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At least 19 recordsLinked to original sources
PubMed2003

Effect of glutathione depletion and hydrophilic bile acids on hepatic acute phase reaction in rats with extrahepatic cholestasis.

BACKGROUND: Extrahepatic cholestasis by biliary obstruction induces an acute phase reaction in the liver. It is a complex process involving cytokines, hormones and growth factors. To determine whether the regulation of acute phase proteins (APP) in cholestasis depends on glutathione (GSH), the effect of buthionine sulfoximine-induced (BSO-induced) GSH depletion on the expression of various APP was studied. In addition, we determined the influence of hepatoprotective bile acids on hepatic APP and underlying cytokine events. METHODS: Liver samples of bile-duct-ligated or sham-operated rats were examined. mRNA expression was quantified by densitometric analysis of Northern blots. RESULTS: Expression of APP increased 2-5-fold in bile-duct-ligated rats as compared to sham-operated controls. This acute phase reaction remained similar independently of whether cholestasis occurred for 5 days or 3 weeks. In contrast to alpha2-macroglobulin and tissue inhibitor of metalloproteinases-1 (TIMP-1), mRNA levels of both beta-fibrinogen and haptoglobin were significantly up-regulated after GSH depletion by BSO in cholestasis. Feeding of ursodeoxycholic and iso-ursodeoxycholic acid markedly down-regulated alpha2-macroglobulin and TIMP-1 expression in cholestasis but did not affect overexpression of beta-fibrinogen and haptoglobin. Cholestasis leads to an increased APP expression accompanied by an increased expression of inflammatory cytokines (IL-6, TNF-alpha). After feeding of hydrophilic bile acids, increases in inflammatory cytokines were abrogated. CONCLUSIONS: We show that GSH is involved in the acute phase reaction during obstructive cholestasis. In addition, bile acids might selectively ameliorate the acute phase response by reducing expression of the APP not affected by GSH depletion (alpha2-macroglobulin and TIMP-1).

Acute-Phase Proteins↗
PubMed1986

Extrahepatic cholestasis in the dog and the differentiation of extrahepatic and intrahepatic cholestasis.

The clinical and pathological features of extrahepatic cholestasis in 19 dogs are presented. The condition was most often caused by partial or complete occlusion of the choledochal duct due to neoplastic diseases (12 cases), inflammatory processes (3 cases), or eventration and incarceration of the liver (1 case). In only three cases was the condition due to intraluminal obstruction of the choledochal duct. The anamnestic, laboratory and pathological parameters of these 19 dogs were compared with the findings in 21 dogs with intrahepatic cholestasis. Statistical analysis of these parameters indicated that the presence of acholic faeces, the degree of icterus and the level of plasma gamma GT where the only parameters of value in the clinical differentiation of extrahepatic from intrahepatic cholestasis. Histological examination of liver biopsies is a simple aid to a confident in vivo diagnosis of extrahepatic cholestasis.

Animals↗
PubMed1991

Integrity of liver inner mitochondrial membrane in rats with extrahepatic cholestasis.

To investigate the effect of extrahepatic cholestasis on integrity of the inner mitochondrial membrane, a study was conducted on two groups of rats: sham-operated control animals (N = 10) and rats subjected to extrahepatic cholestasis (EHC, N = 10) by double ligation of the hepatic duct. The animals were observed for 7 days and then sacrificed. The EHC group presented significantly higher serum levels of alanine aminotransferase, total bilirubins and alkaline phosphatase than the controls (P less than 0.01). Basal mitochondrial respiration (state IV), analyzed separately using either alpha-ketoglutarate or alpha-ketoglutarate + pyruvate as substrates, was similar in the two groups (P greater than 0.01). ADP-activated respiration, state III, diminished significantly in the EHC group. The results show that the decrease in mitochondrial function that has been reported by several investigators to occur in EHC is due to mitochondrial alterations not related to the ability of these organelles to maintain the proton gradient, since the inner mitochondrial membrane continued to be energized throughout the observation period.

Alanine Transaminase↗
PubMed1981

Hepatic and renal disposition of pancuronium and gallamine in patients with extrahepatic cholestasis.

The plasma clearance of pancuronium in patients with extrahepatic cholestasis was 16% lower than in a control group (1.47 +/- 0.11 ml min-1 kg-1 v. 1.76 +/- 0.21 ml min-1 kg-1), but the difference was not significant. A significant increase in the elimination half-life T 1/2 beta of pancuronium (from 141 to 224 min) and a significant increase in the volume of the peripheral compartment (V2) was found in patients with extrahepatic cholestasis when compared with control patients. There was a significantly lower cumulative biliary excretion of pancuronium (0.3 +/- 0.3% v. 10.9 +/- 3.2% in the controls) during the 48-h period of observation. The biotransformation and cumulative urinary excretion patterns of pancuronium revealed no significant differences between the two groups of patients. The increase of T 1/2 beta pancuronium in patients with extrahepatic cholestasis was mainly a consequence of the increase in the volume of distribution. No significant differences in the plasma clearance, T 1/2 beta or in the volume of distribution were observed with gallamine in the patients with extrahepatic cholestasis when compared with the control group. The cumulative urinary excretion of gallamine during 48 h in both groups of patients was approximately 100%. We concluded that in patients with cholestasis and normal glomerular filtration, gallamine is probably more reliable than pancuronium for neuromuscular blockade.

Adult↗
PubMed1996

Structure-function correlation of tight junctional impairment after intrahepatic and extrahepatic cholestasis in rat liver.

BACKGROUND & AIMS: Tight junctions, the only barrier between blood and bile, are crucial in bile formation. The aim of this study was to correlate changes in morphology and permeability by comparing structural parameters with marker secretion into normal and cholestatic rat bile. METHODS: Cholestasis was induced by bile duct ligation of 5 and 21 days of ethinylestradiol administration. Quantitated structural parameters induced junctional length, strand number, junctional depth, and spacing of junctional particles. Junctional permeability was probed with horseradish peroxidase and dextrans of increasing sizes. RESULTS: Junctional length was decreased slightly by ethinylestradiol (-16% after 21 days) but increased by ligation (77%). Mean strand number decreased from 4.6 to 3.7 after 21 days of ethinylestradiol and 3.4 after ligation associated with increased junctional depth. The proportions of morphologically horseradish peroxidase-positive junctions increased from 4% to 15% after 21 days of ethinylestradiol and to 56% after ligation. Horseradish peroxidase secretion was increased twofold by ethinylestradiol and 6.5-fold by ligation, paralleled by an increase of dextran size selectivity from 70,000 to 79,000 daltons after ethinylestradiol and to 266,000 daltons after ligation. CONCLUSIONS: Impairment of junctional integrity is paralleled with the degree of cholestasis, whereas correlation of morphological and physiological alterations shows a close structure-function relationship.

Animals↗
PubMed1981

Cholestasis and hepatic drug metabolism. Comparison of metabolic clearance rate of antipyrine in patients with intrahepatic or extrahepatic cholestasis.

The antipyrine metabolic clearance rate (MCR) was studied in two groups of patients with similar degrees of cholestasis and hepatic damage, but differing mechanisms of cholestasis. The plasma disappearance rate of antipyrine in 18 patients with extrahepatic cholestasis and 11 patients with intrahepatic cholestasis was compared with that of two groups of control subjects without liver disease who were matched for age. Whereas no significant difference was observed for the antipyrine MCR between patients with extrahepatic cholestasis and their controls [30.7 +/- 11.2 (SD) as against 31.6 +/- 10.0 ml/min], the antipyrine MCR was significantly lower (P less than 0.001) in the patients with intrahepatic cholestasis than in their controls (16.2 +/- 4.5 vs 37.4 +/- 17.3 ml/min). These results suggest that cholestasis per se does not change the rate of metabolism of drugs by the liver. The decrease of antipyrine MCR in patients with intrahepatic cholestasis could be due to a reduced functional parenchymal mass related to some degree of hepatic necrosis.

Adult↗
PubMed1984

The nature of urinary bile acid conjugates in patients with extrahepatic cholestasis.

Urinary bile acids from patients with extrahepatic cholestasis were extracted with Sep-pak C18 cartridges and group separated on diethylaminohydroxypropyl Sephadex LH-20. The nature of the different conjugates of cholic and chenodeoxycholic acid in the fractions was studied after further separation by preparative thin-layer chromatography. The free and glycine-conjugated bile acids were quantified by capillary gas chromatography and identified by gas chromatography-mass spectrometry (GC/MS). Taurine conjugates were split with cholylglycine hydrolase and the liberated free bile acids analysed by GC/MS. Sulphate esters were hydrolysed with Helix pomatia and the resulting bile acid derivatives were analysed as above. After hydrolysis with cholylglycine hydrolase, the glucuronides of the unconjugated bile acids were separated and identified by GC/MS. Amino acid analysis of the different fractions revealed that glycine and taurine were the only amino acids present in connection with cholic and chenodeoxycholic acid. Large amounts of monosulphated bile acid conjugates were present but no disulphates. Only 3-sulphates were found. Both sulphates and glucuronides were found exclusively as glycine or taurine conjugates and no such derivatives of unconjugated bile acids were isolated. The isolated conjugates were split either by a combination of acid solvolysis and alkaline hydrolysis or by Helix pomatia and cholylglycine hydrolase.

Amino Acids↗
PubMed1996

Ultrastructural sinusoidal changes in extrahepatic cholestasis. Light and electron microscopic immunohistochemical localization of collagen type III and type IV.

Extrahepatic cholestasis causes excessive extracellular matrix formation perisinusoidally. Ito cells, transitional and endothelial cells are considered to be a source of extracellular matrix proteins in experimental cholestasis. The localization of collagens type III and type IV in human liver in extrahepatic cholestasis was investigated immunohistochemically in the present study. Immersion fixation was used after modification to be applied to surgical biopsies with commercially available kits. Sinusoidal changes were observed that indicated excessive collagen and matrix formation. Light microscopically, increased immunostaining with the two collagen antibodies was found perisinusoidally and portally. Ultrastructurally, collagen type III positive fibres were found beneath basement membranes of vessels, in collagen bundles and as a fibrillar network in the space of Disse. Collagen type IV immunostaining was located in portal tracts and near hepatocyte microvilli. Intracellular staining with collagen type IV was detected in the rough endoplasmic reticulum of some transitional cells. Immunostaining was located around transitional cells, Ito cells or endothelial cells mainly. Our study indicates that Ito cells, transitional and endothelial cells are the main source of collagens type III and IV in the space of Disse in extrahepatic cholestasis in humans.

Adult↗
PubMed1999

Different lobular distributions of altered hepatocyte tight junctions in rat models of intrahepatic and extrahepatic cholestasis.

Hepatocyte tight junctions (TJs), the only intercellular barrier between the sinusoidal and the canalicular spaces, play a key role in bile formation. Although hepatocyte TJs are impaired in cholestasis, attempts to localize the precise site of hepatocyte TJ damage by freeze-fracture electron microscopy have produced limited information. Recently, several TJ-associated proteins like ZO-1 and 7H6 have been identified and characterized. Immunolocalization of 7H6 appears to closely correlate with paracellular permeability. We used rat models of intrahepatic cholestasis by ethinyl estradiol (EE) treatment and extrahepatic cholestasis by bile duct ligation (BDL) to precisely determine the site of TJ damage. Alterations in hepatocyte TJs were assessed by double-immunolabeling for 7H6 and ZO-1 using a confocal laser scanning microscope. In control rats, immunostaining for 7H6 and ZO-1 colocalized to outline bile canaliculi in a continuous fashion. In contrast, 7H6 and ZO-1 immunostaining was more discontinuous, outlining the bile canaliculi after BDL. Immunostaining for 7H6, not ZO-1, decreased and predominantly appeared as discrete signals in the submembranous cytoplasm of periportal hepatocytes after BDL. After EE treatment, changes in immunostaining for 7H6 and ZO-1 were similar to those seen in periportal hepatocytes after BDL, but distributed more diffusely throughout the lobule. This study is the first to demonstrate that impairment of hepatocyte TJs occurs heterogenously in the liver lobule after BDL and suggests that BDL and EE treatments produce different lobular distributions of increased paracellular permeability.

Animals↗