摘要:

AbstractTumor necrosis factor is a cytokine that mediates many of the biologic actions of endotoxin. Recent studies have shown that tumor necrosis factor administration may cause liver injury and that tumor necrosis factor may mediate the lethality of the hepatotoxin galactosamine. One of the most potent inducers of tumor necrosis factor production is endotoxin. Because patients with alcoholic liver disease frequently have endotoxemia and because many of the clinical manifestations of alcoholic hepatitis are known biologic actions of tumor necrosis factor, we thought it would be important to evaluate tumor necrosis factor activity in patients with alcoholic hepatitis. Basal and lipopolysaccharide‐stimulated tumor necrosis factor release from peripheral blood monocytes, a major source of tumor necrosis factor production, was determined in 16 patients with alcoholic hepatitis and 16 healthy volunteers. Eight of 16 alcoholic hepatitis patients and only two of 16 healthy volunteers had detectable spontaneous tumor necrosis factor activity (p<0.05). After lipopolysaccharide stimulation, mean monocyte tumor necrosis factor release from alcoholic hepatitis patients was significantly increased to over twice that of healthy controls (25.3 ± 3.7 vs. 10.9 ± 2.4 units per ml, p<0.005). We conclude that monocytes from alcoholic hepatitis patients have significantly increased spontaneous and lipopolysaccharide‐stimulated tumor necrosis factor release compared to monocytes from healthy volunteers. We suggest that some of the metabolic abnormalities and possibly some of the liver injury of alcoholic hepatitis may be due to enhanced tumor necrosis factor produ

ISSN:0270-9139    

DOI:10.1002/hep.1840090302

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractFat‐storing cells were isolated from 15‐day‐old mouse sinusoidal cell cultures (Kupffer or endothelial cells), where they had multiplied abundantly; they were then purified by a negative selection method based on the fact that they do not possess Fc receptors, as do both other types of cells.The fat‐storing cells, which could be subcultured for at least 10 passages, have the main morphological characteristics already describedin vivo, in particular, the rough endoplasmic reticulum and the lipid droplets, which become less and less apparent as the number of passages increases. Subcultured fat‐storing cells, almost devoid of lipid droplets and vitamin A, were able to take up retinol, as the appearance of a typical autofluorescence indicated; the number of lipid droplets increased concomitantly. Furthermore, the cultured fat‐storing cells were able to internalize one‐μm‐sized latex beads by phagocytosis. Infection of fat‐storing cells with mouse hepatitis virus 3, ectromelia or Sindbis virus led to multiplication of the virus particles. There was a direct relation between the multiplication of mouse hepatitis virus 3 in cultured fat‐storing cells and the susceptibility of the animals to the virus. In the case of Sindbis virus, interferon is produced, its production being independent of the p

ISSN:0270-9139    

DOI:10.1002/hep.1840090303

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractDigoxin‐like immunoreactive substances, which cross‐react with digoxin antibody, have been found to have natriuretic effect and Na+,K+‐ATPase inhibitory effect. The role of digoxin‐like immunoreactive substances in chronic liver disease was studied by radioimmunoassay in 63 serum and 60 urine samples from 58 patients with chronic liver disease and compared with 16 controls. Although the mean serum digoxin‐like immunoreactive substances level of compensated chronic liver disease patients (0.06 ± 0.05 ng per ml, p<0.01) was higher than that of controls (0.02 ± 0.03 ng per ml), only four patients had serum digoxin‐like immunoreactive substances higher than 0.10 ng per ml. Mean serum digoxin‐like immunoreactive substances level was much higher in patients with decompensated chronic liver disease who had ascites (0.32 ± 0.17 ng per ml, p<0.001), hepatorenal syndrome (0.57 ± 0.20 ng per ml, p<0.001) and hepatic encephalopathy (0.43 ± 0.20 ng per ml, p<0.001). Five patients with recent variceal hemorrhage requiring transfusions and saline infusion had significantly increased serum digoxin‐like immunoreactive substances (mean: 0.16 ± 0.06 ng per ml, p<0.001) before the development of clinically detectable ascites. The serum digoxin‐like immunoreactive substances level was positively correlated with serum total bilirubin (r = 0.581, p<0.001), AST (r = 0.454, p<0.001), serum creatinine (r = 0.539, p<0.001), urine digoxin‐like immunoreactive substances (ng of urine digoxin‐like immunoreactive substances per gm of urine creatinine, r = 0.578, p<0.001) and negatively correlated with serum albumin (r=−0.604, p<0.001), prothrombin activity (r=−0.589, p<0.001), serum sodium (r=−0.685, p<0.001) and urine sodium (mEq of urine sodium per gm of urine creatinine; r=−0.476, p<0.001). The present study shows increased serum digoxin‐like immunoreactive substances in decompensated chronic liver disease. The negative correlation between serum digoxin‐like immunoreactive substances and urine sodium suggests that digoxin‐like immunoreactive substances level is higher in patients having low urinary sodium output. This finding may be explained by a possible renal insensitivity to digoxin‐like immunoreactive substa

ISSN:0270-9139    

DOI:10.1002/hep.1840090304

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractImmunohistochemical analysis of human liver (8 to 94 years) shows a compartmentation of ammonia‐metabolizing enzymes across the acinus. The highest concentration of carbamoylphosphate synthetase (ammonia) is found in the parenchymal cells around the terminal portal venules. Glutamine synthetase is found in a small pericentral compartment two to three cells thick. In contrast to observations in rat liver, in human liver a well‐recognizable intermediate zone can be distinguished in which neither enzyme can be detected. This intermediate zone is not yet established at the age of 8 years but can be recognized in livers from 25 years onward.Carbamoylphosphate synthetase can already be detected in the liver of human fetuses at 5 weeks of development. The enzyme distribution reveals a random heterogeneity among the hepatocytes, suggesting that not all hepatocytes start to accumulate carbamoylphosphate synthetase at the same time. From 9 weeks of development onward, the enzyme becomes homogeneously distributed throughout the liver parenchyma until at least 2 days after birth. Glutamine synthetase cannot be detected during this period. In addition, the definitive architecture of the acinus is not yet completed at birth.These results therefore support the idea that in human liver, metabolic zonation with respect to NH3metabolism exists as it does in rat liver. Furthermore, the data show that this functional compartmentation becomes established concomitant with the development of the acinar architecture. The fact that enzymic zonation is not yet established in the perinatal period may have important consequences for the regulation of ammonia fixation and pH homeostasis in preterm infants and neona

ISSN:0270-9139    

DOI:10.1002/hep.1840090305

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractWe produced moderately severe, inactive micronodular cirrhosis in rats using CCl4and measured the urea cycle enzyme activities in liver after feeding a 15% casein diet for 1 week and again after a 60% casein diet for 1 week. There was no deficiency of any of the five urea cycle enzymes in cirrhotic livers of rats pair‐fed the 15% casein diet. Argininosuccinate synthetase and carbamyl phosphate synthetase activities were lower than in non‐pair‐fed controls by some baselines. All five enzymes in cirrhotic livers were induced 1.5‐ to 3‐fold by the high‐protein diet expressed as units per 100 gm of rat. The level of carbamyl phosphate synthetase activity was lower in the livers of rats pair‐fed the 60% casein diet than in control livers based on wet weight, collagen‐free protein and DNA, but the activities were equal expressed as units per 100 gm of rat. This example of CCl4‐induced cirrhosis in the rat does not serve as a good model for human cirrhosis, in which the urea cycle enzymes are reported to be decr

ISSN:0270-9139    

DOI:10.1002/hep.1840090306

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractRats were treated with 17α‐ethinyl estradiol to induce high levels of low‐density lipoprotein receptors in hepatocytes. When these rats were given intravenous injections of low‐density lipoprotein‐colloidal gold complexes, most of the gold (labeled with195Au) appeared to be taken up by Kupffer cells, as were complexes of colloidal gold with albumin or polyvinylpyrrolidone. However, when these rats were also administered gadolinium chloride, which blocks Kupffer cell activity, most of the low‐density lipoprotein‐gold (but not gold complexed with albumin or polyvinylpyrrolidone) was taken up into hepatocytes by receptor‐mediated endocytosis and concentrated in peribiliary lysosomes, as determined by electron microscopy. Colloidal gold taken up as a complex with low‐density lipoprotein was excreted into the feces via the common bile duct at a maximal rate of about 5% daily, 4 to 12 days after injection. Thereafter, the rate of gold excretion fell off until reaching a plateau after 3 weeks. At this late time, most of the colloidal gold was shown by electron microscopy to be in Kupffer cells, whereas earlier (6 days after injection) it was contained mainly in older hepatocytic lysosomes, identified by lipofuscin granules. It is concluded that, in rats, hepatocytic lysosomes empty most of their contents into bile every week or two, apparent

ISSN:0270-9139    

DOI:10.1002/hep.1840090307

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractA major factor in poor bioavailability of cyclosporine in children undergoing orthotopic liver transplantation appears to be poor absorption of the drug. Our hypothesis is that the Roux‐en‐Y choledochojejunostomy used for biliary drainage in these children causes cyclosporine malabsorption by reducing the length of bowel available for absorption and by distally displacing the entry of bile into the intestine. In these experiments, we determined the effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in Sprague‐Dawley rats.Experimental rats (n = 24) were prepared for study by constructing self‐emptying jejunal blind loops. Sham rats (n = 9) had jejunal transection and reanastomosis. Control rats (n = 26) had no operation. Two to 4 weeks later, chronic biliary‐enteric fistulae were formed in all animals. In experiments, [3H]cyclosporine was delivered into the duodenum while the site of bile delivery varied. Hourly and cumulative [3H]cyclosporine excretion into bile was quantitated, which our preliminary data show to be a valid estimate of absorption. In control rats, bile was delivered into the duodenum or was replaced with saline and sucrose solution. In experimental rats, bile was infused either into the duodenum, which tested bowel shortening only, or into the proximal end of the blind loop, which tested the combined effects of bowel shortening and distal displacement of bile entry. In sham rats, bile was infused into the duodenum, which controlled for previous abdominal surgery, or into the mid‐jejunum, which tested for distal bile entry only.Two effects of biliary enteroenterostomy on cyclosporine absorption were observed. First, distal displacement of bile entry into the intestinal lumen reduced drug absorption by about 50%. Compared to control rats with duodenal bile (n = 15), which excreted 14.8 ± 3.3% of the label into bile in 24 hr, and sham rats with duodenal bile (n = 4), which excreted 14.6 ± 1.3%, experimental animals with loop bile (n = 13) excreted 7.7 ± 2.1% and sham rats with midjejunal bile (n = 5) excreted 7.2 ± 1.8%. Control rats with no bile (n = 11) excreted 3.2 ± 1.6%. Second, reduction of bowel length by constructing the enteroenterostomy reduced absorption by 25%. Experimental rats with duodenal bile (n = 11) excreted 11.2 ± 2.5%. These data suggest that the surgical approach to biliary reconstruction after orthotopic liver transplantation in children can contribute to poor cyclosporin

ISSN:0270-9139    

DOI:10.1002/hep.1840090308

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractPeroxidative decomposition of organelle membrane phospholipids with subsequent organelle dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. We studied the effects of different α‐tocopherol concentrations on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload. There was no evidence of mitochondrial lipid peroxidation (conjugated dienes) or alteration in mitochondrial oxidative metabolism in α‐tocopherol‐deficient rats with normal hepatic iron levels. Significant reductions in mitochondrial respiratory control ratios and oxidative phosphorylation ratios were seen in association with increased conjugated dienes in all three groups of iron‐loaded rats regardless of the α‐tocopherol status (deficient, normal or excess); thus, the α‐tocopherol deficiency associated with dietary iron overload in this experimental model is not responsible for the mitochondrial abnormalities observed. In addition, chronic parenteral administration of α‐tocopherol to iron‐loaded animals, which increased hepatic levels of this substance 3‐fold, did not ameliorate the hepatic mitochondrial lipid peroxidation or the defects in mitochondrial oxidative metabolism result

ISSN:0270-9139    

DOI:10.1002/hep.1840090309

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractThe role of Kupffer cells during reparative regeneration of rat liver was investigated with anin vitroexperimental model. Conditioned media from primary cultures of Kupffer cells isolated from intact and regenerating liver were added to primary cultures of hepatocytes, and [3H]thymidine incorporation into DNA was studied. Kupffer cell‐conditioned media from intact liver and regenerating remnant liver significantly stimulated DNA synthesis in hepatocytes as compared with control media (p<0.05). Moreover, the stimulating activity of Kupffer cells prepared from regenerating liver at 6 and 12 hr after partial hepatectomy was significantly higher than that of Kupffer cells from untreated rats (p<0.05). The activity was found in serum‐free conditioned media. This stimulating activity exponentially increased as the increase of the number of the cultured cells, indicating that the stimulating activity was released directly by cultured Kupffer cells. These results suggest that Kupffer cells stimulate DNA synthesis in hepatocytes by producing and releasing certain factor(s) at an early stage of liver regeneration after partial hepatect

ISSN:0270-9139    

DOI:10.1002/hep.1840090310

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY

摘要:

AbstractThe availability of recombinant mitochondrial autoantigens may permit the experimental study of the pathophysiology of primary biliary cirrhosis. Previously, we demonstrated that high‐titer antibodies to the 74 kD mitochondrial autoantigen dihydrolipoamide acetyltransferase could be generated when BALB/c mice were immunized with purified recombinant protein. Based on these data, we attempted an 8‐month study to induce antibodies and liver dysfunction by immunizing AKR/J, C3H/J and CBA/HeJ mice as well as rats, guinea pigs, rabbits and rhesus monkeys with purified recombinant human dihydrolipoamide acetyltransferase. Antibodies to dihydrolipoamide acetyltransferase were readily induced and detected in all species of experimental animals with species and strain differences in the titer of the responses. Of particular interest, rabbits and guinea pigs produced antibodies which were specifically reactive with the functional site of dihydrolipoamide acetyltransferase, whereas the other strains and species produced antibodies to other epitopes on the molecule. Finally, similar to data on humans with primary biliary cirrhosis, the pyruvate dehydrogenase enzyme pathway was inhibited in the presence of immunized animal sera. These data imply that features other than simply an antibody response to mitochondrial enzymes are required for the development of primary biliary cirrhosis. Further studies will be necessary to determine the mechanisms by which mitochondrial proteins elicit an immune respo

ISSN:0270-9139    

DOI:10.1002/hep.1840090311

出版商:W.B. Saunders    

年代:1989

数据来源: WILEY