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PubMed1998

Establishment of chimerism in donor liver with recipient-type bone marrow cells prior to liver transplantation produces marked suppression of allograft rejection in rats.

In this study, we investigated whether establishment of chimerism in donor liver with recipient-type bone marrow cells (BMCs) prior to liver transplantation could prolong the liver allograft survival. Donor female ACI rats were inoculated with recipient-type BMCs of male LEW rats via the portal vein, with or without irradiation as cytoablation, followed by intramuscular administration of FK506 for 5 days. At 1-2 months later, livers were harvested and transplanted into naive female LEW rats. No immunosuppressants were used. Chimerism in donor rats was confirmed by primers specific for the sex determinant Y chromosome of rats. With livers from rats pretreated with recipient-type BMCs, survival of liver allografts was significantly extended, irrespective of irradiation. These results showed that modification of the donor liver by intraportal injection of recipient-type BMCs and concomitant administration of FK506 prior to liver transplantation prolonged liver allograft survival in rats.

Animals↗
PubMed2005

Liver resection or cryotherapy for colorectal liver metastases: a prospective case control study.

BACKGROUND AND AIMS: While there is promising survival data for cryosurgery of colorectal liver metastases, local recurrence following cryoablation remains a problem. We aimed to compare morbidity and mortality, as well as the recurrence pattern and survival after liver resection and cryotherapy (alone or in combination with resection) for liver metastases. PATIENTS AND METHODS: Between 1996 and 2002, 168 patients underwent liver resection alone and 55 patients had cryotherapy (25 in combination with liver resection) for colorectal liver metastases. The patient, tumour and operative details were recorded prospectively and the two patient groups were compared regarding morbidity, survival and recurrence. RESULTS: More patients had a prior liver resection, liver metastases were smaller and less frequently synchronous, morbidity was significantly lower and hepatic recurrence was significantly more frequent in the cryotherapy group. Five-year survival rates following resection and cryotherapy were comparable (23 and 26% respectively), while overall and hepatic recurrence-free survival was inferior following cryotherapy. CONCLUSION: Cryotherapy is a valuable treatment option for some patients with non-resectable colorectal liver metastases. While survival is comparable to that after resection, higher hepatic recurrence rates following cryotherapy should caution against the use of cryotherapy for resectable disease until the results of randomized controlled trials are available.

Colorectal Neoplasms↗
PubMed1999

The incorporation of fatty acids of different chain length into liver and biliary lipids in the perfused rat liver.

In an attempt to correlate the incorporation of fatty acids (FA) of different chain length into liver and biliary lipids, isolated rat livers were perfused for 2 h with Krebs-Ringer bicarbonate containing 1% albumin and 10 mumol of [1-14C]-labeled FA: C2, C8, C10, C12, C16, and C18:1. One to 1.36 mumol of medium-chain fatty acids (MCFA, C8, C10, and C12) and 6.6 mumol of long-chain FA (LCFA) were incorporated into liver lipids, 40% of the latter into phosphatidylcholine (PC). 14C-acetate (13 nmol) was incorporated into biliary cholesterol; 14C-MCFA contributed only 3.2-5 nmol; LCFA did not lead to newly synthesized cholesterol. Newly synthesized liver PC (2.75 to 3.25%) and newly synthesized liver cholesterol (6.5 to 10%) were secreted into bile. The specific radioactivity of biliary PC after infusion of all-saturated FA was 3.8-6.8 times higher than that of liver PC; for C18:1 it was only 1.7-fold. The specific radioactivity of biliary cholesterol, as compared to liver cholesterol, was 12 times higher for C2 and five times higher for MCFA. This indicates that a considerable proportion of the newly synthesized lipids was secreted into bile prior to significant mixing with preexisting liver PC and cholesterol pools. Liver PC contained 8% of unchanged 14C-C12; while 14C-C10 was not detected. Biliary PC, in contrast, contained 18% of unchanged 14C-C12 and 3% 14C-C10. These results suggest that after prolonged infusion of medium-chain triacylglycerols/long-chain triacylglycerols to patients, biliary PC may become enriched with MCTA. In addition, the oxidation of these FA may provide C-2 units which increase cholesterol synthesis.

Animals↗
PubMed1991

Hepatic lipase-mediated hydrolysis versus liver uptake of HDL phospholipids and triacylglycerols by the perfused rat liver.

Hepatic triacylglycerol-lipase-mediated hydrolysis and liver uptake of high-density lipoprotein (HDL) lipid components were studied in a recirculating rat liver perfusion, a situation where the enzyme is physiologically expressed and active at the vascular bed. Human native HDL were labelled with tri-[3H]oleoylglycerol, [N-methyl-3H]dipalmitoylphosphatidylcholine (DPPC), 1-palmitoyl,2-[14C]linoleoylphosphatidylcholine (PLPC), 1-palmitoyl,2-[14C]linoleoylphosphatidyl-ethanolamine (PLPE) and 1-palmitoyl,2-[14C]palmitoylphosphatidylethanolamine (DPPE). (1) Relative degradation rates of phosphatidylethanolamine molecular species were 2- to 10-fold higher than those of phosphatidylcholine. Considering [14C] PLPC and [14C] PLPE as representative of HDL phosphatidylcholine and phosphatidylethanolamine, respectively, the amounts of lysophosphatidylcholine and lysophosphatidylethanolamine generated after a 60 min perfusion were comparable. The enzyme showed a clear preference for the molecular species bearing an unsaturated fatty acid at the 2 position of glycerol; this was the most pronounced in the case of phosphatidylethanolamine molecular species. (2) Relative liver uptake of HDL-phosphatidylethanolamine was 4- to 5-fold higher than that of HDL-phosphatidylcholine, irrespective of the constitutive fatty acids. Nevertheless, mass estimation indicated that 3 times more molecules of phosphatidylcholine than of phosphatidylethanolamine were transferred. No correlation could be found between the relative degradation rates of phospholipids and their relative liver uptake, indicating a dissociation between the two processes. (3) Perfusate decay and relative liver uptake of labelled HDL-triacylglycerol were higher than that of any phospholipid class. No circulating radiolabelled free fatty acids accumulated in the perfusate, but they were found acylated into liver cell phospholipids and triacylglycerols. (4) A prior 10-12-min washout of the liver vascular bed with heparin removed over 80% of the hepatic lipase activity, as assessed by specific immunoinhibition. Hepatic lipase-depleted liver displayed impaired phospholipid hydrolysis and triacyglycerol uptake, whereas the transfer of HDL phospholipids to liver tissue was unaffected.

Animals↗
PubMed1989

Histamine inhibition of mixed function oxidase activity in rat and human liver microsomes and in the isolated perfused rat liver.

The imidazole ring is a common structural feature of some xenobiotics that inhibit cytochrome P-450-catalysed reactions. Histamine is a 4-substituted imidazole and a preliminary study has shown it to be an inhibitor of rat liver microsomal drug oxidation. This work has now been extended. Histamine appears to be a competitive inhibitor of the alpha-hydroxylation (HM) (Ki = 164 microM; IC50 at 20 microM = 308 microM) and O-demethylation (ODM) (Ki = 243 microns; IC50 at 20 microM = 400 microM) of metoprolol in rat liver microsomes. Of the metabolites of histamine only N-acetylhistamine showed comparable inhibitory potency to that of the parent compound. Histamine impaired the disappearance of lignocaine when incubated with rat liver microsomes. This was accompanied by a corresponding inhibition of 3-hydroxy-lignocaine appearance. Histamine produced a type II spectral interaction with rat liver microsomes (lambda max = 432 nm, lambda min = 408 nm; Ks = 0.11 mM). When histamine was incubated alone with rat liver microsomes no loss of substrate was observed. The oxidation of metoprolol by human liver microsomes was impaired by histamine (IC50 values for ODM appearance at 25 microM: liver HL1 greater than 10, HL3 = 3.8 and HL4 = 3.7 mM). In comparison, cimetidine had an IC50 value of 1.5 mM using microsomes from liver HL3. Addition of histamine impaired the elimination of metoprolol by the isolated perfused rat liver in a dose-dependent manner (P less than 0.001, one-way analysis of variance). These data demonstrate that histamine can enter hepatocytes, interact with cytochrome P-450 and inhibit some drug oxidation reactions. The physiological relevance of inhibition of drug metabolism by histamine remains to be determined.

Animals↗
PubMed1986

Evaluation of liver weight changes following repeated administration of carbon tetrachloride in rats and body-liver weight relationship.

The proper method of evaluating liver weight changes resulting from the primary toxic effect of a chemical was studied. We used a pair-feeding method with carbon tetrachloride (CCl4), a chemical known to cause an increase in liver weight. Male rats were assigned to an untreated control group, CCl4-treated groups (daily dose of 10 microliter or 50 microliter of CCl4 in olive oil/100 g body wt), olive oil-treated plus feed-restricted groups, and feed-restricted groups. In the 2 types of feed-restricted groups the body weight changes of the CCl4-treated groups were duplicated by imposing restrictions on feeding. Absolute and relative liver weights were compared among the 4 types of groups after treatment for 14 or 25 days. Either absolute or relative liver weight of the treated group when compared to that of the feed-restricted group was the most reliable and sensitive toxicity indicator. In comparing the treated group with the untreated control group, relative liver weight was a more sensitive toxicity indicator than absolute liver weight. However, when liver weight data for about 200 normal male rats were plotted against body weight, and the 95% confidence limits of the regression line (y = ax) were estimated, most of the data for the feed-restricted rats were outside the lower confidence limit. This means that a comparison of the relative liver weights of the treated rats and untreated control rats is not strictly valid, because the body weight-liver weight relationships are not the same in the 2 groups.

Administration, Oral↗
PubMed2004

Modulation of fibronectin gene expression in inflammatory mononuclear phagocytes of rat liver after acute liver injury.

BACKGROUND/AIMS: In acute liver injury, fibronectin (FN) is deposited at the site of hepatocellular necrosis. We have previously shown that liver inflammatory mononuclear phagocytes (MNP), in contrast to quiescent hepatic macrophages, synthesize abundant amounts of FN. We now analyzed effects of agents known to influence macrophage functions to better understand liver damage and repair. METHODS: Acute rat liver injury was induced by CCl(4). Liver cellular FN (cFN) expression was analyzed by in situ-hybridization. Liver MNP were isolated and characterized immunocytochemically. Protein synthesis was studied by biosynthetic labeling, immunoprecipitation, and SDS-PAGE. RNA was analyzed by Northern Blotting. RESULTS: cFN gene expression was localized by in situ-hybridization and immunohistochemistry within the pericentral inflammatory infiltrate. Treatment of inflammatory MNP with dexamethasone, or interferon-gamma, or lipopolysaccharide induced a dose-dependent decrease in cFN gene expression, whereas transforming growth factor-beta increased cFN gene expression. CONCLUSIONS: 1. Inflammatory MNP express cFN. 2. Downregulation of cFN expression by dexamethasone in inflammatory MNP may explain delayed wound healing after corticosteroid therapy. Interferon-gamma and lipopolysaccharide could also delay the repair process in the liver. Transforming growth factor-beta may promote liver wound healing after acute liver injury by increasing local cFN synthesis in inflammatory mononuclear phagocytes of the inflammatory infiltrate.

Acute Disease↗
PubMed2005

Evaluation of cultured, precision-cut rat liver slices as a model to study drug-induced liver apoptosis.

The precision-cut liver slice culture model has been used widely to investigate drug metabolism and drug-induced necrosis. However, apoptosis, a key mediator of liver toxicity remains to be studied in this model. We evaluated apoptosis induced by thioacetamide (TAA) in rat liver slices, and in livers taken from TAA-treated rats as a control. Rat liver slices were treated with 50, 75 and 100 mM of TAA for 15 h. Histopathological examination of the liver slices revealed specific centrilobular localization of apoptotic hepatocytes at 75 mM but randomly distributed at 100 mM. Apoptosis in centrilobular hepatocytes was confirmed by appearance of cleavage products of caspase-3 and DNA fragmentation studied by TUNEL method. A concentration-dependent release of cytochrome c was observed in the slices, suggesting a role for mitochondria in the apoptosis triggered by TAA. The in vitro results were compared to the data obtained in male Sprague-Dawley rats given a single ip injection of 40 mg/kg TAA and sacrificed 1, 2, 3 and 6 h after dosing. Histopathological analyses showed specific centrilobular localization of apoptosis after 6 h treatment. Caspase-3 activation, DNA fragmentation and cytochrome c release were also observed in the liver of rats treated with TAA. Overall these data indicated that precision-cut liver slices provide a valuable in vitro system to study drug-induced liver apoptosis.

Animals↗
PubMed1997

One-shot delayed-type hypersensitivity reaction in the mouse liver causes a sustained liver injury to picryl chloride.

The developmental characteristics of liver injury induced by a delayed-type hypersensitivity (DTH) mechanism against picryl chloride were examined for 9 consecutive weeks in 3 mouse strains, BALB/c, Kunming and ICR mice. The changes of most biochemical parameters were similar in these three strains, namely, the activities of serum transaminases, lactic dehydrogenase, and prolidase were elevated significantly on day 1, during the first several weeks, and almost throughout the duration, respectively, of liver injury. The content of liver hydroxyproline was also increased after 1-9 weeks of liver injury. In addition, a significant decrease of liver weight, serum alkaline phosphatase and albumin level was observed in BALB/c and Kunming mice. Similar changes in liver histology were also found in the three strains. The hepatocellular necrosis and inflammatory infiltration into the portal area were the predominant features on day 1 and were still distinct during the subsequent several weeks. The mild or moderate hepatocellular degeneration, regeneration and connective tissue hyperplasia were observed after 1 or 3 weeks. A bridging necrosis between portal and portal was observed in several BALB/c and ICR mice, reflecting the possibility of exacerbation of liver injury. These results suggest that the liver injury could be caused and sustained by a one-shot DTH reaction to picryl chloride. The chronicity of the biochemical and histopathological characteristics may be helpful in elucidating the mechanisms of chronic development of liver injury.

Animals↗
PubMed2005

Liver fatty-acid-binding protein (L-FABP) gene ablation alters liver bile acid metabolism in male mice.

Although the physiological roles of the individual bile acid synthetic enzymes have been extensively examined, relatively little is known regarding the function of intracellular bile acid-binding proteins. Male L-FABP (liver fatty-acid-binding protein) gene-ablated mice were used to determine a role for L-FABP, the major liver bile acid-binding protein, in bile acid and biliary cholesterol metabolism. First, in control-fed mice L-FABP gene ablation alone increased the total bile acid pool size by 1.5-fold, especially in gall-bladder and liver, but without altering the proportions of bile acid, cholesterol and phospholipid. Loss of liver L-FABP was more than compensated by up-regulation of: other liver cytosolic bile acid-binding proteins [GST (glutathione S-transferase), 3alpha-HSD (3alpha-hydroxysteroid dehydrogenase)], key hepatic bile acid synthetic enzymes [CYP7A1 (cholesterol 7alpha-hydroxylase) and CYP27A1 (sterol 27alpha-hydroxylase)], membrane bile acid translocases [canalicular BSEP (bile salt export pump), canalicular MRP2 (multidrug resistance associated protein 2), and basolateral/serosal OATP-1 (organic anion transporting polypeptide 1)], and positive alterations in nuclear receptors [more LXRalpha (liver X receptor alpha) and less SHP (short heterodimer partner)]. Secondly, L-FABP gene ablation reversed the cholesterol-responsiveness of bile acid metabolic parameters such that total bile acid pool size, especially in gall-bladder and liver, was reduced 4-fold, while the mass of biliary cholesterol increased 1.9-fold. The dramatically reduced bile acid levels in cholesterol-fed male L-FABP (-/-) mice were associated with reduced expression of: (i) liver cytosolic bile acid-binding proteins (L-FABP, GST and 3alpha-HSD), (ii) hepatic bile acid synthetic enzymes [CYP7A1, CYP27A1 and SCP-x (sterol carrier protein-x/3-ketoacyl-CoA thiolase)] concomitant with decreased positive nuclear receptor alterations (i.e. less LXRalpha and more SHP), and (iii) membrane bile acid transporters (BSEP, MRP2 and OATP-1). These are the first results suggesting a physiological role for the major cytosolic bile acid-binding protein (L-FABP) in influencing liver bile metabolic phenotype and gall-bladder bile lipids of male mice, especially in response to dietary cholesterol.

Animals↗
PubMed1985

Conversion of 5-aminolaevulinate into haem by homogenates of human liver. Comparison with rat and chick-embryo liver homogenates.

To assess whether the synthesis of haem can be studied in small amounts of human liver, we measured kinetics of the conversion of 5-aminolaevulinate into haem and haem precursors in homogenates of human livers. We used methods previously developed in our laboratory for studies of rat and chick-embryo livers [Healey, Bonkowsky, Sinclair & Sinclair (1981) Biochem. J. 198, 595-604]. The maximal rate at which homogenates of human livers converted 5-aminolaevulinate into protoporphyrin was only 26% of that for rat, and 58% of that for chick embryo. In the absence of added Fe2+, homogenates of fresh human liver resembled those of chick embryos in that protoporphyrin and haem accumulated in similar amounts, whereas fresh rat liver homogenate accumulated about twice as much haem as protoporphyrin. However, when Fe2+ (0.25 mM) was added to human liver homogenates, mainly haem accumulated, indicating that the supply of reduced iron limited the activity of haem synthase, the final enzyme in the haem-biosynthesis pathway. Addition of the potent iron chelator desferrioxamine after 30 min of incubation with 5-amino[14C]laevulinate stopped further haem synthesis without affecting synthesis of protoporphyrin. Thus the prelabelled haem was stable after addition of desferrioxamine. Since the conversion of 5-amino[14C]laevulinate into haem and protoporphyrin was carried out at pH 7.4, whereas the pH optimum for rat or bovine hepatic 5-aminolaevulinate dehydratase is about 6.3, we determined kinetic parameters of the human hepatic dehydrase at both pH values. The Vmax was the same at both pH values, whereas the Km was slightly higher at the lower pH. Our results indicate that the synthesis of porphyrins and haem from 5-aminolaevulinate can be studied with the small amounts of human liver obtainable by percutaneous needle biopsy. We discuss the implications of our results in relation to use of rat or chick-embryo livers as experimental models for the biochemical features of human acute porphyria.

Aminolevulinic Acid↗
PubMed1998

Hepatitis G infection: role in cryptogenic chronic liver disease and primary liver cell cancer in the UK. Trent Hepatitis C virus Study Group.

Hepatitis G virus (HGV) is a flavivirus that can cause acute hepatitis and persistent infection but its role in chronic liver disease or primary liver cancer is unproven. In this study we have examined the prevalence of HGV RNA in the serum of patients with hepatitis C virus (HCV) infection and in patients with cryptogenic chronic liver disease, including non-alcoholic steatohepatitis (NASH), and in patients with HCV-related hepatocellular carcinoma (HCC) and HCC arising in patients with cryptogenic liver disease. One-hundred and thirty patients who were positive for antibody to HCV (anti-HCV), 54 patients with cryptogenic chronic liver disease (including 17 patients with NASH) and 46 patients with hepatitis C-related (n = 27) or cryptogenic liver disease-related HCC (n = 19) were studied. HGV RNA was detected using nested reverse transcriptase-polymerase chain reaction (RT-PCR) and was found in 16.1% of patients with HCV infection. HGV RNA was not detected in any patient with cryptogenic liver disease. In patients with HCC, 7/34 samples were positive for HGV RNA and six out of seven HGV-positive subjects also had HCV infection. Only one patient with HCC in cryptogenic liver disease was positive for HGV RNA. Hence, cryptogenic liver disease in the UK is not caused by HGV/GBVc infection. It seems unlikely that HGV plays a significant role in hepatocarcinogenesis.

Carcinoma, Hepatocellular↗
PubMed2001

Liver transplantation: current status and novel approaches to liver replacement.

The major challenge currently facing liver transplantation is the performance of a greater number of liver transplants, which has been fueled by the large and growing disparity between the increasing number of qualified patients listed for transplantation and the relatively static number of available cadaver donor organs. In the past 2 years, approximately 4500 liver transplants have been performed annually, with 1-year survival rates in the 85%-90% range, while the waiting list has expanded as of November 2000 to more than 16,000 patients, resulting in an increasing death rate among listed patients. In the short term, there will continue to be a major focus on more effective use of available cadaver donor organs to balance the competing principles of justice (patients with most urgent need for transplant and lower probability of posttransplant survival) and medical utility (patients with less urgent need for transplant and higher odds of postoperative survival). Over the long term, there will be an increasing application of novel approaches to liver replacement including cadaver split liver transplantation and adult living donor liver transplantation and possibly, in the more distant future, xenotransplantation and hepatocyte transplantation. The treatment, and ideally the prevention, of recurrent disease after liver transplantation, particularly chronic hepatitis C-the most common indication for transplantation-is a major priority to optimize the use of liver grafts. Finally, improved immunosuppressive strategies, including movement toward minimal immunosuppression and steroid withdrawal and the development of safer and more effective drugs, is another important factor that has the potential to increase the success of liver transplantation.

Animals↗
PubMed2001

Characterization of liver T-cell receptor gammadelta T cells obtained from individuals chronically infected with hepatitis C virus (HCV): evidence for these T cells playing a role in the liver pathology associated with HCV infections.

The pathogenic mechanisms involved in viral hepatitis are not completely understood. Evidence suggests that the pathology associated with hepatitis C virus (HCV) and hepatitis B virus (HBV) infections are a result of the immune response in the liver to these viruses. The livers of patients with viral hepatitis have been shown to contain elevated numbers of T cells expressing the gamma/delta form of the T-cell receptor for antigen (TCRgammadelta). In this study, we investigated whether liver biopsy specimens obtained from individuals with viral (HCV and/or HBV) or nonviral hepatitis contained TCRgammadelta(+) T cells that could be expanded in vitro by cytokines. A high percentage of liver biopsy specimens obtained from HCV- and/or HBV-infected individuals contained high numbers of TCRgammadelta(+) T cells. In contrast, T-cell lines generated from liver biopsy tissues obtained from individuals with nonviral hepatitis or from normal controls had no preferential expansion of TCRgammadelta(+) T cells. Liver TCRgammadelta(+) T-cell lines from HCV-infected individuals had high levels of non-major histocompatibility complex (MHC)-restricted cytotoxic activity against different targets including primary hepatocytes and produced interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin 8 (IL-8) following activation by anti-CD3. Surprisingly, none of these liver TCRgammadelta(+) T-cell lines could recognize any of the structural or nonstructural proteins of HCV and had no cytotoxic activity against cells infected with recombinant vaccinia viruses expressing different HCV proteins. However, the crosslinking of CD81, which has been shown to bind HCV particles and E2, resulted in significant levels of IFN-gamma and TNF-alpha production by liver TCRgammadelta(+) T cells. These results suggest that TCRgammadelta(+) T cells may play a role in the liver pathology of HCV infections.

Adult↗
PubMed1981

Degradation of insulin in perfused liver and skeletal muscle and insulin secretion in perfused pancreas of liver injury rat.

To study the mechanism of hyperinsulinism and glucose intolerance in liver disease, insulin removal rate by liver and muscle, glucose uptake by muscle and insulin secretion from pancreas were measured using the perfusion in rats with injured liver induced by carbon tetrachloride (liver injury rat). In the perfused liver, insulin removal rate of liver injury rat decreased to 62% of that of normal rat, but it did not alter in the perfused muscle. Insulin response to arginine by the perfused pancreas of liver injury rat was similar to that of normal rat. Before insulin infusion, glucose uptake by the perfused muscle was similar in liver injury rat and normal rat. In contrast, during insulin infusion, glucose uptake by the perfused muscle was 1.5 times higher in liver injury rat than in normal rat. These results suggested that the peripheral hyperinsulinism was solely due to decreased hepatic insulin degradation, but not hypersecretion of insulin from pancreas and furthermore, might suggest that the insulin resistance was related to appearance of biologically inactive endogenous insulin, because of exogenous insulin completely acting on peripheral target tissue.

Animals↗
PubMed1995

The human insulin-like growth factor-II promoter P1 is not restricted to liver: evidence for expression of P1 in other tissues and for a homologous promoter in baboon liver.

The human insulin-like growth factor (IGF)-II gene (IGF2) contains 4 different promoters (P1-P4), three of which (P2-P4) are homologous to the 3 promoters found in murine IGF-II genes. IGF-II is abundantly expressed in adult humans and primates, but IGF2 is only expressed in brain in adult rat and mouse. Previously, promoter P1 had been found exclusively in human adult liver but not in other human tissues or in rat or mouse liver. Although mouse liver does not express a homologue of human P1 mRNA, 5' "pseudo-exons" which are homologues of human exons 2 and 3 have been identified in murine IGF2. Based on the published DNA sequences of human exon 2 and the homologous murine pseudo-exon psi 1, we designed a 5'-oligonucleotide common to both human and murine IGF2 and a 3'-oligonucleotide primer from coding exon 7. We amplified specific cDNA from human and baboon livers, but no specific band was seen in rat or mouse liver. Chain-termination DNA sequencing confirmed that the P1 mRNA sequence from baboon liver shares 90% homology with human P1 mRNA in the 5' noncoding region (exons 2 and 3). Mature baboon IGF-II peptide is identical to human IGF-II, but there are 7 amino acid differences in the E region of the IGF-II prohormone. In humans, IGF-II mRNA transcripts containing P1 were also found in human myometrium and myomas. Our results demonstrate that the P1 promoter of the IGF-II gene is present in human and baboon adult liver, although it is absent from murine liver. In humans, promoter P1 is also utilized in tissues other than adult liver. We speculate that promoter P1 may be an important factor in persistent IGF-II synthesis.

Adult↗
PubMed2000

Natural killer cell and alphabeta and gammadelta lymphocyte traffic into the liver graft immediately after liver transplantation.

BACKGROUND: The persistence and migration of donor leukocytes has been well established, but cellular kinetics immediately after revascularization and the potential relevance of these different lymphocyte populations to spontaneous tolerance remain unclear. During the early hours of revascularization, there is a transitory "congestion" of the liver graft, which is evidence of an early phase that we have termed "first cellular contact." METHODS: We have carried out by flow cytometry a prospective comparative study of the peak kinetics of lymphocyte subpopulations contained in: (a) peripheral blood and liver grafts at the time of multi-organ extraction from 14 brain-dead donors, (b) recipient peripheral blood before transplantation, and (c) recipient peripheral blood and liver grafts after (t=2 h) declamping and vascularization of the liver graft. RESULTS: Before transplantation, the liver grafts contained large numbers of natural killer (NK) and NK-like cells with early lymphocyte activation. Immediately after revascularization, there was an influx of recipient NK and NK-like cells into the liver. CONCLUSIONS: NK and CD3+CD56+ (NK-like) cells flooding into the liver graft immediately after revascularization could rapidly destroy allogeneic cells. However, spontaneous tolerance and the persistence of donor lymphocytes after orthotopic liver transplant could be a result of donor TCRalphabeta NK1.1 liver graft lymphocytes, which may be involved in the destruction of CD8+ T lymphocytes that would have received the apoptosis signal, and to NK and NK-like cell inhibition via inhibitory NK receptors. The decrease in gammadelta T lymphocytes in the two compartments suggests a mechanism of recirculation and capture in other lymphoid organs.

Adult↗
PubMed1994

Role of non-parenchymal liver cells in ischaemia-reperfusion liver injury: protective effects of muramyl dipeptide.

It has been suggested that non-parenchymal liver cells play a central role after ischaemia and reperfusion of the liver. Male Lewis rats were subjected to 90 min of warm liver ischaemia. Four groups were constituted: group 1, no treatment; group 2, muramyl dipeptide treatment, activation of Kupffer cells; group 3, dextran sulphate injection, Kupffer cell blockade; and group 4, gadolinium chloride administration, Kupffer cell blockade. Dextran sulphate (4 mg/100 g) and gadolinium chloride (GdCl2, 0.7 mg/100 g) were given intravenously on day 2. MDP was injected intravenously (500 mg/250 g) 24 h before and 10 min after the intervention. Mortality rates were assessed and serum transaminases, histology of the liver and Kupffer cell phagocytic activity were evaluated 6 h after the end of ischaemia. MDP treatment significantly (P < 0.001) reduced mortality (30%) in comparison with the non-treated group (60%). The mortality rate was significantly higher in the dextran sulphate-treated (80%) and gadolinium chloride-treated (90%) groups in comparison with group 1. A significant reduction in transaminase levels was observed after MDP treatment, while blockade of Kupffer cells resulted in higher serum transaminase levels. The extent of necrosis and congestion was improved by MDP administration, while disruption of the vascular and sinusoidal integrity of the liver and extensive areas of necrosis were observed in dextran sulphate and gadolinium chloride-treated rats. Sheep red blood cell 51Cr liver uptake was deeply depressed 6 h after the end of ischaemia in group 1 (10 +/- 1.2%/g tissue). MDP injection restored the Kupffer cell activity (30.6 +/- 3.22%/g tissue) while dextran sulphate and gadolinium chloride administration markedly decreased SRBC 51Cr liver uptake. Our findings demonstrate that MDP in able to protect the liver from ischaemic insult while blockade of Kupffer cells was deleterious in rats subjected to liver ischaemia.

Acetylmuramyl-Alanyl-Isoglutamine↗