Lianbao Kong

Antifibrotic Effect of Hepatocyte Growth Factor-Expressing Mesenchymal Stem Cells in Small-for-Size Liver Transplant Rats

Ischemia-reperfusion and chronic injuries associated with small-for-size liver transplantation (SFSLT) impair the regeneration of liver graft and induce liver fibrosis. Mesenchymal stem cells (MSCs) can prevent the development of liver fibrosis, and hepatocyte growth factor (HGF) can also attenuate liver cirrhosis. Our previous studies have demonstrated that higher occurrence of liver fibrosis existed in rats post-SFSLT, and that implantation of HGF/MSCs, the human HGF (hHGF)-expressing MSCs, can improve liver regeneration, reduce mortality of rats, as well as have the potent antifibrotic effect in this SFSLT model. In the present study, we implanted HGF/MSCs into liver grafts via the portal vein and investigated their role in antifibrosis effect, using a 30% SFSLT rat model. Fibrosis indexes, including laminin (LN), hyaluronic acid (HA) levels in serum and hydroxyproline (Hyp) content in the liver grafts, the expression of transforming growth factor-beta1 (TGF-beta(1)), rat HGF (rHGF), alpha-smooth muscle actin (alpha-SMA) in hepatic stellate cells (HSCs), alanine aminotransferase (ALT), total bilirubin (BIL), and albumin (ALB) levels in serum, in rats in different treatment groups were assessed at different time points. We found that HGF/MSCs significantly inhibited the formation of liver fibrosis in rats undergoing SFSLT, while MSCs and HGF had synergistic effects in the process. The antifibrosis effect of HGF/MSCs may have contributed in modulating the activation and apoptosis of HSCs, elevating the rHGF expression level, and decreasing the TGF-beta(1) secretion of activated HSCs. These studies suggest that HGF/MSCs may be a novel therapeutic option for the treatment of liver fibrosis after SFSLT.

Outcomes of Living-Related Liver Transplantation for Wilson's Disease : A Single-Center Experience in China

Background. Although orthotopic liver transplantation provides a therapeutic option for patients with Wilson’s disease (WD) presenting fulminant liver failure or drug resistance, it is still unclear whether the living-related liver transplantation (LRLT) can result in long-term therapeutic effect on WD. Methods. Here, we report a retrospective analysis of LRLT for 36 cases of WD patients. The indications for LRLT were fulminant hepatic failure in two patients and chronic advanced liver disease in 32 patients including 13 patients with Wilsonian neurologic manifestations. Two patients presented with severe Wilsonian neurologic manifestations even though their liver functions were stable. Results. Results revealed that the survival of posttransplant patients or grafts at 1, 3, and 5 years was 91.7%, 83.3%, 75%, or 86.1%, 77.8%, 75%, respectively. Pretransplant intensive care unit-bound and model for end-stage liver disease score were indicated as independent factors predictive of patient survival. Patients with neurologic abnormalities showed significant improvement after liver transplant. Conclusion. Our results indicate LRLT is an excellent therapeutic modality for WD patients with end-stage liver disease. Better pretransplant conditions appeared to be advantageous in gaining better survival outcomes of patients undergoing LRLT.

miR-146a Ameliorates Liver Ischemia/Reperfusion Injury by Suppressing IRAK1 and TRAF6

A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor– associated factor 6(TRAF6), in the pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury in vivo and in vitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a in vivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6.

Protective effect of adenosine A2A receptor activation in small-for-size liver transplantation.

The aim of the present study was to investigate the potential role of adenosine A2A receptor (A2AR) activation in small‐for‐size liver transplantation. A rat orthotopic liver transplantation model was performed by using 40% (range: 36–46%) liver grafts. Recipients were given either saline (control group) or CGS 21680 (2‐p‐(2‐Carboxyethyl)phenethylamino‐5′‐N‐ethylcarboxamidoadenosine hydrochloride, a selective A2AR agonist), or CGS 21680+ ZM 241385 (a selective A2AR antagonist) immediately after reperfusion for 3 h. Compared with control group, CGS 21680 used at both low dose (0.05 μg/kg/min) and high dose (0.5 μg/kg/min) increased the survival rate from 16.7% (2/12) to 83.3% (10/12) and 66.7% (8/12), respectively. These effects correlated with improved liver function and preserved hepatic architecture. CGS 21680 effectively decreased neutrophil infiltration, suppressed pro‐inflammatory (TNF‐α, IL‐1β and IL‐6) expression, promoted expression of antiapoptotic molecules, and inhibited apoptosis. The effects of CGS 21680 were prevented when ZM 241385 was co‐administrated. In conclusion, the present study showed that A2AR activation alleviated portal hypertension, suppressed inflammatory response, reduced apoptosis, and potentiated the survival of small‐for‐size liver grafts. Our findings provide the rationale for a novel therapeutic approach using A2AR activation to maximize the availability of small‐for‐size liver grafts.

The microRNA-146a/b attenuates acute small-for-size liver graft injury in rats

A critical role of the Toll‐like receptor (TLR)‐4 and its downstream mediators in the pathogenesis of small‐for‐size liver graft injury has been documented. Recently, the microRNA‐146 (miR‐146) was identified as a potent negative regulator of the TLR4 signalling pathway. In this study, the role of miR‐146a and miR‐146b in the attenuation of TLR‐4 signalling and small‐for‐size liver graft injury was investigated.

Allograft Inflammatory Factor-1 is Up-regulated in Warm and Cold Ischemia-Reperfusion Injury in Rat Liver and May be Inhibited by FK506

BACKGROUND Allograft inflammatory factor-1 (AIF-1) plays an important role in immune response and vasculopathy in allografts. The present study investigated activation of AIF-1 in warm and cold ischemia-reperfusion (IR) injury of rat liver, and the potential inhibitory effect of FK506. METHODS We used warm IR injury, orthotopic transplantation, and allograft rejection models in this study. We assessed expression of AIF-1 mRNA and protein, as well as its inducers interferon-γ (IFN-γ) and interleukin-1β (IL-1β). The potential inhibitory effect of FK506 on AIF-1 in a rat macrophage cell line and in these three models was also assessed. RESULTS AIF-1 mRNA and protein, as well as its inducers IFN-γ and IL-1β, were significantly increased in the warm IR injury, orthotopic transplantation, and allograft rejection models. Real-time RT-PCR and Western blotting showed that pretreatment with low-dose FK506 partially inhibited AIF-1 activation as well as its inducers (IFN-γ and IL-1β) in these three models. Western blotting showed that IFN-γ and IL-1β activated AIF-1 in a macrophage cell line, but pretreatment with FK506 did not inhibit AIF-1 activation in vitro. Hematoxylin and eosin staining showed that edema and necrosis in the liver, as well as alanine aminotransferase (ALT) in serum, of these three groups was reduced after FK506 pretreatment. CONCLUSION AIF-1 was activated in warm and cold IR injury, and pretreatment with low-dose FK506 partly inhibited AIF-1 activation and reduced warm and cold IR injury.

Dermatomyositis associated with gallbladder carcinoma: A case report

Patients with gallbladder carcinoma can present with a variety of paraneoplastic syndromes, including Cushings syndrome, hypercalcemia, acanthosis nigricans, bullous pemphigoid, dermatomyositis and the sign of Leser-Trélat. Surgical resection of the primary tumor results in resolution of these paraneoplastic syndromes. We present a 67-year old female with facial and cervical erythema who was initially diagnosed with dermatomyositis. However, an abdominal computed tomography (CT) and positron emission tomography-CT scan was suspicious for gallbladder carcinoma with lymph node metastasis. After surgical resection, her dermatomyositis was resolved. This case demonstrates that dermatomyositis may be a manifestation of preexisting gallbladder carcinoma.

Emergency adult living donor right lobe liver transplantation for fulminant hepatic failure

Fulminant hepatitis is fatal in most cases and timely liver transplantation is the only effective treatment. This study evaluates the survival outcomes of patients who underwent living-donor liver transplantation (LDLT) using right lobe liver grafts for fulminant liver failure due to hepatitis B infection. Nine cases of adult right lobe LDLT were performed in our department from September 2002 to August 2005 and the clinical and following-up data were reviewed. According to the pre-transplant Child-Pugh-Turcotte classification, the nine patients were classified as grade C. The model for end-stage liver disease (MELD) score of these patients ranged from 16 to 42. The principal complications before transplantation included abnormal renal function, hepatic coma of different degrees and alimentary tract hemorrhage. The main complications after transplantation included pulmonary infection in two cases, acute renal failure in three cases and transplantation-related encephalopathy in one case. No primary failure of vascular or biliary complications occurred. The one-year survival rate was 55.6%. There were no serious complications or deaths in donors. In general, it is extremely difficult to treat fulminant hepatitis by conservative regimen, particularly, in cases with rapid progression. Emergency adult living-donor liver transplantation is an effective treatment for fulminant hepatitis patients and is relatively safe for donors.

De novo phyllodes tumor in an adolescent female after liver transplantation.

Cheng F, Qin J‐J, Yu M‐N, Zhang F, Li X‐C, Sun B‐C, Kong L‐B, Wang X‐H. De novo phyllodes tumor in an adolescent female after liver transplantation.
Pediatr Transplantation 2011: 15:E12–E14.

The Technique and Outcomes of Branch-Patch Arterial Reconstruction in Living Donor Liver Transplantation

BACKGROUND Although living donor liver transplantation (LDLT) is now an established therapeutic modality for end-stage liver disease, technical dilemmas exist. The pretransplant imaging findings may not clearly define the surgical anatomy of the hepatic artery (HA), especially its diameter. A tiny artery (<2 mm) has always been found during the hilar dissection. Its size is discrepant to the diameter to the recipient arterial stump. The aim of this paper was to report a hepatic arterial reconstruction technique for small diameter (<2 mm) vessels in a partial liver graft. METHODS Since January 2002 to May 2007, we performed 9 LDLT with small hepatic arteries (<2 mm), which were analyzed retrospectively for this report. In this technique, we transect the donor hepatic artery proximally and distally to the tiny graft artery, take off and create a patch for arterial anastomosis. Computed tomographic angiography is used to evaluate the vascular anatomy and to measure the diameter of the graft HAs. RESULTS All donors were discharged without any vascular complications. One donor experienced a bile leakage from the dissections plane of the liver, which was treated by draining the abdominal cavity. Eight of the 9 patients survived without evidence of hepatic artery thrombosis during 32 months (range, 14-72); one subject died due to cytomegalovirus infection. CONCLUSION The arterial reconstruction technique enabled use of tiny arteries, eliminating the problems of diameter discrepancy without increasing donor complications.