Induced Liver Failure Research Articles

Protective effect of daidzin against d‐galactosamine and lipopolysaccharide‐induced hepatic failure in mice

This study examined the effects of daidzin, a major isoflavone from Puerariae Radix, on D-galactosamine (D-GalN) and lipopolysaccharide (LPS)-induced liver failure. Mice were given an intraperitoneal injection of daidzin (25, 50, 100 and 200 mg/kg) 1 h before receiving an injection of D-GalN (700 mg/kg)/LPS (10 microg/kg). Daidzin markedly reduced the elevated serum aminotransferase activity and the levels of lipid peroxidation and tumor necrosis factor-alpha. The glutathione content was lower in the D-GalN/LPS group, which was attenuated by daidzin. The daidzin pretreatment attenuated the swollen mitochondria observed in the d-GalN/LPS group. Daidzin attenuated the apoptosis of hepatocytes, which was confirmed using the terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling method and a caspase-3 assay. Overall, these results suggest that the liver protection of daidzin is due to reduced oxidative stress and its antiapoptotic activity.

Bile Acids Metabonomic Study on the CCl4- and α-Naphthylisothiocyanate-Induced Animal Models: Quantitative Analysis of 22 Bile Acids by Ultraperformance Liquid Chromatography−Mass Spectrometry

Bile acids (BAs) are crucial for the diagnosis, follow-up, and prognostics of liver and intestinal disorders and other diseases affecting BA metabolism. A rapid, simple, and sensitive analytical method is needed to demonstrate the full metabolic profile and simultaneously determine the individual BAs in biological samples. In our present study, an ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) method has been established and validated for simultaneous quantitation of 22 BAs and a metabonomic study was performed based on the chemometric analysis of the serum samples from carbon tetrachloride (CCl4)- and alpha-naphthylisothiocyanate (ANIT)-induced liver failure rats. The optimal chromatographic condition was effected by UPLC (Acquity UPLC BEH column, 1.7 microm, 2.1 mm x 100 mm) using a linear gradient elution system of methanol-5 mM ammonium acetate containing 0.01% acetic acid after a simple-step deproteinization by precipitation. The separation of the 22 BAs can be finished in less than 12 min, and the concentrations of these BAs in rat serums were simultaneously determined using a selective ions monitoring mode. The method was validated with respect to repeatability (relative standard deviation < 9.78%) and accuracy (relative errors from -13.55 to 9.58%). The range of each BA was found from not detected (nd) to 8301 ng mL(-1), respectively. Furthermore, the developed method was successfully applied to the metabonomics analysis of BAs in CCl4- and ANIT-induced liver failure rats, using principle component analysis and canonical discriminant analysis. The serum samples from the two types of rat liver injury could be distinguished from each other and from the untreated animals according to the varieties of BAs. It indicated that the level of BAs could be considered as a sensitive parameter of hepatotoxicity induced by different chemical toxins. This novel metabonomics study of BAs based on the UPLC-MS profile provides not only an accurate quantitative assay of the serum concentrations of biomarkers but also a promising methodology for evaluation of liver injury.

Alveolar Echinococcosis induced liver failure: salvage by liver transplantation in an otherwise uniformly fatal disease

A technically difficult liver transplant was performed in a 68-yr-old male with Alveolar Echinococcosis causing end-stage liver disease. The pathology was extensive and included hepatic artery thrombosis, Budd-Chiari syndrome, and right hemidiaphragm invasion necessitating resection of this portion of diaphragm and direct donor cava anastomosis to the right atrium. The patient is now 21 months since transplant disease free with normal liver function.

Sulfamethoxazole/Trimethoprim induced liver failure: a case report.

Sulfamethoxazole/Trimethoprim (SMX/TMP) is a commonly used antibiotic, its' known adverse reaction of hepatotoxicity leading to acute liver failure is considered rare. We present a case of a 22 year old female who developed jaundice and acute liver failure one week after taking SMX/TMP for a UTI. After an extensive work up, a clinical diagnosis of SMX/TMP induced liver failure was reached. Over the course of several weeks she made a good clinical and biochemical recovery with supportive care. In this case report we describe her clinical presentation and course, and present a brief review of the literature.

Control of acute, chronic, and constitutive hyperammonemia by wild‐type and genetically engineered Lactobacillus plantarum in rodents†

Hyperammonemia is a common complication of acute and chronic liver diseases. Often accompanied with side effects, therapeutic interventions such as antibiotics or lactulose are generally targeted to decrease the intestinal production and absorption of ammonia. In this study, we aimed to modulate hyperammonemia in three rodent models by administration of wild-type Lactobacillus plantarum, a genetically engineered ammonia hyperconsuming strain, and a strain deficient for the ammonia transporter. Wild-type and metabolically engineered L. plantarum strains were administered in ornithine transcarbamoylase-deficient Sparse-fur mice, a model of constitutive hyperammonemia, in a carbon tetrachloride rat model of chronic liver insufficiency and in a thioacetamide-induced acute liver failure mice model. Constitutive hyperammonemia in Sparse-fur mice and hyperammonemia in a rat model of chronic hepatic insufficiency were efficiently decreased by Lactobacillus administration. In a murine thioacetamide-induced model of acute liver failure, administration of probiotics significantly increased survival and decreased blood and fecal ammonia. The ammonia hyperconsuming strain exhibited a beneficial effect at a lower dose than its wild-type counterpart. Improved survival in the acute liver failure mice model was associated with lower blood ammonia levels but also with a decrease of astrocyte swelling in the brain cortex. Modulation of ammonia was abolished after administration of the strain deficient in the ammonium transporter. Intestinal pH was clearly lowered for all strains and no changes in gut flora were observed. Hyperammonemia in constitutive model or after acute or chronic induced liver failure can be controlled by the administration of L. plantarum with a significant effect on survival. The mechanism involved in this ammonia decrease implicates direct ammonia consumption in the gut.

Metabonomic analysis of hepatitis B virus-induced liver failure: identification of potential diagnostic biomarkers by fuzzy support vector machine

Hepatitis B virus (HBV)-induced liver failure is an emergent liver disease leading to high mortality. The severity of liver failure may be reflected by the profile of some metabolites. This study assessed the potential of using metabolites as biomarkers for liver failure by identifying metabolites with good discriminative performance for its phenotype. The serum samples from 24 HBV-induced liver failure patients and 23 healthy volunteers were collected and analyzed by gas chromatography-mass spectrometry (GC-MS) to generate metabolite profiles. The 24 patients were further grouped into two classes according to the severity of liver failure. Twenty-five commensal peaks in all metabolite profiles were extracted, and the relative area values of these peaks were used as features for each sample. Three algorithms, F-test, k-nearest neighbor (KNN) and fuzzy support vector machine (FSVM) combined with exhaustive search (ES), were employed to identify a subset of metabolites (biomarkers) that best predict liver failure. Based on the achieved experimental dataset, 93.62% predictive accuracy by 6 features was selected with FSVM-ES and three key metabolites, glyceric acid, cis-aconitic acid and citric acid, are identified as potential diagnostic biomarkers.

467 Aspirin Blocks Acetaminophen Induced Hepatotoxicity and Mortality in Mice - Dependent On the ASC/Caspase-1 Inflammasome

Acetaminophen (APAP) hepatotoxicity is dependent on the immune system, but the responsible molecular pathways have not been identified. Recently it was reported that IL-1 receptor signaling is required for APAP induced hepatotoxicity (Nature Med. July 2007, vol. 13,7. p851). The protein complex of pattern recognition molecules, the adaptor protein ASC and caspase-1 constitutes the inflammasome. Activation of the inflammasome results in production of IL-1 beta, resulting in IL-1 receptor signaling. Aims: i) Determine the role of the inflammasome in APAP hepatotoxicity. ii) Test if aspirin down-modulates the inflammasome pathway. iii) Test if aspirin blocks APAP hepatotoxicity. Methods: APAP hepatotoxicity (500 mg/kg ip single injection) was induced in wild-type C57BL/6 mice, and mice deficient in inflammasome components ASC, or caspase-1. An In-Vivo assay of inflammation dependent on the ASC/Caspase-1 pathway was used to test if aspirin can reduce inflammation mediated by this pathway. This consisted of intraperitoneal (ip) injection of monosodium urate (MSU) (3mg/mouse), with quantification of peritoneal neutrophils at 3 hrs. The ability of aspirin (approx 6mg/kg in drinking water starting 3 days prior to APAP), the platelet inhibitor clopidogrel (30 mg/kg by gavage every 24 hrs starting 2 days prior to APAP) and a cox-1 inhibitor (SC-560, 5mg/kg by gavage every 12 hrs starting 60 hrs before APAP) to protect from APAP induced injury was tested. Results: Mice deficient in the adaptor protein ASC or caspase-1 had reduced mortality from hepatotoxic doses of APAP (P<0.027 and P<0.013 respectively). In wild-type mice aspirin reduced inflammation mediated by the ASC/Caspase1 inflammasome as demonstrated by reduced ip neutrophil accumulation (P<0.015). In wild-type mice at 12 hrs after APAP injection aspirin improved histology and transaminitis (control group mean ALT 2365 iu/ml SD 1801 vs aspirin group mean ALT 944 iu/ml SD 373 p<0.04). In wild-type mice aspirin also reduced mortality from APAP hepatotoxicity (at 72 hrs after APAP mortality was 10/13 in control group and 3/17 in group receiving aspirin P<0.015). Clopidogrel and the cox-1 inhibitor SC-560 did not reduce mortality from APAP hepatotoxicity, suggesting that the mechanism of action of aspirin was not via inhibition of platelet degranulation or cox-1. Conclusions: The ASC/Caspase-1 inflammasome is required for APAP induced hepatotoxicity, and can be suppressed by aspirin. Aspirin reduces APAP induced mortality. Co-formulation of aspirin with APAP may reduce APAP induced liver failure.

Updated Results of High-Dose Yttrium 90 (90Y) Ibritumomab Tiuxetan with High-Dose Etoposide (VP-16) and Cyclophosphamide (CY) Followed by Autologous Hematopoietic Cell Transplant (AHSCT) for Poor-Risk or Refractory B-Cell Non-Hodgkin's Lymphoma.

Background: 90Y ibritumomab tiuxetan (Zevalin®) has been shown to be an effective therapy for patients with both follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We have previously reported the feasibility of adding high-dose 90Y ibritumomab tiuxetan to high-dose VP-16 and CY followed by AHSCT without additional toxicity. Herein, we reported longer follow-up results of this high-dose regimen.Methods: Patients undergo dosimetry study (day-21) with 5 mCi 111In-ibritumomab tiuxetan following 250 mg/m2of rituximab, followed by 90Y ibritumomab tiuxetan (day-14) to deliver a target dose of 1000 cGy to highest normal organ and then VP-16 (day-4), and CY (day-2). Bone marrow biopsy is done on day-7 to estimate the radiation dose. Stem cells are re-infused when the radiation dose to re-infused stem cells is estimated to be <5 cGy.Results: Between 5/00 and 7/05, 53 patients were enrolled; 11 had an imaging study but did not proceed to treatment due to dosimetry ineligibility (7), progressive disease (2), reaction to 111In-ibritumomab tiuxetan (1) and reaction to rituximab (1). 42 patients (25 M: 17F), median age 51 yrs (range 25–59.6) with FL (n=13), DLBCL (n=20), mantle cell (MCL) (n=8) and transformed lymphoma (n=1) were treated. Disease status at AHSCT: 1stCR/PR=11, ≥2ndCR=13, REL=9 and IF=9. Twenty-three (55%) had prior BM involvement. Median number of prior chemo regimens was 2 (range 1–6). All but two had received rituximab. As part of phase I/II trial, 6 received VP-16 40mg/kg and the rest received 60 mg/kg. The median 90Y ibritumomab tiuxetan dose delivered was 70.8 mCi (range 37–105). The treatment was well tolerated with mucositis and neutropenic fever being the most common acute toxicities. All but one patient engrafted. The median time to reach ANC>500/μl and platelet>20,000/μl was 10 days (range 8–17) and 12.5days (range 8–123), respectively. The transplant-related mortality (TRM) at day 100 was 2%. There were 8 deaths due to relapse (3), second malignancies (2), graft failure (1), alcohol induced liver failure (1) and sudden death (1). Secondary malignancies occurred in 3 (7%) heavily pre-treated FL: pancreatic cancer at 3.8 yrs, acute myeloid leukemia at 5 years and one with abnormal chromosome but without morphologic evidence of MDS at 1 year. At a median follow-up of 55 months (range, 25–84) for the surviving patients, the 4-year estimated overall survival (OS) and disease-free survival (DFS) is 81% (95% CI, 67–89%), and 65% (95% CI, 54–74%), respectively (figure.1). The 4-year estimated DFS for FL, DLBCL and MCL is 71% (95% CI, 51–85%), 67% (95% CI, 49–79%) and 47% (95% CI, 29–63%), respectively.Conclusion: Our long-term results suggest that the combination of high-dose 90Y ibritumomab tiuxetan and high-dose VP-16 and CY is an effective high-dose regimen, especially for FL and DLBCL. Short term toxicities appear comparable to other conventional high-dose regimens. Further prospective studies are ongoing to determine the curability and long term toxicities of this preparative regimen. [Display omitted]

Liver transplantation for nonsteroidal anti-inflammatory drug-induced liver failure: nimesulide as the first implicated compound

Among industrialized countries, the rate of drug-induced liver failure varies widely accounting for about 1-12% of the indications for liver transplantation. Nonsteroidal anti-inflammatory drugs (NSAIDs) are with antibiotics the most frequently involved compounds. In this single-center series of 57 consecutive cases of acute liver failure treated by orthotopic liver transplantation, five were related to NSAIDs-induced liver damage, three being due to nimesulide use. This has to be taken as a further warning about the potential for this compound to induce liver failure.

EFFECT OF ANGIOTENSIN AT1RECEPTOR ANTAGONIST ON d-GALACTOSAMINE-INDUCED ACUTE LIVER INJURY

1. Acute liver injury is a severe disease in which metabolic homeostasis is affected. The presence of liver cell death triggers a cascade of inflammatory responses leading to various degrees of liver damage. The pathophysiology of liver injury is complex, involving an interplay between parenchymal and non-parenchymal cells. 2. There is increasing evidence for a role of the local renin-angiotensin system (RAS) in liver cell death, inflammatory response and liver regeneration. It has been shown that the local RAS plays an important regulatory role in a variety of tissues. In experimental hepatic fibrogenesis, the angiotensin AT(1) receptor (AT(1)R) blocker losartan has been shown to be able to attenuate transforming growth factor-b1 activity and collagen gene expression. 3. In the present study, using a D-galactosamine (GalN)-induced liver failure rat, AT(1)R were localized around the centrilobular region, which was not evident in normal liver. Blood tests showed an elevation of total bilirubin and alanine aminotransferase. Furthermore, there was an increase in tissue-specific inhibitor of metalloproteinase (TIMP)-1 protein in the liver. Losartan treatment was able to reduce all these parameters. Levels of TIMP-1 protein were reduced by 1.5- and 1.56-fold on Days 1 and 3, respectively (both P < 0.05), in the losartan-treated group relative to the GalN-treated group. The survival rate of the losartan-treated group was significantly higher than that of the GalN-treated group (5 day survival 85 vs 42.5%, respectively; P < 0.05). 4. In conclusion, the AT(1)R blocker losartan suppresses GalN-induced liver injury. This may indicate that AT(1)R blockers may have therapeutic potential in the treatment of acute liver injury.

Intrinsic resistance to TNF-α-induced hepatocyte apoptosis in ICR mice correlates with expression of a short form of c-FLIP

The administration of tumor necrosis factor-α (TNF-α) or the anti-Fas antibody (Jo-2) to mice causes acute liver failure, which is lethal within hours as a result of the induction of apoptosis in hepatocytes. It was recently reported that nonobese diabetic (NOD) mice are less sensitive to TNF-α/D-galactosamine (GalN)-induced liver failure than C57BL/6J (B6) mice, whereas both NOD and B6 mice were sensitive to the lethal effect of Jo-2. In the present study, we investigated the differences between the apoptotic liver cell death induced by TNF-α/GalN and that induced by Jo-2. B6, NOD, and Jcl-Imperial Cancer Research (ICR) mice were injected intravenously with TNF-α/GalN or Jo-2. ICR mice were less sensitive to TNF-α/GalN-induced liver failure than NOD and B6 mice (P<0.0001). In contrast, ICR mice were more sensitive to Jo-2-induced liver failure than B6 mice (P=0.0003). The liver caspase-3, -8 activity, serum transaminase levels, and the number of apoptotic liver nuclei all decreased in ICR in comparison to B6 mice treated with TNF-α/GalN. The mRNA expression of TNFR-associated death domain, Fas associated protein with death domain, and Bcl family and nuclear factor-κB activation induced by TNF-α/GalN were similar in both mice. Interestingly, the short form of cellular FLICE/caspase-8-inhibitory protein (c-FLIPS) was constitutively upregulated in ICR mice. In conclusion, these results suggest that ICR mice have an intrinsic resistance to TNF-α-induced hepatocyte apoptosis, and that c-FLIPS may play a role in TNF-α/GalN-induced liver failure, but not in Fas-induced liver failure.

Gatifloxacin Induced Liver Failure in Patient with Underlying Fibrin Ring Granuloma Caused by Q Fever

Gatifloxacin Induced Liver Failure in Patient with Underlying Fibrin Ring Granuloma Caused by Q Fever

Combined Living Donor Liver/Small Bowel Transplantation

We are reporting the first known case of sequential combined living donor liver/small bowel transplantation (LDL/SBT). A 2-year-old boy born with gastroschisis and intestinal malrotation lost his entire small bowel and colon shortly after birth. He underwent a living donor small bowel transplant at 1 year of age that was lost 4 months after implantation for posttransplant lymphoproliferative disease (PTLD). He recovered from PTLD but developed total parenteral nutrition (TPN)-induced liver failure. He received a combined left lateral liver and terminal ileum transplant that we chose to perform sequentially due to the presence of preformed antibodies against his mother's tissues. The mother had no complications and a cumulative hospital stay of 7 days. At 9 months postsurgery, the patient is on full enteral nutrition and has suffered neither technical complications nor rejection. The technique described here is reproducible and makes combined living donor LDL/SBT an alternative to combined cadaveric liver-small bowel transplant.

ME3738 protects from con a induced liver failure via an IL6-dependent mechanism: Christian Klein, Michael P Manns, Christian Trautwein, Medical school Hannover, Hannover Germany

ME3738 protects from con a induced liver failure via an IL6-dependent mechanism: Christian Klein, Michael P Manns, Christian Trautwein, Medical school Hannover, Hannover Germany

Schmidt Syndrome Presenting as Acute Liver Failure

The Schmidt Syndrome (Type II Autoimmune-Syndrome) is characterised by an autoimmune adrenalitis in combination with a chronic lymphocellular thyreoiditis resulting in insufficiency of these organs in adulthood. Combination with diabetes is possible. The diagnosis is usually established by clinical examination and analysis of serum hormone levels (adrenocorticotropin hormone [ACTH], cortisol, thyroid stimulating hormone [TSH], triiodothyronine [fT3], thyroxine [fT4]). In the present case, initial diagnosis was rapid progressive liver failure of unknown origin with consecutive multiple organ dysfunction syndrome including dysfunction of heart, lungs, and kidneys. Frequent and less frequent causes of liver failure were ruled out, e.g. viral or autoimmune hepatitis, Budd-Chiari-syndrome, toxic, or drug induced liver failure. In retrospect, the multiple organ dysfunction syndrome was caused by hypoperfusion due to severe hypovolemia and hypoperfusion was induced by adrenocortical insufficiency proven by endocrinological testing. The clinical course of this case stresses the importance of the hormone balance in the critical ill patient. The guideline for treatment of patients with assumed hormonal dysregulation should include a full hormone status prior to substitution. The present case report also illustrates the importance of clinical signs and careful consideration of the medical history in detecting an autoimmune endocrine disease.

Characteristics of hepatocytes derived from early ES cells and treatment of surgically induced liver failure rats by transplantation

Background Although liver transplantation has become a standard therapy for diseases such as fulminant hepatitis and cirrhosis, the lack of donor organs remains a major problem. One solution is the development of transplantable hepatocytes. The metabolic characteristics as well as function and adaptation of hepatocytes (R-EES-hep cell) derived from rat early embryonic stem cells were examined after transplantation into rats with surgically induced liver failure. Methods Rat hepatocyte cell lines were established from early embryonic stem cells cultured in the presence of embryotrophic factors by colony cloning methods. The cell lines were established from two cell embryos taken from spontaneous dwarf rats using the novel method of Ishiwata et al. Morphologic differentiation as well as albumin and bilirubin production were observed by immunostaining. R-EES-hep cells were transplanted into the spleens of 90% hepatectomized, surgically induced liver failure rats to analyze survival rates. Results When cultured in type I collagen gel the cells formed cordlike structures resembling the liver. Both albumin and bilirubin production were observed when transplanted; the spleen was converted into a liver-like structure with prolonged survival of the 90% hepatectomized rats for up to 3 months up to the time of killing. Conclusions R-EES-hep cells showed many of the distinctive metabolic characteristics of the liver. These cells may be efficient for further research and application for hepatic cell transplantation to treat liver insufficiency patients and as biologic artificial organs.

Liver Function During Extracorporeal Whole Liver Perfusion in a Pig Model of Acute Ischemic Liver Failure

The shortage of livers for transplant has renewed interest in the potential of temporary liver support such as extra corporeal whole liver perfusion. In an ischemic induced liver failure model we perfused an extra corporeal liver through only a portal vein and assessed the function of this ex vivo liver by using hepatic tests to estimate elimination as well as synthesis capacities. Acute liver failure was performed in five control pigs by a hepatic devascularization associated to an end to side portocaval shunt. In a treated group, 5 to 6 h after this hepatic devascularization, animals were connected to an extra corporeal liver perfused via the portal vein with blood withdrawn from the ischemic liver animal from its portal vein. Devascularization of the liver induced an increase in liver enzymes and ammonia, a drop in the ratio of branched chain amino acids to aromatic amino acids, and a decrease in blood urea and indocyanine green and galactose clearances. In treated animals, urea, amino acid ratio, and clearances increased after the ex vivo liver perfusion. In this group, mean bile production and mean liver oxygen consumption were 13.7 +/- 3.6 ml/h and 16.1 +/- 7.7 ml/min, respectively. In an acute ischemic liver failure pig model, an extra corporeal whole liver perfusion demonstrated detoxification properties as well as synthesis capacities.

ACUTE PERIPARTUM INTESTINAL ISCHEMIA AND INTESTINAL TRANSPLANTATION

P620 Aims: Acute intestinal ischemia is a rare complication during the antepartum and postpartum periods. The subsequent development of short gut syndrome, however, often results in intestinal failure and chronic need for total parenteral nutrition (TPN). The commonly associated postpartum hepatic steatosis in these patients may accelerate the risk of TPN induced liver failure and indicate the early need for intestinal transplantation. This report describes 4 female intestinal recipients who developed peripartum irreversible intestinal failure and underwent visceral transplantation at variable intervals from the onset of TPN therapy. Methods: Over the last 13 years, 75 (56%) out of 135 consecutive intestinal and multivisceral adult recipients who were transplanted at the University of Pittsburgh Medical Center were female with a mean (SD) age of 43±11 years. Of these 75 patients, 4 were young reproductive white females (median age of 27) who required transplantation secondary to acute intestinal ischemia during pregnancy (n=2) or in the postpartum period (n=2). Of these 4 female recipients, 2 required combined liver and intestinal transplantation and 2 received an isolated intestinal graft. The prepartum intestinal ischemia and subsequent enterectomy occurred at the 6th and 7th month of the gestational period. The other 2 postpartum incidents occurred approximately 3 weeks after delivery. The underlying etiology of the intestinal ischemia was vascular thrombosis due to idiopathic thrombocytopenic purpura (n=1) and midgut volvulous (n=3). Life threatening liver failure developed 30 to140 months after initiation of TPN therapy in 2 patients that were rescued with combined liver and intestinal transplantation. The indications for the 2 isolated intestinal transplantations were ultra- short gut syndrome with gastrointestinal discontinuity and steatohepatitis (n=1) and TPN induced severe hepatic steatosis (n=1). All patients received tacrolimus based immunosuppression with anti IL2 antagonist induction therapy in 1 and rATG pretreatment in the most recent case. Results: With a median follow-up of 7 years (range: 2 months –13.5 years), all 4 recipients are currently alive with fully functioning grafts and complete restoration of their life style. Only one of the isolated intestinal recipients required retransplantation due to chronic rejection. Interestingly, the 2 patients who required simultaneous hepatic replacement were on TPN for a significantly longer period (140 and 30 months) compared to those who received intestine alone (4 and 6 months). Conclusions: Early intestinal transplantation should be considered for young women who develop pre- and post-partum irreversible intestinal failure. Such a recommendation is supported by the reported herein associated high risk of TPN induced liver failure.

Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis.

S-adenosyl-L-methionine (SAM) is synthesized by methionine adenosyltransferases (MATs). Ablation of the liver-specific MAT1A gene results in liver neoplasia and sensitivity to oxidant injury. Here we show that acidic sphingomyelinase (ASMase) mediates the downregulation of MAT1A by TNF-alpha. The levels of MAT1A mRNA as well as MAT I/III protein decreased in cultured rat hepatocytes by in situ generation of ceramide from exogenous human placenta ASMase. Hepatocytes lacking the ASMase gene (ASMase-/-) were insensitive to TNF-alpha but were responsive to exogenous ASMase-induced downregulation of MAT1A. In an in vivo model of lethal hepatitis by TNF-alpha, depletion of SAM preceded activation of caspases 8 and 3, massive liver damage, and death of the mice. In contrast, minimal hepatic SAM depletion, caspase activation, and liver damage were seen in ASMase-/- mice. Moreover, therapeutic treatment with SAM abrogated caspase activation and liver injury, thus rescuing ASMase+/+ mice from TNF-alpha-induced lethality. Thus, we have demonstrated a new role for ASMase in TNF-alpha-induced liver failure through downregulation of MAT1A, and maintenance of SAM may be useful in the treatment of acute and chronic liver diseases.

Ask(1) and You Shall Receive: A New Link Between Antioxidants and Cell Death Signaling

Hepatoprotection mediated by free radical scavenging molecules such as dimethyl sulfoxide (Me2SO) arose the question as to whether this effect involved one or several anti–apoptotic signals. Here, using primary cultures of rat hepatocytes and in vivo thioacetamide–induced liver failure, we showed that Me2SO failed to prevent any cleavage of initiator caspase–8 and –9 but constantly inhibited procaspase–3 maturation and apoptosis execution, pointing to an efficient inhibition of cleaved initiator caspase activities. Evidence was recently provided that apoptosis might require both caspase and ASK1/JNK–p38 activities. We demonstrated that this kinase pathway was strongly inhibited in the presence of Me2SO whereas overexpression of ASK1 was able to restore caspase–3 activity and apoptosis. Interestingly, we also found that GST M1/2 and GST A1/2 dropped under apoptotic conditions; furthermore transfection of GST M1, A1, or P1 to cells overexpressing ASK1, abolished caspase–3 activity and restored viability. This role of GSTs was further assessed by showing that their high expression level was tightly associated with inhibition of ASK1 activity in Me2SO–protected hepatocytes. Together, these results demonstrate that Me2SO–mediated hepatoprotection involves a dual inhibition of cleaved initiator caspase and ASK1/JNK–p38 activities. Furthermore, in highlighting the control of apoptosis by GSTs, these data provide new insights for analyzing the complex mechanisms of hepatoprotection.