Ming-Man Zhang

Analysis of Biliary Epithelial-Mesenchymal Transition in Portal Tract Fibrogenesis in Biliary Atresia

BackgroundThe cellular origin of myofibroblast in the liver fibrosis remains unclear. This study was designed to investigate whether biliary epithelial cells (BECs) undergoing epithelial–mesenchymal transition (EMT) might be found in patients with biliary atresia, thereby serving as a source of fibrotic myofibroblasts.MethodsLiver sections from patients with biliary atresia were evaluated to detect antigen for the BECs marker 4 and cytokeratin-7 (CK-7), proteins (fibroblast-specific protein 1, also known S100A4; the collagen chaperone heat shock protein 47, HSP47) characteristically expressed by cells undergoing EMT, as well as myofibroblasts marker a-smooth muscle actin (a-SMA).ResultsNormal bile ducts BECs could express CK-7 and low levels of a-SMA; they did not express S100A4 and HSP47. However, BECs from biliary atresia resulted in increased expression of a-SMA, S100A4, with concurrent transition to a fibroblast-like morphology and decreased expression of AK-7. Furthermore, BECs in biliary atresia were associated with significant bile ductular proliferation and coexpressed both epithelial and mesenchymal markers.ConclusionsFrom significant histologic evidence, the BECs forming small- and medium-sized bile ducts undergoing EMT may account for prominent bile ductular proliferation and directly contribute to fibrogenesis in BA.

Combinatory effects of hepatic CD8 + and NK lymphocytes in bile duct injury from biliary atresia

Introduction:To our knowledge, elucidating the immune pathogenesis of disease, especially characteristic T-cell and natural killer (NK) cell expansions, has not been performed before now. We investigated the role of T lymphocytes and NK lymphocytes in the destruction of extrahepatic bile ducts of patients with biliary atresia.Methods:Lymphocytes from the liver and extrahepatic bile duct remnants of patients with biliary atresia were characterized by immunofluorescence staining, fluorescence-activated cell sorter analysis, and real-time reverse-transcriptase PCR. Cholangiocyte lysis assays were performed to confirm cytotoxicity of activated hepatic NK lymphocytes or CD8+ cells.Results:The inflammatory milieu from portal tracts and/or biliary remnants consisted of greater numbers of Kupffer cells, T lymphocytes, and NK lymphocytes in the patients with biliary atresia as compared with the cholestatic and noncholestatic controls. In patients with biliary atresia, expression of NK or CD8+ costimulatory molecules was upregulated as compared with controls. Hepatic NK lymphocytes or CD8+ cells from patients with biliary atresia were demonstrated to be cytotoxic to the duct epithelium.Discussion:Specific immune responses from NK and CD8+ cells were involved in the injury to the duct epithelium and play a significant role in the phenotype of experimental biliary atresia.

Prognostic value of hedgehog signal component expressions in hepatoblastoma patients

ObjectiveActivation of hedgehog (Hh) pathway has been implicated in the development of human malignancies. Hh as well as related downstream target genes has been extensively studied in many kinds of malignant tumours for clinical diagnostic or prognostic utilities. This study aimed at investigating whether Hh molecules provides a molecular marker of hepatoblastoma malignancy.MethodsWe obtained tissue sections from 32 patients with hepatoblastoma as well as cholestasis and normal control. Immunohistochemical analysis were performed to determine Hh signal components in human hepatoblastoma. The prognostic significance of single expression of Hh signal components were evaluated using Cox proportional hazards regression models and Kaplan-Meier survival analysis for statistical analysis.ResultsExpression of Hh signal components showed an increase in hepatoblastoma compared with chole stasis and normal tissues. There was a positive correlation between Smo or Gli1 expression and tumor clinicopathological features, such as histological type, tumor grade, tumor size and clinical stage. Both Smo or Gli1 protein high expression was significantly associated with poor prognosis by univariate analyses and multivariate analyses.ConclusionsAbnormal Hh signaling activation plays important roles in the malignant potential of hepatoblastoma. Gli1 expression is an independent prognostic marker.

Chemosensitization in non‐small cell lung cancer cells by IKK inhibitor occurs via NF‐κB and mitochondrial cytochrome c cascade

In this study, we demonstrated with mechanistic evidence that parthenolide, a sesquiterpene lactone, could antagonize paclitaxel‐mediated NF‐κB nuclear translocation and activation by selectively targeting I‐κB kinase (IKK) activity. We also found that parthenolide could target IKK activity and then inhibit NF‐κB; this promoted cytochrome c release and activation of caspases 3 and 9. Inhibition of caspase activity blocked the activation of caspase cascade, implying that the observed synergy was related to caspases 3 and 9 activation of parthenolide. In contrast, paclitaxel individually induced apoptosis via a pathway independent of the mitochondrial cytochrome c cascade. Finally, exposure to parthenolide resulted in the inhibition of several NF‐κB transcript anti‐apoptotic proteins such as c‐IAP1 and Bcl‐xl. These data strengthen the rationale for using parthenolide to decrease the apoptotic threshold via caspase‐dependent processes for treatment of non‐small cell lung cancer with paclitaxel chemoresistance.

The pre-Kasai procedure in living donor liver transplantation for children with biliary atresia

BACKGROUND Biliary atresia (BA) is a major cause of chronic cholestasis, a fatal disorder in infants. This study was undertaken to evaluate the safety and effectiveness of primary living donor liver transplantation (LDLT) in comparison with the traditional first-line treatment, the Kasai procedure. METHODS We assessed 28 children with BA at age of less than two years (3-21.3 months) who had undergone LDLT in two hospitals in Southwest China during the period of 2008-2011. Eighteen children who had had primary LDLT were included in a primary LDLT group, and ten children who had undergone the Kasai operation in a pre-Kasai group. All patients were followed up after discharge from the hospital. The records of the BA patients and donors were reviewed. RESULTS The time of follow-up ranged 12-44.5 months with a median of 31 months. The 30-day and 1-year survival rates were 85.7% and 78.6%, respectively. There was no significant difference in the 30-day or 1-year survival between the two groups (83.3% vs 90% and 77.8% vs 80%, P>0.05). The main cause of death was hepatic artery thrombosis. There were more patients with complications who required intensive medical care or re-operation in the pre-Kasai group (8, 80%) than in the primary LDLT group (9, 50%) (P=0.226). But no significant differences were observed in operating time (9.3 vs 8.9 hours, P=0.77), intraoperative blood loss (208.6 vs 197.0 mL, P=0.84) and blood transfusion (105.6 vs 100.0 mL, P=0.91) between the two groups. The durations of ICU and hospital stay in the primary LDLT group and pre-Kasai group were 180.4 vs 157.7 hours (P=0.18) and 27 vs 29 days (P=0.29), respectively. CONCLUSIONS Primary LDLT is a safe and efficient management for young pediatric patients with BA. Compared with the outcome of LDLT for patients receiving a previous Kasai operation, a similar survival rate and a low rate of re-operation and intensive medical care for patients with BA can be obtained.

Adult to pediatric living donor liver transplantation for portal cavernoma

Aim:  Portal cavernoma (PC) is an important cause of non‐cirrhotic portal hypertension with severe complications, such as variceal hemorrhage in pediatric patients. With the development of new surgical techniques, living donor liver transplantation (LDLT) has recently been recognized as a viable but challenging treatment option for PC. The purpose of the present study was to summarize the efficacy of LDLT in PC patients and to carry out a follow‐up study of pediatric recipients.

Early postoperative care of liver transplantation for infants with biliary atresia during pediatric intensive care unit stay.

SUBJECT The aim of this study was to present our institutional experience with the pediatric intensive care unit (PICU) stays of liver recipients to understand prevention of complications. METHODS This retrospective review included 22 infants who weighed 8.8 kg or less and underwent 23 transplantations. No grafts were from executed prisoners. We summarized the diagnosis, evaluation, medicine usage, and therapeutic intervention associated with subjects experiencing complications of rejection episodes, surgery, or infection during their ICU stay. RESULTS There was one perioperative death from primary graft nonfunction. The most common postoperative complications were infections, gastrointestinal bleeding, and vascular complications. Rejection episodes occurred among 25% of patients. The most common isolated pathogenic bacteria was Staphylococcus epidermidis. Median initial ICU stay was 10 days. Mean requirement for artificial ventilation was 37.6 hour. Mean times of use of dobutamine, prostaglandin E1, and dopamine was 3.3, 7.5, and 8.8 days, respectively. Parenteral nutrition was started at a mean of 12 hours and oral food intake at a mean of 72 hours. CONCLUSIONS Although challenging, orthotopic liver transplantation (OLT) in small infants can be successfully performed with meticulous surgical technique and keen postoperative surveillance.

Sixty-four-slice computed tomography in surgical strategy of portal vein cavernous transformation

AIM To investigate the role of 64-slice computed tomography (CT) in portal vein cavernous transformation to determine surgical strategy. METHODS The site of lesions and extent of collateral circulation in 12 pediatric cases of cavernous transformation of the portal vein with surgical treatment were analyzed. RESULTS Eleven of 12 children had esophageal varices and were treated with lower esophageal and gastric devascularization and splenectomy, and the other case was only treated with splenectomy. There were eight cases with spontaneous spleen/stomach-renal shunt, four with Retzius vein opening, which was reserved during surgery. Three cases of lesions involving the intrahepatic portal vein (PV) were treated with living donor liver transplantation. One patient died from PV thrombosis after liver transplantation, and the rest had no significant complications. CONCLUSION The PV, its branches and collateral circulation were clearly seen by 64-slice spiral CT angiography, which helped with preoperative surgical planning.

Successful treatment of Epstein-Barr Virus-associated haemophagocytic syndrome arising after living donor liver transplantation

A 6‐year‐old girl received an orthotopic liver transplant secondary to liver failure of unknown etiology. Several days after liver transplantation, she developed pancytopenia and Epstein –Barr Virus (EBV)‐positive seroconvert after transplant. Taking of medical history to provide evidence of pancytopenia correlated with EBV infection after transplant. Bone‐marrow biopsy was carry out to confirm haemophagocytic syndrome (HPS). Laboratory investigations, including blood routine count, microscopic blood film examination, serum ferritin concentration, and liver function tests were carried out starting from the first day of suspected HPS infection, continuing until 15 weeks post‐infection. Liver transplantation followed with a combination of cyclosporin A, corticosteroids, VP‐16, and supportive strategies.