Late Protective Effects of the Anticalmodulin Drug Fluphenazine on Carbon Tetrachloride-induced Liver Necrosis

Fluphenazine (FP) treatment (50mg/kg bw, ip in saline) 30 min before or 6 or 10 h after CCl4 administration (1 ml/kg ip in olive oil) significantly prevented the liver necrosis produced by the hepatotoxin at 24 h. FP had enhancing effects on the covalent binding of CCl4 reactive metabolites to cellular constituents and on CCl4 induced lipid peroaldation.FP lowered bOdy temperature of the CCl4-poisoned animals during the 24 h observation period. The obtained results are compatible but do not prove the hypothesis that calmodulin (CaM) had participation in late occurring events preceding necrosis. FP lowering action on body temperature, however, might also play a role in the effects of this drug on the onset of CCl4 induced liver necrosis. FP levels in liver tissue as determined by gas chromatography-mass spectrometry evidenced the presence of the drug in amounts suffi cient to inhibit CaM and that suggests that not all preventive effects of FP are due to its indirect actions on the central nervous system via decreased body temperature

TIPSS for variceal hemorrhage after living related liver transplantation:A dangerous indication

The introduction of transjugular intrahepatic portalsystemic stent-shunt （TIPSS） has been a major breakthrough in the treatment of portal hypertension, which has evolved to a large extent, into a routine procedure. A 21-year-old male patient with progressive graft fibrosis/cirrhosis requiring TIPSS for variceal hemorrhage in the esophagus due to portal hypertension was unresponsive to conventional measures two years after living related liver transplantation （LDLT）. Subsequently, variceal hemorrhage was controlled, however, liver function decreased dramatically with consecutive multi organ failure. CT scan revealed substantial necrosis in the liver. The patient underwent successful ＂high urgent＂ cadaveric liver transplantation and was discharged on postoperative d 20 in a stable condition.

ER Stress-Mediated Cell Damage Contributes to the Release of EDA~＋ Fibronectin from Hepatocytes in Nonalcoholic Fatty Liver Disease

Fibronectin containing extra domain A（EDA~＋ FN）,a functional glycoprotein participating in several cellular processes,correlates with chronic liver disease.Herein,we aim to investigate the expression and secretion of EDA~＋ FN from hepatocytes in nonalcoholic fatty liver disease（NAFLD） and the underlying mechanisms.Circulating levels of EDA~＋ FN were determined by ELISA in clinical samples.Western blotting and flow cytometry were performed on L02 and Hep G2 cell lines to analyze whether the levels of EDA~＋ FN were associated with endoplasmic reticulum（ER） stress-related cell death.Circulating levels of EDA~＋ FN in NAFLD patients were significantly higher than those in control subjects,and positively related with severity of ultrasonographic steatosis score.In cultured hepatocytes,palmitate up-regulated the expression of EDA~＋ FN in a dose-dependent manner.Conversely,when the cells were pretreated with 4-phenylbutyrate,a specific inhibitor of ER stress,up-regulation of EDA~＋ FN could be abrogated.Moreover,silencing CHOP by sh RNA enhanced the release of EDA~＋ FN from hepatocytes following palmitate treatment,which was involved in ER stress-related cell damage.These findings suggest that the up-regulated level of EDA~＋ FN is associated with liver damage in NAFLD,and ER stress-mediated cell damage contributes to the release of EDA~＋ FN from hepatocytes.

ENDOTOXIN-INDUCED LIVER INJURY AND CHANGES IN THE LEVELS OF PLASMA TUMOR NECROSIS FACTOR-α AND INTERLEUKIN-6 IN RABBITS

ELISA was employed to detect changes in plasma TNF-α and IL-6 level in rabbits having endotoxin-induced generalized Shwartzman reaction. Liver injury was assessed by the increase of serum ALT and hepatic histopathologic changes. The results showed that plasma TNF-α and IL-6 levels increased remarkably 12h after intravenous injection of endotoxin twice at a 24h interval, and these changes corresponded with the degree of liver injury. Coinjection of dexamethasone and endotoxin partly prevented the elevation of TNF-α and IL-6 levels and reduced liver injury. These results indicated that TNF-α and IL-6 were involved in endotoxin-induced liver injury.

Clinical management of inflammatory bowel disease in the organ recipient

There was estimated a higher incidence of de novo inflammatory bowel disease (IBD) after solid organ transplantation than in the general population. The onset of IBD in the organ transplant recipient population is an important clinical situation which is associated to higher morbidity and difficulty in the medical therapeutic management because of possible interaction between anti-reject therapy and IBD therapy. IBD course after liver transplantation (LT) is variable, but about one third of patients may worsen, needing an increase in medical therapy or a colectomy. Active IBD at the time of LT, discontinuation of 5-aminosalicylic acid or azathioprine at the time of LT and use of tacrolimus-based immunosuppression may be associated with an unfavorable outcome of IBD after LT. Anti-tumor necrosis factor alpha (TNFα) therapy for refractory IBD may be an effective and safe therapeutic option after LT. The little experience of the use of biological therapy in transplanted patients, with concomitant anti-rejection therapy, suggests there be a higher more careful surveillance regarding the risk of infectious diseases, autoimmune diseases, and neoplasms. An increased risk of colorectal cancer (CRC) is present also after LT in IBD patients with primary sclerosing cholangitis (PSC). An annual program of endoscopic surveillance with serial biopsies for CRC is recommended. A prophylactic colectomy in selected IBD/PSC patients with CRC risk factors could be a good management strategy in the CRC prevention, but it is used infrequently in the majority of LT centers. About 30% of patients develop multiple IBD recurrence and 20% of patients require a colectomy after renal transplantation. Like in the liver transplantation, anti-TNFα therapy could be an effective treatment in IBD patients with conventional refractory therapy after renal or heart transplantation. A large number of patients are needed to confirm the preliminary observations. Regarding the higher clinical complexity of this subgroup of IBD patients, a close multidisciplinary approach between an IBD dedicated gastroenterologist and surgeon and an organ transplantation specialist is necessary in order to have the best clinical management of IBD after transplantation.

Experimental study on early liver injury and expressions of TNF-α mRNA in burn rats with endotoxemia

Objective: To observe tissue distribution and cell localization of TNF α mRNA and its protein and study their role in the pathogenesis of liver injury in burn rats. Methods: An animal model of rats subjected to 20% TBSA Ⅲ degree burns combined with intraperitoneal injection of lipopolysaccharide (LPS) was used for this experiment. The changes of hepatic morphology and functions and serum TNF α content and expression and localization of liver TNF α and TNF α mRNA were determined with light microscope (LM) and electron microscope (EM), quantitative analysis, immunohistochemistry (IHC) and in situ hybridization (ISH). Results: It showed that there were sinusoid reaction, KCs activation and degeneration, necrosis of HCs, and platelets aggregation, fibrins deposition and PMNs attachment in sinusoid. The activity of ALT was obviously elevated and ALB content was slightly decreased. The serum content of TNF α showed peak at 3 hours. TNF α was mainly localized in sinusoid endothelial cells (SECs) and Kupffer cells (KCs), and TNF α mRNA was mainly distributed in KCs, polymorphonuclears neutrophils (PMNs) and macrophages (MPs). Conclusions: It suggests that TNF α mRNA and its protein expression and localization are coincident with the pathological changes of liver injury. TNF α is one of the key cytokines in the pathogenesis of liver injury in burn rats with endotoxemia.