomy time were identified using logistic regression., Results: Two factors were identified as significant predictors in multivariate analysis for survival after liver transplantation: hepatocellular carcinoma (hazard ratio [HR] 1.9, 95% CI 1.1 to 3.2) and intraoperative blood transfusion requirement per unit (HR 1.01, 95% CI 1.0 to 1.02). Threshold analysis revealed that intraoperative blood transfusion volume ≥28 units or 85(th) percentile (HR 2.5, 95% CI 1.3 to 4.7) was a significant risk factor for patient survival. Four covariates were identified as significant risk factors for intraoperative blood requirement: warm ischemia time (odds ratio [OR] 1.12, 95% CI 1.06 to 1.18), bilirubin (OR 1.04, 95% CI 1.02 to 1.08), previous surgery (OR 1.7, 95% CI 1.02 to 2.9), and hepatectomy time (OR 1.01, 95% CI 1.00 to 1.02). The only risk factor for prolonged hepatectomy time was previous major abdominal surgery (OR 4.0, 95% CI 1.7 to 9.5)., Conclusions: Intraoperative blood transfusion requirement is an important risk factor for mortality after liver transplantation. The strongest risk factors for intraoperative blood transfusion requirement are warm ischemia time and bilirubin levels. Intraoperative blood loss and its risk factors should be incorporated into models to predict survival after liver transplantation., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Our aim was to analyze our single-center experience with orthotopic liver transplantation for metabolic lethal genetic syndromes in children and adults., Study Design: From 1984 to 2012, all pediatric (younger than 18 years) and adult (18 years and older) patients who underwent orthotopic liver transplantation for lethal genetic disorders were identified. Data on diagnostic pathways and specific outcomes were analyzed for both groups. Outcomes measures included recurrence rate as well as graft and patient survival., Results: Metabolic lethal genetic syndrome was the primary indication for orthotopic liver transplantation in 152 of 4,564 patients (3.3%) at University of California, Los Angeles during the study period (74 pediatric patients and 78 adults). Genetic testing was performed in only 12% of the 152 patients and in 39% of patients after 2006. Two patients (1.3%) experienced a recurrence of the genetic disease. Overall 5- and 20-year survival rates were 89% and 77% for children and 73% and 50% for adults. Survival of pediatric patients was superior to adults (log-rank p < 0.009). Multivariate analysis identified age (hazard ratio = 2.18), preoperative life support (hazard ratio = 2.68), and earlier transplantation (hazard ratio = 3.41) as independent predictors of reduced survival., Conclusions: Orthotopic liver transplantation achieved excellent long-term survival in pediatric and adult patients with lethal genetic syndromes and represents a model of personalized genomic medicine by providing gene therapy through solid organ transplantation., (Copyright © 2013 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

An accurate clinical assessment of hepatic steatosis before transplantation is critical for successful outcomes after liver transplantation, especially if a pathologist is not available at the time of procurement. This prospective study investigated the surgeon's accuracy in predicting hepatic steatosis and organ quality in 201 adult donor livers. A steatosis assessment by a blinded expert pathologist served as the reference gold standard. The surgeon's steatosis estimate correlated more strongly with large-droplet macrovesicular steatosis [ld-MaS; nonparametric Spearman correlation coefficient (rS ) = 0.504] versus small-droplet macrovesicular steatosis (sd-MaS; rS  = 0.398). True microvesicular steatosis was present in only 2 donors (1%). Liver texture criteria (yellowness, absence of scratch marks, and round edges) were mainly associated with ld-MaS (variance = 0.619) and were less associated with sd-MaS (variance = 0.264). The prediction of ≥30% ld-MaS versus <30% ld-MaS was excellent when liver texture criteria were used (accuracy = 86.2%), but it was less accurate when the surgeon's direct estimation of the steatosis percentage was used (accuracy = 75.5%). The surgeon's quality grading correlated with the degree of ld-MaS and the surgeon's steatosis estimate as well as the incidence of poor initial function and primary nonfunction. In conclusion, the precise estimation of steatosis remains challenging even in experienced hands. Liver texture characteristics are more helpful in identifying macrosteatotic organs than the surgeon's actual perception of steatosis. These findings are especially important when histological assessment is not available at the donor's hospital., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Importance: Since the 1980s, pancreas transplant has become the most effective treatment strategy to restore euglycemia in patients with type 1 diabetes mellitus. However, technical complications and BK virus nephropathy continue to be important causes of early and late graft loss. These and other complications lead to cited 1- and 3-year graft survival rates of 74% and 67% (pancreas) and 81% and 73% (kidney)., Objective: To examine our center's outcomes with pancreas-kidney transplant and early BK virus screening and treatment., Design: Prospective study from August 2004 to January 2012., Setting: University medical center., Participants: Sixty-five patients with type 1 diabetes who underwent simultaneous kidney and pancreas, pancreas after kidney, or pancreas transplant alone at a single center., Intervention: Pancreas transplant., Main Outcome Measures: Pancreas and kidney survival; patient survival; and kidney loss due to BK virus nephropathy., Results: Patient survival at 1, 3, and 5 years was 100%, 98.4%, and 98.4%, respectively. Of 2 early pancreatic allograft losses, 1 was due to thrombosis (1.6%). One- and 5-year pancreas graft survival rates were 95.4% and 92.3%; losses after more than 1 year were due to rejection. Kidney survival rates were 100% and 95.2% at 1 and 5 years; losses were due to nephropathy and noncompliance, with 1 death with function. BK virus incidence was 29.2%, with no graft losses due to BK infection., Conclusions and Relevance: While pancreas transplant can be complicated by early graft loss, our results suggest that excellent outcomes at 5 years can be achieved. Posttransplant BK virus screening and treatment are essential tools to long-term success.

Unlabelled: Dendritic cells (DCs) are critical mediators of immune responses that integrate signals from the innate immune system to orchestrate adaptive host immunity. This study was designed to investigate the role and molecular mechanisms of STAT3-induced β-catenin in the regulation of DC function and inflammatory responses in vitro and in vivo. STAT3 induction in lipopolysaccharide (LPS)-stimulated mouse bone marrow-derived DCs (BMDCs) triggered β-catenin activation by way of GSK-3β phosphorylation. The activation of β-catenin inhibited phosphatase and tensin homolog delete on chromosome 10 (PTEN) and promoted the phosphoinositide 3-kinase (PI3K)/Akt pathway, which in turn down-regulated DC maturation and function. In contrast, knockdown of β-catenin increased PTEN/TLR4 (Toll-like receptor 4), interferon regulatory factor-3 (IRF3), nuclear factor kappa B (NF-κB) activity, and proinflammatory cytokine programs in response to LPS stimulation. In a mouse model of warm liver ischemia and reperfusion injury (IRI), disruption of β-catenin signaling increased the hepatocellular damage, enhanced hepatic DC maturation/function, and PTEN/TLR4 local inflammation in vivo., Conclusion: These findings underscore the role of β-catenin to modulate DC maturation and function at the innate-adaptive interface. Activation of β-catenin triggered PI3K/Akt, which in turn inhibited TLR4-driven inflammatory response in a negative feedback regulatory mechanism. By identifying the molecular pathways by which β-catenin regulates DC function, our findings provide the rationale for novel therapeutic approaches to manage local inflammation and injury in IR-stressed liver., (Copyright © 2012 American Association for the Study of Liver Diseases.)

The aim of this study was to determine the prognostic value of complete tumor encapsulation as visualized on magnetic resonance imaging (MRI) in patients with a solitary large hepatocellular carcinoma (HCC) beyond the Milan criteria for liver transplantation (LT). Between December 2000 and March 2011, 57 patients who had a solitary HCC exceeding 5 cm in diameter at the time of initial MRI before any treatment were identified. MRI images of the patients were independently reviewed by 2 experienced readers for the presence of complete tumoral encapsulation. The medical records of the patients were reviewed for an outcome analysis. Thirty of the 57 patients had completely encapsulated HCC according to MRI. There was excellent interobserver agreement between the 2 readers for the assessment of complete encapsulation (κ=0.86). Overall survival was significantly longer for patients with completely encapsulated HCC versus patients with incompletely or nonencapsulated tumors (P<0.001), and this included a subanalysis of 33 patients who received locoregional treatment (LRT; P=0.04). The presence of complete encapsulation was a strong predictor for survival in these patients according to both univariate [hazard ratio (HR)=0.24, 95% confidence interval (CI)=0.12-0.52, P<0.001] and multivariate analyses (HR=0.25, 95% CI=0.07-0.85, P=0.03). The rates of down-staging (P<0.001) and eventual LT (P=0.02) after LRT were also significantly higher in the patients with completely encapsulated tumors. In conclusion, complete tumor encapsulation on MRI is a potentially useful predictor for favorable biology in patients with a solitary large HCC. This new imaging biomarker may have a role in treatment selection for patients whose tumors exceed the Milan criteria size limits., (Copyright © 2013 American Association for the Study of Liver Diseases.)

Unlabelled: Hepatic ischemia and reperfusion injury (IRI), an exogenous antigen-independent local inflammation response, occurs in multiple clinical settings, including liver transplantation, hepatic resection, trauma, and shock. The immune system and the nervous system maintain extensive communication and mount a variety of integrated responses to danger signals through intricate chemical messengers. This study examined the function and potential therapeutic potential of neuropeptide pituitary adenylate cyclase-activating polypeptides (PACAP) in a murine model of partial liver "warm" ischemia (90 minutes) followed by reperfusion. Liver IRI readily triggered the expression of intrinsic PACAP and its receptors, whereas the hepatocellular damage was exacerbated in PACAP-deficient mice. Conversely, PACAP27, or PACAP38 peptide monotherapy, which elevates intracellular cyclic adenosine monophosphate/protein kinase A (cAMP-PKA) signaling, protected livers from IRI, as evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. The liver protection rendered by PACAP peptides was accompanied by diminished neutrophil/macrophage infiltration and activation, reduced hepatocyte necrosis/apoptosis, and selectively augmented hepatic interleukin (IL)-10 expression. Strikingly, PKA inhibition readily restored liver damage in otherwise IR-resistant, PACAP-conditioned mice. In vitro, PACAP treatment not only diminished macrophage tumor necrosis factor alpha/IL-6/IL-12 levels in a PKA-dependent manner, but also prevented necrosis and apoptosis in primary mouse hepatocyte cultures., Conclusion: Our novel findings document the importance of PACAP-mediated cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. Because the enhancement of neural modulation differentially regulates local inflammation and prevents hepatocyte death, these results provide the rationale for novel approaches to manage liver inflammation and IRI in transplant patients., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Ischaemia-reperfusion injury (IRI) in the liver, a major complication of haemorrhagic shock, resection and transplantation, is a dynamic process that involves the two interrelated phases of local ischaemic insult and inflammation-mediated reperfusion injury. This Review highlights the latest mechanistic insights into innate-adaptive immune crosstalk and cell activation cascades that lead to inflammation-mediated injury in livers stressed by ischaemia-reperfusion, discusses progress in large animal experiments and examines efforts to minimize liver IRI in patients who have received a liver transplant. The interlinked signalling pathways in multiple hepatic cell types, the IRI kinetics and positive versus negative regulatory loops at the innate-adaptive immune interface are discussed. The current gaps in our knowledge and the pathophysiology aspects of IRI in which basic and translational research is still required are stressed. An improved appreciation of cellular immune events that trigger and sustain local inflammatory responses, which are ultimately responsible for organ injury, is fundamental to developing innovative strategies for treating patients who have received a liver transplant and developed ischaemia-reperfusion inflammation and organ dysfunction.

Unlabelled: The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) regulates innate immune responses inversely with phosphoinositide 3-kinase (PI3K) and its direct downstream target gene, Akt. The Forkhead box O (Foxo) transcription factors are essential in the regulation of tissue development, immune homeostasis, and cell survival. This study was designed to investigate the role of PTEN-mediated Akt/β-catenin/Foxo1 signaling in the regulation of in vivo and in vitro innate immune responses in a mouse model of hepatic inflammatory injury induced by 90 minutes of liver partial warm ischemia followed by 6 hours of reperfusion. We found that knockdown of PTEN with small interfering RNA (siRNA) promoted Akt/β-catenin/Foxo1 signaling, leading to resistance against liver ischemia/reperfusion (IR) damage, local enhancement of antiapoptotic function, and downregulation of innate Toll-like receptor 4 (TLR4) expression. A specific PI3K blockade inhibited Akt/β-catenin signaling, increased Foxo1-mediated TLR4-driven local inflammation, and recreated cardinal features of liver IR injury. Moreover, knockdown of PTEN in lipopolysaccharide-stimulated mouse bone marrow-derived macrophages enhanced β-catenin activity, which in turn provided a negative regulatory feedback to the Foxo1 function, leading to the inhibition of TLR4 and NF-κB, with ultimate depression of proinflammatory cytokine programs in vitro., Conclusion: Our novel findings identify the PTEN-mediated Akt/β-catenin/Foxo1 axis as a key regulator of innate inflammatory response in the mouse liver. By identifying molecular mechanisms of PTEN-mediated Akt/β-catenin/Foxo1 signaling in TLR4 innate immune regulation, our study provides a rationale for therapeutic approaches to manage inflammation injury in IR-stressed liver., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Hepatic injury due to cold storage followed by reperfusion remains a major cause of morbidity and mortality after orthotopic liver transplantation (OLT). CD4 T cell TIM-1 signaling costimulates a variety of immune responses in allograft recipients. This study analyzes mechanisms by which TIM-1 affects liver ischemia-reperfusion injury (IRI) in a murine model of prolonged cold storage followed by OLT. Livers from C57BL/6 mice, preserved at 4°C in the UW solution for 20 h, were transplanted to syngeneic recipients. There was an early (1 h) increased accumulation of TIM-1+ activated CD4 T cells in the ischemic OLTs. Disruption of TIM-1 signaling with a blocking mAb (RMT1-10) ameliorated liver damage, evidenced by reduced sALT levels and well-preserved architecture. Unlike in controls, TIM-1 blockade diminished OLT expression of Tbet/IFN-γ, but amplified IL-4/IL-10/IL-22; abolished neutrophil and macrophage infiltration/activation and inhibited NF-κB while enhancing Bcl-2/Bcl-xl. Although adoptive transfer of CD4 T cells triggered liver damage in otherwise IR-resistant RAG(-/-) mice, adjunctive TIM-1 blockade reduced Tbet transcription and abolished macrophage activation, restoring homeostasis in IR-stressed livers. Further, transfer of TIM-1(Hi) CD4+, but not TIM-1(Lo) CD4+ T cells, recreated liver IRI in RAG(-/-) mice. Thus, TIM-1 expressing CD4 T cells are required in the mechanism of innate immune-mediated hepatic IRI in OLTs., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Antithymocyte therapy, specifically antithymocyte globulin (ATG; Thymoglobulin), is increasingly being used in organ transplantation to reduce allograft rejection. The T-lymphocyte has been purported to also play a role in ischemia and reperfusion injury (IRI); however, it has not been well studied. Our aim is to determine if ATG treatment impacts murine intestinal IRI., Methods: Under anesthesia, male C57BL6 mice underwent 100 minutes of warm intestinal IRI by clamping the superior mesenteric artery. The treatment group received rabbit anti-murine ATG (10 mg/kg) intraperitoneally 6 hours before IRI. Separate survival and analysis groups were performed. Intestinal tissue was procured at 4 and 24 hours after IRI. Tissue analysis included hematoxylin-eosin staining, CD3, CD4, and CD8 immunostaining, myeloperoxidase assay (MPO), quantitative real-time polymerase chain reaction studies, and Western blot., Results: ATG treatment led to marked improvement in 7-day survival and a reduction in tissue injury by histology. MPO was also reduced, and immunostaining confirmed a significant reduction in CD3(+), CD4(+), and CD8(+) infiltrating cells in the treatment group. Quantitative real-time polymerase chain reaction analysis revealed the decreased expression of tumor necrosis factor-α, interferon-inducible protein 10, monocyte chemotactic protein-1, interferon-γ, interleukin-2, and increased production of interleukins -13 and -10 in the treatment group. Western blot analysis revealed decreased caspase-3 and increased signal transducer and activator of transcription 6 levels in the ATG-treated group., Conclusion: This study is the first to show that ATG treatment ameliorates intestinal IRI. Treatment with ATG leads to reduced local infiltration by T-lymphocytes, with fewer inflammatory and chemotactic programs and less apoptosis. Treatment also is associated with a T(H)2-type cytokine switch. These novel findings suggest that T-lymphocytes represent important mediators of intestinal IRI and that ATG therapies may be beneficial in the prevention of IRI., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: Alterations in the central nervous system in patients with acute liver failure (ALF) present unique challenges in the perioperative period. In this retrospective study, we examined pretransplant neurological presentation and the incidence, clinical presentation, and risk factors associated with severe posttransplant brain injury (BI) in ALF patients undergoing orthotopic liver transplantation (OLT)., Methods: After institutional review board approval, ALF patients who underwent OLT between 2004 and 2010 at our center were reviewed. Pretransplant neurological presentation and severe posttransplant BI were examined. Risk factors for the latter were identified., Results: During the study period, 90 (67 adults and 23 children) ALF patients underwent primary OLT. Preoperatively, all patients developed encephalopathy, 6 had seizure activity, 32 had radiological evidence of cerebral edema, and 11 had severe cerebral edema. After OLT, 7 patients developed severe posttransplant BI. Of these 7 patients, 4 had brain death, and 3 had irreversible injury that precluded them from living independently. Severe pretransplant cerebral edema and a higher posttransplant international normalized ratio (odds ratios and 95% confidence intervals: 50.2, 5.8-433.5 [P<0.001] and 3.1, 1.1-8.8 [P=0.031], respectively) were risk factors associated with severe posttransplant BI., Conclusions: Pretransplant neurological complications were prevalent, and severe posttransplant BI occurred at a rate of 7.8% and was significantly associated with severe pretransplant cerebral edema and postoperative international normalized ratio. Our findings support the use of pretransplant computed tomography. If severe pretransplant cerebral edema is confirmed, efforts should be made to aggressively control intracranial pressure and select a proper donor to minimize the risk of severe posttransplant BI and futile transplantation.

Background: Recent studies suggest that the storage age of red blood cells (RBCs) may be associated with morbidity and mortality in surgical patients. We studied perioperative effects of RBC storage age in patients undergoing orthotopic liver transplant (OLT)., Methods: Adult patients who received ≥ 5 U of RBCs during OLT between January 2004 and June 2009 were studied. The subjects were divided into two groups according to the mean storage age of RBCs they received: new or old RBCs (stored ≤ 14 or >14 days, respectively). Effects of storage age of transfused RBCs during OLT on intraoperative potassium (K(+)) concentrations, incidence of hyperkalemia (K(+) ≥ 5.5 mmol/L), postoperative morbidity, and patient and graft survival were studied., Results: The mean serum K(+) concentrations and the incidence of hyperkalemia during OLT were significantly associated with storage age of the RBCs. Logistic analysis showed that storage age of RBCs was an independent risk factor for intraoperative hyperkalemia (odds ratios 1.067-1.085, p < 0.001) in addition to baseline K(+) concentration and units of RBCs transfused. Patient and graft survival and postoperative morbidity including postoperative ventilation, reoperation, acute renal dysfunction defined by the RIFLE criteria was not associated with old RBCs., Conclusions: Transfusion of RBCs stored for a longer time was associated with intraoperative hyperkalemia but not with postoperative adverse outcomes in adult OLT. Prevention and treatment of potentially harmful hyperkalemia should be considered when old RBCs are administered.

Liver ischemia-reperfusion injury (IRI) remains a challenging problem in clinical settings. The expression of fibronectin (FN) by endothelial cells is a prominent feature of the hepatic response to injury. Here we investigate the effects of the connecting segment-1 (CS-1) peptide therapy, which blocks FN-α4β1 integrin leukocyte interactions, in a well-established model of 24-h cold liver IRI. CS-1 peptides significantly inhibited leukocyte recruitment and local release of proinflammatory mediators (COX-2, iNOS and TNF-α), ameliorating liver IRI and improving recipient survival rate. CS1 therapy inhibited the phosphorylation of p38 MAPK, a kinase linked to inflammatory processes. Moreover, in addition to downregulating the expression of matrix metalloproteinase-9 (MMP-9) in hepatic IRI, CS-1 peptide therapy depressed the expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) by macrophages, a membrane-tethered MMP important for focal matrix proteolysis. Inhibition of p38 MAPK activity, with its pharmacological antagonist SB203580, downregulated MMP-9 and MT1-MMP/MMP-14 expressions by FN-stimulated macrophages, suggesting that p38 MAPK kinase pathway controls FN-mediated inductions of MMP-9 and MT1-MMP/MMP-14. Hence, this study provides new insights on the role of FN in liver injury, which can potentially be applied to the development of new pharmacological strategies for the successful protection against hepatic IRI., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Objective: To analyze incidence, outcomes, and utilization of health care resources in liver transplantation (LT) for nonalcoholic steatohepatitis (NASH)., Summary of Background Data: With the epidemic of obesity and metabolic syndrome in nearly 33% of the US population, NASH is projected to become the leading indication for LT in the next several years. Data on predictors of outcome and utilization of health care resources after LT in NASH is limited., Methods: We conducted an analysis from our prospective database of 144 adult NASH patients who underwent LT between December 1993 and August 2011. Outcomes and resource utilization were compared with other common indications for LT. Independent predictors of graft and patient survival were identified., Results: The average Model for End-Stage Liver Disease score was 33. The frequency of NASH as the primary indication for LT increased from 3% in 2002 to 19% in 2011 to become the second most common indication for LT at our center behind hepatitis C. NASH patients had significantly longer operative times (402 vs 322 minutes; P < 0.001), operative blood loss (18 vs 14 packed red blood cell units; P = 0.001), and posttransplant length of stay (35 vs 29 days; P = 0.032), but 1-, 3-, and 5-year graft (81%, 71%, 63%) and patient (84%, 75%, 70%) survival were comparable with other diagnoses. Age greater than 55 years, pretransplant intubation, dialysis, hospitalization, presence of hepatocellular carcinoma on explant, donor age greater than 55 years, and cold ischemia time greater than 550 minutes were significant independent predictors of survival for all patients, whereas body mass index greater than 35 was a predictor in NASH patients only., Conclusions: We report the largest single institution experience of LT for NASH. Over a 10-year period, the frequency of LT for NASH has increased 5-fold. Although outcomes are comparable with LT for other indications, health care resources are stressed significantly by this new and increasing group of transplant candidates.

Unlabelled: Hepatic ischemia and reperfusion injury (IRI) remains an important challenge in clinical orthotopic liver transplantation (OLT). Tissue inhibitor of metalloproteinase-1 (TIMP-1) is the major endogenous regulator of matrix metalloproteinase-9 (MMP-9). In this study we investigated the functional significance of TIMP-1 expression in a well-established mouse model of partial liver IRI. Compared to wildtype mice, TIMP-1(-/-) mice showed further impaired liver function and histological preservation after IRI. Notably, TIMP-1 deficiency led to lethal liver IRI, as over 60% of the TIMP-1(-/-) mice died postreperfusion, whereas all TIMP-1(+/+) mice recovered and survived surgery. Lack of TIMP-1 expression was accompanied by markedly high levels of MMP-9 activity, which facilitates leukocyte transmigration across vascular barriers in hepatic IRI. Indeed, TIMP-1(-/-) livers were characterized by massive leukocyte infiltration and by up-regulation of proinflammatory mediators, including tumor necrosis factor alpha, interferon-gamma, and inducible nitric oxide synthase post-IRI. The inability of TIMP-1(-/-) mice to express TIMP-1 increased the levels of active caspase-3 and depressed the expression of Bcl-2 and the phosphorylation of Akt, emphasizing an important role for TIMP-1 expression on hepatocyte survival. Using independent parameters of regeneration, 5-bromodeoxyuridine incorporation, proliferating cell nuclear antigen expression, and histone H3 phosphorylation, we provide evidence that hepatocyte progression into S phase and mitosis was impaired in TIMP-1-deficient livers after IRI. Inhibition of the cell cycle progression by TIMP-1 deficiency was linked to depressed levels of cyclins-D1 and -E and to a disrupted c-Met signaling pathway, as evidenced by reduced phosphorylated c-Met expression and elevated c-Met ectodomain shedding postliver IRI., Conclusion: These results support a critical protective function for TIMP-1 expression on promoting survival and proliferation of liver cells and on regulating leukocyte recruitment and activation in liver IRI., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Although endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of organ ischemia-reperfusion injury (IRI), the underlying mechanisms have yet to be fully elucidated. In particular, because tissue proinflammatory immune response is the key mediator of local IRI, how ER stress impacts liver immune cell activation cascade remains to be determined., Methods: In vitro, ER stress in macrophages and hepatocytes were induced by pharmacological agents. Macrophage Toll-like receptor 4 and hepatocyte tumor necrosis factor α responses were studied. In vivo, the induction of ER stress by ischemia-reperfusion and the impact of ER stress amelioration by a small molecule chaperon 4-phenylbutyric acid on liver immune response were studied in a murine partial liver warm ischemia model., Results: ER-stressed macrophages generated a significantly enhanced proinflammatory immune response against Toll-like receptor 4 stimulation, whereas ER-stressed hepatocytes became more susceptible to tumor necrosis factor α-induced cell death. Ischemia-reperfusion resulted in up-regulations of spliced X-box binding protein 1 and activating transcription factor 6 levels in affected livers. Mice pretreated with 4-phenylbutyric acid were protected from liver IRI, in parallel with diminished local proinflammatory gene induction program., Conclusions: Our study documents a potential immune regulatory role of ER stress in the mechanism of liver IRI and provides a rationale for targeting stress response as a new therapeutic means to ameliorate tissue inflammation in organ transplant recipients.

Much has changed since the early years of liver transplantation. Improvements in post-transplant survival are largely due to more selective and less toxic immunosuppression regimens and advances in operative and perioperative care. This has allowed liver transplantation to become an extremely successful treatment option for patients with endstage liver disease. Beginning with cyclosporine, a cyclic endecapeptide of fungal origin and the first of the calcineurin inhibitors to find widespread use, immunosuppressive regimens have evolved to include additional calcineurin inhibitors, steroids, mTOR inhibitors, antimetabolites and antibodies, mostly targeting T-cell activation. This review will present currently available immunosuppressive agents used in the perioperative period of liver transplantation, as well as maintenance treatments, tailoring therapeutic strategies for specific populations, and advances in immune monitoring and tolerance.

Ischemia/reperfusion injury (IRI) remains unresolved problem in clinical organ transplantation. We analyzed the role of Type-I interferon (IFN) pathway in a clinically relevant murine model of extended hepatic cold preservation followed by orthotopic liver transplantation (OLT). Livers from Type-I IFN receptor (IFNAR) knockout (KO) or wild-type (WT) mice (C57/BL6) were harvested, preserved at 4°C in UW solution for 20 h and transplanted to groups of syngeneic IFNAR KO or WT recipients. Liver graft but not recipient IFNAR deficiency was required to consistently ameliorate IRI in OLTs. Indeed, disruption of Type-I IFN signaling decreased serum alanine aminotransferase (sALT) levels (p < 0.001), diminished Suzuki's score of histological OLT damage (p < 0.01) and improved 14-day survival (from 42%[5/12] in WT to 92%[11/12] in IFNAR KO; p < 0.05). Unlike in WT group, IFNAR deficiency attenuated OLT expression of TNF-α, IL-1β, IL-6, MCP-1, CXCL-10, ICAM-1; diminished infiltration by macrophages/PMNs; and enhanced expression of antioxidant HO-1/Nrf2. The frequency of TUNEL+ apoptotic cells and caspase-3 activity/expression selectively decreased in IFNAR KO group. Small interfering (si)RNA-directed targeting of HO-1 restored cardinal features of liver IRI in otherwise resistant IFNAR-deficient OLTs. Thus, intact Type-I IFN signaling is required for hepatic IRI, whereas HO-1 is needed for cytoprotection against innate immunity-dominated organ preservation damage in IFNAR-deficient liver transplants., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Until the present time, the first experimental liver transplant which led to the development of human liver transplantation is attributed to C. Stuart Welch who performed a heterotopic transplant in the canine species in 1955. In 1956, Jack Cannon is credited with the first animal orthotopic liver transplant although the species was not disclosed. This report is intended to set the historical record straight by acknowledging that Vittorio Staudacher in 1952 was the first to perform a liver transplant in a large animal model., (© Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Hepatic ischemia/reperfusion injury (IRI) occurs in multiple clinical settings, including liver transplantation. The cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) pathway inhibits hepatocellular apoptosis and regulates toll-like receptor 4-triggered inflammation responses in vitro. Here we examined the function and therapeutic potential of cAMP-PKA activation in a murine (C57/BL6) model of liver warm ischemia (90 minutes) followed by reperfusion. Liver IRI triggered cAMP-PKA activation, whereas the administration of its specific inhibitor, H89, exacerbated hepatocellular damage. Conversely, forskolin therapy, which activates PKA by elevating cAMP levels, protected livers from IRI; this was evidenced by diminished serum alanine aminotransferase levels and well-preserved tissue architecture. Liver protection due to cAMP-PKA stimulation was accompanied by diminished neutrophil and macrophage infiltration/activation, reduced hepatocyte necrosis/apoptosis, and increased cAMP response element-binding protein (CREB) expression and augmented interleukin-10 (IL-10) expression. The neutralization of IL-10 restored liver damage in otherwise ischemia/reperfusion-resistant, forskolin-treated mice. In vitro, cAMP-PKA activation diminished macrophage tumor necrosis factor α, IL-6, and IL-12 in an IL-10-dependent manner and prevented necrosis/apoptosis in primary mouse hepatocyte cultures. Our novel findings in a mouse model of liver IRI document the importance of cAMP-PKA signaling in hepatic homeostasis and cytoprotection in vivo. The activation of cAMP-PKA signaling differentially regulates local inflammation and prevents hepatocyte death, and this provides a rationale for novel therapeutic approaches to combating liver IRI in transplant recipients., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Background: Ischemia-reperfusion injury (IRI) can occur during hepatic surgery and transplantation. IRI causes hepatic mitochondrial and microcirculatory impairment, resulting in acute liver dysfunction and failure. We proposed a novel strategy of regulated hepatic reperfusion (RHR) to reverse the cellular metabolic deficit that incurred during organ ischemia by using a substrate-enriched, oxygen-saturated, and leukocyte-depleted perfusate delivered under regulated reperfusion pressure, temperature, and pH. We investigate the use of RHR in mitigating IRI after a prolonged period of warm ischemia., Methods: Using a 2-hour liver warm ischemia swine model, 2 methods of liver reperfusion were compared. The control group (n = 6) received conventional reperfusion with unmodified portal venous blood under unregulated reperfusion pressure, temperature, and pH. The experimental group (n = 6) received RHR. We analyzed the effects of RHR on post-reperfusion hemodynamic changes, liver function, and 7-day animal survival., Results: RHR resulted in 100% survival compared with 50% in the control group (p = 0.05). Post-reperfusion syndrome was not observed in the RHR group, but it occurred in 83% of the control group. RHR resulted in a lesser degree of change from baseline serum alanine aminotransferase levels, aspartate aminotransferase, and lactate dehydrogenase after reperfusion compared with the control group. Histopathologic evaluation showed minimal ischemic changes in the RHR group, whereas a considerable degree of coagulative hepatocellular necrosis was observed in the control group., Conclusions: Regulated hepatic reperfusion mitigates IRI, facilitates liver function recovery, and improves survival after a prolonged period of hepatic warm ischemia. This novel strategy has potential applicability to clinical hepatic surgery and liver transplantation when marginal grafts are used., (Copyright © 2012 American College of Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Ischemia-reperfusion injury (IRI) is common in general surgery and organ transplantation, and in the case of liver, it triggers proinflammatory innate immune cascade and hepatic necrosis, leading to increased incidence of early and late organ rejection. Interleukin (IL)-22, an inducible cytokine of T-cell origin and a member of the IL-10 superfamily, acts on target tissues through IL-22 receptor (IL-22R1)., Methods: Partial hepatic warm ischemia was induced in C57Bl/6 wild-type (WT) and type 1 interferon receptor-deficient (KO) mice for 90 min followed by 6 to 24 hr of reperfusion. WT mice were treated at 30 min before the ischemia insult with recombinant IL-22 or anti-IL-22 neutralizing antibody; phosphate-buffered saline and IgG served as respective controls., Results: IL-22 was detected at 24 hr but not 6 hr of liver IRI. The expression of IL-22R1 was increased by 6 hr of reperfusion in WT but not type 1 interferon receptor KO mice that were protected from IRI. Treatment of WT mice with recombinant IL-22 decreased serum aspartate aminotransferase levels, ameliorated cardinal histological features of IR damage (Suzuki's score) and diminished leukocyte sequestration, along with the expression of IL-22R1 and pro-inflammatory cytokines. IL-22 antibody did not appreciably affect IRI but increased IL-22R1 transcription in the liver. Administration of IL-22 protein exerted hepatoprotection by STAT3 activation., Conclusions: This is the first report investigating immune modulation by T-cell-derived IL-22 in liver injury caused by warm ischemia and reperfusion. Treatment with IL-22 protein may represent a novel therapeutic strategy to prevent liver IRI in transplant recipients.

Background & Aims: Signal transducer and activator of transcription 3 (STAT3), a key mediator of anti-inflammatory cytokine signaling, is essential for heme oxygenase-1 (HO-1)-induced cytoprotection. The phosphoinositide 3-kinase (PI3K)/phosphatase and tensin homolog delete on chromosome 10 (PTEN) pathways regulate diverse innate immune responses. This study was designed to investigate the role of STAT3 in the regulation of PI3K/PTEN cascade after HO-1 induction in a mouse model of innate immune-dominated liver ischemia/reperfusion injury (IRI)., Methods: Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6h of reperfusion., Results: Mice subjected to Ad-HO-1 transfer were resistant to liver IRI, and this cytoprotective effect correlated with increased intrahepatic PI3K/Akt and diminished PTEN expression. In contrast, mice undergoing adjunctive Ad-HO-1 treatment and STAT3 knockdown (siRNA) remained susceptible to IR-mediated local inflammatory response and hepatocellular damage. Consistent with decreased cell apoptosis and inhibited TLR4 expression after PI3K/Akt activation, treatment with specific PI3k inhibitor increased local inflammation and recreated liver IRI despite Ad-HO-1 gene transfer. Parallel in vitro studies with bone marrow derived-macrophages have confirmed that HO-1-STAT3 axis-induced PI3K/Akt negatively regulated PTEN expression in TLR4-dependent fashion., Conclusions: These findings underscore the role of HO-1 induced STAT3 in modulating PI3K/PTEN in liver IRI cascade. Activating PI3K/Akt provides negative feedback mechanism for TLR4-driven inflammation. Identifying molecular pathways of STAT3 modulation in the innate immune system provides the rationale for novel therapeutic approaches for the management of liver inflammation and IRI in transplant patients., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Stimulation of vascular endothelial growth factor (VEGF) has been observed following transarterial chemoembolization (TACE) in hepatocellular cancer (HCC) and may contribute to tumor regrowth. This pilot study examined whether intravenous (IV) bevacizumab, a monoclonal antibody against VEGF, could inhibit neovessel formation after TACE., Methods: 30 subjects with HCC undergoing TACE at a single academic institution were randomized with a computer-generated allocation in a one to one ratio to either bevacizumab at a dose of 10 mg/kg IV every 14 days beginning 1 week prior to TACE (TACE-BEV arm) or observation (TACE-O arm). Angiography was performed with TACE at day 8, and again at weeks 10 and 14. Repeat TACE was performed at week 14 if indicated. TACE-BEV subjects were allowed to continue bevacizumab beyond week 16. TACE-O subjects were allowed to cross-over to bevacizumab at week 16 in the setting of progressive disease. The main outcome measure was a comparison of neovessel formation by serial angiography. Secondary outcome measures were progression free survival (PFS) at 16 weeks, overall survival (OS), bevacizumab safety, and an analysis of VEGF levels before and after TACE with and without bevacizumab., Results: Among the 30 subjects enrolled, 9 of 15 randomized to the TACE-O arm and 14 of 15 randomized to the TACE-BEV arm completed all 3 angiograms. At week 14, 3 of 9 (33%) TACE-O subjects and 2 of 14 (14%) TACE-BEV subjects demonstrated neovascularity. The PFS at 16 weeks was 0.19 in the TACE-O arm and 0.79 in the TACE-BEV arm (p = 0.021). The median OS was 61 months in the TACE-O arm and 49 months in the TACE-BEV arm (p = 0.21). No life-threatening bevacizumab-related toxicities were observed. There were no substantial differences in bevacizumab pharmacokinetics compared to historical controls. Bevacizumab attenuated the increase in VEGF observed post-TACE., Conclusions: IV bevacizumab was well tolerated in selected HCC subjects undergoing TACE, and appeared to diminish neovessel formation at week 14., Trial Registration: ClinicalTrials.gov NCT00049322.

Hepatic ischemia/reperfusion (IRI) injury remains a major challenge in clinical orthotopic liver transplantation (OLT). Tenascin-C (Tnc) is an extracellular matrix protein (ECM) involved in various aspects of immunity and tissue injury. Using a Tnc-deficient mouse model, we present data that suggest an active role for Tnc in liver IRI. We show that Tnc-deficient mice have a reduction in liver damage and a significant improvement in liver regeneration after IRI. The inability of Tnc(-/-) mice to express Tnc significantly reduced the levels of active caspase-3/transferase-mediated dUTP nick end-labeling (TUNEL) apoptotic markers and enhanced the expression of the proliferation cell nuclear antigen (PCNA) after liver IRI. The lack of Tnc expression resulted in impaired leukocyte recruitment and decreased expressions of interleukin (IL)-1β, IL-6, and CXCL2 after liver reperfusion. Tnc-deficient livers were characterized by altered expression patterns of vascular adhesion molecules, such as vascular cell adhesion molecule-1 and platelet endothelial cell adhesion molecule-1 post-IRI. Moreover, matrix metalloproteinase-9 (MMP-9) synthesis, which facilitates leukocyte transmigration across vascular barriers in liver IRI, was markedly down-regulated in the absence of Tnc. We also show that Tnc is capable of inducing MMP-9 expression in isolated neutrophils through Toll-like receptor 4. Therefore, our data suggest that Tnc is a relevant mediator of the pathogenic events underlying liver IRI. The data also support the view that studies aimed at further understanding how newly synthesized ECM molecules, such as Tnc, participate in inflammatory responses are needed to improve therapeutic approaches in liver IRI., (Copyright © 2011 American Association for the Study of Liver Diseases.)

As outcomes after ITx improve, greater emphasis is needed on HRQOL. The primary aims of this study were to (i) assess the feasibility of measuring HRQOL in pediatric ITx recipients, (ii) measure HRQOL using validated instruments, and (iii) compare HRQOL in ITx recipients to healthy normal (NL) children. The CHQ and Pediatric Quality of Life (PedsQL4.0) instruments were administered to both patients and parents at outpatient visits. All 24 eligible patients were enrolled. The median age at study enrollment was 6.0 yr (range: 2-18 yr), and the median time from transplant to study enrollment was 2.8 yr (range: 0.5-11.8 yr). The majority of subjects were male (58%), Latino (58%), and liver-inclusive (92%) recipients. For CHQ and PedsQL4.0, parental responses were significantly lower in multiple categories including physical health and social functioning compared to healthy norms. Patient responses were not different from NL using CHQ but using PedsQL4.0 were significantly lower in the school functioning subcategory and psychosocial health summary score. HRQOL as reported by children and families after ITx is significantly lower in multiple categories compared to NL., (© 2011 John Wiley & Sons A/S.)

Background: Advances in intestinal transplantation (ITx) have resulted in improved survival and the opportunity to examine nutritional outcomes. The aim of this study was to describe detailed, long-term nutritional results and identify positive predictors of growth and weight gain following pediatric ITx., Methods: A single-center retrospective, Institutional Review Board-approved review of a prospective database was conducted. Inclusion criteria were ITx recipients 18 years or younger with survival of 6 months or more. Outcomes included anthropometric measurements and biochemical markers at 6, 12, 24, 36, and 48 months post-ITx. More than 25 ITx-related variables were analyzed as potential predictors of growth and weight gain. Statistical analysis was performed using chi-square test, t test, and analysis of variance., Results: Between November 1991 and April 2007, 50 children received 55 ITx; 33 patients met eligibility criteria. Median age at ITx was 2.2 years, follow-up time was 3.8 years, and time from ITx to cessation of total parenteral nutrition was 31 days. The most common micronutrient deficiencies post-ITx were zinc, iron, and copper. Serum protein levels improved significantly over time. Weight gain occurred within 6 months and vertical growth within 12 months, although limited catch-up growth was seen. Early predictors of weight gain and growth included shorter hospitalization and absence of rejection. Long-term predictors were low steroid dosage, infrequent hospitalization, and the use of peptide-based formulas., Conclusions: This represents one of the largest and most comprehensive long-term studies on nutritional outcomes in pediatric ITx. Overall, positive growth and weight gain were seen as were micronutrient deficiencies. Numerous long-term nutritional challenges exist which require a multidisciplinary approach and future prospective studies.

Sotraustaurin (STN), a small molecule, targeted protein kinase C (PKC) inhibitor that prevents T-lymphocyte activation via a calcineurin-independent pathway, is currently being tested in Phase II renal and liver transplantation clinical trials. We have documented the key role of activated T cells in the inflammation cascade leading to liver ischemia/reperfusion injury (IRI). This study explores putative cytoprotective functions of STN in a clinically relevant rat model of hepatic cold ischemia followed by orthotopic liver transplantation (OLT). Livers from Sprague-Dawley rats were stored for 30 h at 4°C in UW solution, and then transplanted to syngeneic recipients. STN treatment of liver donors/recipients or recipients only prolonged OLT survival to >90% (vs. 40% in controls), decreased hepatocellular damage and improved histological features of IRI. STN treatment decreased activation of T cells, and diminished macrophage/neutrophil accumulation in OLTs. These beneficial effects were accompanied by diminished apoptosis, NF-κB/ERK signaling, depressed proapoptotic cleaved caspase-3, yet upregulated antiapoptotic Bcl-2/Bcl-xl and hepatic cell proliferation. In vitro, STN decreased PKCθ/IκBα activation and IL-2/IFN-γ production in ConA-stimulated spleen T cells, and diminished TNF-α/IL-1β in macrophage-T cell cocultures. This study documents positive effects of STN on liver IRI in OLT rat model that may translate as an additional benefit of STN in clinical liver transplantation., (©2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Graft thrombosis and infectious complications are the main early causes of pancreatic allograft loss in recipients of whole vascularized pancreas transplants, resulting in loss rates up to 10 per cent in the first post transplant week. In this study we sought to determine if initiation of a standardized selection criteria and posttransplant chemoprophylaxis regimen could reduce the rate of early allograft loss; we compared the rate of early allograft loss after introduction of these changes. Of the 61 diabetic recipients who underwent these protocols, 50.8 per cent were female. Average age was 42.9 ± 7.4 years of age, average length of stay was 12.7 ± 8.7 days, with all transplants performed heterotopic to the right lower quadrant with venous drainage to the proximal external or common iliac vein. Organ donors were 21.4 ± 4.8 years of age, body mass index was 23.9 ± 2.8 kg/m(2), with a length of stay of 3.7 ± 1.6 days. One-week pancreatic allograft survival for the protocolized versus nonprotocolized patients was 100 per cent versus 96.7 per cent, 1 month was 98.4 per cent versus 93.4 per cent, and 1 year was 96.7 per cent versus 88.5 per cent, respectively. In the protocolized group there were two graft losses due to infectious complications and none due to thrombosis. Before initiation of the protocols patient survival at 1 year was 91.8 per cent and after was 100 per cent. Pancreas transplantation is arguably the most technically demanding organ transplant from a complication and loss standpoint. However, highly successful outcomes can be obtained with standardized protocols beginning pretransplant to reduce the incidence of posttransplant complications.

Objective: To develop a prognostic scoring system for risk stratification of patients with hepatic graft failure (GF) undergoing retransplants of the liver (ReLT) and improve patient selection., Summary of Background Data: Retransplantation of the liver remains controversial because of inferior outcomes compared with the primary orthotopic liver transplantation (OLT) and raises concerns of inappropriate utilization of a scarce donor organ resource. Data on risk stratification of ReLT patients for long-term survival outcomes are limited., Methods: We conducted an analysis from our prospective database of 466 adults' ReLT between February 1984 and September 2010. Mean follow-up was 3 years. Each independent predictor for allograft failure was assigned risk score (RS) points of 1 or 2, proportional to the corresponding parameter estimate under the Cox model: Predictive index category (PIC) 1, RS = 0; PIC II, RS = 1 to 2; PIC III, RS = 3 to 4; and PIC IV, RS = 5 to 12., Results: Eight risk factors predictive for GF after ReLT included recipient age greater than 55 years, Model for End-Stage Liver Disease score greater than 27, history of prior OLT greater than 1, pre-ReLT requirement for mechanical ventilation, serum albumin less than 2.5 g/dL, donor age greater than 45 years, intraoperative requirement of packed red blood cell transfusion greater than 30 units, and performance of ReLT between 15 and 180 days from the prior OLT. Five-year GF-free survival was significantly higher in PIC I (65%) than in PIC II (53%), PIC III (43%), and PIC IV (20%) groups (P < 0.001)., Conclusions: This risk-stratification model was highly predictive of long-term outcome after liver retransplantation in adult recipients. This formula provides a practical guide for selection of candidates for retransplantation of the liver that can lead to improved patient outcomes and optimal utilization of a scarce resource.

Objective: To define a prognostic scoring system for risk stratification of patients undergoing orthotopic liver transplantation (OLT) using grafts from donation after cardiac death (DCD)., Design: Retrospective study., Setting: University transplant center., Patients: Eighty-one patients underwent OLT using DCD grafts from March 1, 1994, to November 30, 2010. The mean follow-up was 2 years. Independent risk factors for graft failure after OLT were identified using Cox model and assigned risk score points. Points were summed and assigned to predictive index categories: 0 or 1 for low risk, 2 to 4 for intermediate risk, and 5 to 9 for high risk., Results: Six multivariate factors predictive for graft failure after OLT using DCD grafts included the following: for recipients, (1) diagnosis of hepatitis C virus with malignancy, non-hepatitis C virus with malignancy, or hepatitis C virus only, (2) previous OLT, and (3) body mass index (calculated as weight in kilograms divided by height in meters squared) greater than 30; for donors, (4) hepatitis B core antibody positivity and (5) mean arterial pressure lower than 60 mm Hg for longer than 20 minutes after withdrawal of life support; and for grafts, (6) cold ischemia time longer than 6 hours. Five-year graft failure-free survival was significantly higher for the low-risk group (83%) compared with the intermediate-risk (62%) and high-risk (0%) groups (P < .001). Overall biliary complications occurred in 24 patients (29%), with ischemic cholangiopathy in 8 patients (9.9%)., Conclusions: Our study showed superior long-term patient survival with liver transplantation using DCD organs in highly selected donors and recipients. We propose a practical risk stratification system highly predictive of long-term survival outcomes after OLT using DCD grafts. Application of this predictive index for transplant candidates receiving DCD liver grafts would improve patients' outcomes and optimize use of scarce resources.

Objective: The purpose of our study was to evaluate the exposure of our institution's liver transplantation population to gadolinium-based contrast agents and assess the rate of nephrogenic systemic fibrosis (NSF) within this unique group., Materials and Methods: Institutional review board approval was obtained for a retrospective review of medical records of patients who had undergone liver transplantation at our institution between 1997 and 2008. Informed consent was not required. Demographic information, history of gadolinium-based contrast agent exposure, stage of chronic kidney disease (CKD), and evidence of NSF were recorded., Results: A total of 2142 patients who had undergone liver transplantation at our institution between 1997 and 2008 were identified. Of this total, 33% (709/2142) had documented gadolinium-based contrast agent exposure peritransplantation. Patients in CKD1 and 2, CKD3, CKD4, and CKD5 comprised 50% (352/709), 28% (200/709), 8% (60/709), and 14% (97/709), respectively. Of patients in CKD5, 76% (74/97) required dialysis. Thorough review of all patients' medical records identified one biopsy-confirmed case of NSF in the 709 patients. This patient was also in CKD5 and required dialysis., Conclusion: Within our institution, only 0.1% (1/709) of all liver transplantation patients exposed to gadolinium-based contrast agents or 1.4% (1/74) of CKD5 patients requiring dialysis had biopsy proof of NSF. This incidence is consistent with the rate of NSF in all patients exposed to gadolinium-based contrast agents regardless of liver transplantation reported in the literature. Therefore, liver transplantation may not be an independent risk factor in development of NSF in patients exposed to gadolinium-based contrast agents.

Liver transplantation is the gold standard of care in patients with end-stage liver disease and those with tumors of hepatic origin in the setting of liver dysfunction. From 1988 to 2009, liver transplantation in the United States grew 3.7-fold from 1713 to 6320 transplants annually. The expansion of liver transplantation is chiefly driven by scientific breakthroughs that have extended patient and graft survival well beyond those expected 50 years ago. The success of liver transplantation is now its primary obstacle, as the pool of donor livers fails to keep pace with the growing number of patients added to the national liver transplant waiting list. This review focuses on three major challenges facing liver transplantation in the United States and discusses new areas of investigation that address each issue: (1) the need for an expanded number of useable donor organs, (2) the need for improved therapies to treat recurrent hepatitis C after transplantation and (3) the need for improved detection, risk stratification based upon tumor biology and molecular inhibitors to combat hepatocellular carcinoma., (© 2011 The Authors Journal compilation © 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Unlabelled: The ubiquitous serine/threonine kinase glycogen synthase kinase 3 beta (Gsk3β) differentially regulates macrophage Toll-like receptor (TLR)-triggered pro- and anti-inflammatory cytokine programs. This study was designed to determine the in vivo role and therapeutic potential of Gsk3β modulation in tissue inflammation and injury in a murine model of liver partial warm ischemia/reperfusion injury (IRI). As a constitutively activated liver kinase, Gsk3β became quickly inactivated (phosphorylated) following IR. The active Gsk3β, however, was essential for the development of IRI pathology, as administration of its specific inhibitor, SB216763, ameliorated the hepatocellular damage, evidenced by reduced serum alanine aminotransferase (sALT) levels and well-preserved liver architecture compared with controls. The liver protective effect of Gsk3β inhibition was dependent on an immune regulatory mechanism, rather than direct cytoprotection via mitochondria permeability transition pores (MPTP). Indeed: (1) coadministration of SB216763 and atractyloside (MPTP opener) failed to abrogate a local cytoprotective Gsk3β inhibition effect; (2) SB216763 selectively inhibited IR-triggered liver pro-inflammatory, but spared interleukin (IL)-10, gene induction programs; and (3) IL-10 neutralization restored liver inflammation and IRI in SB216763-treated mice. Gsk3β inactivation by IR was a self-regulatory mechanism in liver homeostasis, critically dependent on phosphoinositide 3 (PI3)-kinase activation, as administration of a PI3 kinase inhibitor, wortmannin, reduced Gsk3 phosphorylation and augmented liver damage. In vitro, IL-10 was critical for the suppression of pro-inflammatory gene programs by Gsk3 inhibition in bone marrow-derived macrophages in response to TLR4 stimulation., Conclusion: Our novel findings document the key immune regulatory function of Gsk3β signaling in the pathophysiology of liver IRI, and provide a rationale to target Gsk3β as a refined therapeutic strategy to ameliorate liver IRI., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Ischemia and reperfusion injury (IRI) is a dynamic process that involves two distinctive yet interrelated phases of ischemic organ damage and inflammation-mediated reperfusion injury. Although multiple cellular and molecular pathways contribute and regulate tissue/organ damage, integration of different players into a unified mechanism is warranted. The crosstalk between innate and adaptive immune systems plays a significant role in the pathogenesis of liver IRI. In this review, we focus on recent progress in the mechanism of liver innate immune activation by IR. Kupffer cells (KC), DCs, NK, as well as T cells initiate local inflammation response, the hallmark of IRI, by utilizing distinctive immune receptors to recognize and/or trigger various molecules, both endogenous and exogenous. The interlocked molecular signaling pathways in the context of multiple liver cell types, the IRI kinetics and positive versus negative regulatory loops in the innate immune activation process are discussed. Better appreciation of molecular interactions that mediate these intricate cascades, should allow for the development of novel therapeutic approached against IRI in liver transplant recipients., (No claim to original US government works Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)