Cholestasis may be extrahepatic or intrahepatic in origin. The block in bile secretion may be complete or incomplete to variable extent. Complete cholestasis occurs in case of primary parenchymal disease (intrahepatic cholestasis) or total obstruction of extrahepatic bile ducts (extrahepatic cholestasis). Incomplete block in bile secretion is due to incomplete obstruction of intra- or extrahepatic bile ducts (intra- or extrahepatic cholestasis or both). Histologically, it is useful to distinguish between bilirubionstasis and cholate-stasis. Complete secretory block causes as early changers: bilirubinostasis (in hepatocytes, canaliculi and Kupffer cells) in acinar zone 3, and "ductular reaction" in acinar zone 1. The latter refers to an increase in periportal ductular profiles, associated with neutrophil infiltration. With longer duration of cholestasis, further lesions ensue: feathery degeneration of hepatocytes due to retention of detergent bile acids, cholestatic liver cell rosettes representing a shift from hepatocellular to biliary differentiation, xanthomatous cells reflecting hyperlipidemia, cholate stasis in acinar zone 1 due to overload of membrane-damaging bile acids, eventually paraportal bile infarcts, and progressive ductular reaction. The latter may be due to multiplication of pre-existing ductules, to metaplasia of periportal hepatocytes, or to activation of progenitor cells. It is invariably associated with periductular fibrosis: the pacemaker for increasing matrix deposition, resulting in biliary fibrosis and eventually in true biliary cirrhosis. Incomplete cholestasis (e.g. PBC, PSC) is characterized by absence of bilirubinostasis during long periods of time, whereas the afore mentioned features of chronic cholestasis do appear. Hence follows that the most reliable markers of chronic incomplete cholestasis are cholate stasis, cholestatic rosettes and ductular reaction. Bilirubinostasis is only a late and often ominous sign.
"Inhibition of transport proteins may mediate liver injury by increasing the intracellular accumulation of potentially toxic compounds (parent drug/xenobiotic and/or metabolites), as well as endogenous BAs, which can cause toxicity through detergent effects on cellular membranes, mitochondrial dysfunction, and ultimately cellular apoptosis or necrosis (Delzenne et al. 1992; Desmet 1995; Gores et al. 1998; Pauli-Magnus et al. 2005). A number of drugs inhibit rat and/or human Bsep/BSEP-mediated biliary secretion of TCA in vitro including cyclosporin A, glibenclamide, rifampin, bosentan, ritonavir, saquinavir, efavirenz, and troglitazone (TRO) (Fattinger et al. 2001; Funk et al. 2001a; Kemp et al. 2005; McRae et al. 2006; Pauli-Magnus and Meier 2006; Stieger et al. 2000). "
[Show abstract][Hide abstract] ABSTRACT: Sandwich-cultured hepatocytes (SCH) are used commonly to investigate hepatic transport protein-mediated uptake and biliary excretion of substrates. However, little is known about the disposition of endogenous bile acids (BAs) in SCH. In this study, four endogenous conjugated BAs common to rats and humans [taurocholic acid (TCA), glycocholic acid (GCA), taurochenodeoxycholic acid (TCDCA), and glycochenodeoxycholic acid (GCDCA)], as well as two BA species specific to rodents (α- and β-tauromuricholic acid; α/β TMCA), were profiled in primary rat and human SCH. Using B-CLEAR® technology, BAs were measured in cells+bile canaliculi, cells, and medium of SCH by LC-MS/MS. Results indicated that, just as in vivo, taurine-conjugated BA species were predominant in rat SCH, while glycine-conjugated BAs were predominant in human SCH. Total intracellular BAs remained relatively constant over days in culture in rat SCH. Total BAs in control (CTL) cells+bile, cells, and medium were approximately 3.4, 2.9, and 8.3-fold greater in human than in rat. The estimated intracellular concentrations of the measured total BAs were 64.3±5.9 μM in CTL rat and 183±56 μM in CTL human SCH, while medium concentrations of the total BAs measured were 1.16±0.21 μM in CTL rat SCH and 9.61±6.36 μM in CTL human SCH. Treatment of cells for 24h with 10 μM troglitazone (TRO), an inhibitor of the bile salt export pump (BSEP) and the Na⁺-taurocholate cotransporting polypeptide (NTCP), had no significant effect on endogenous BAs measured at the end of the 24-h culture period, potentially due to compensatory mechanisms that maintain BA homeostasis. These data demonstrate that BAs in SCH are similar to in vivo, and that SCH may be a useful in vitro model to study alterations in BA disposition if species differences are taken into account.
"The stimulation for bile duct cell proliferation may be regarded as intraluminal or interstitial. Intraluminal stimulation is present during chronic biliary tract obstruction in humans and after ligation of the common bile duct in experimental animals [21,22]. Interstitial stimulation is that associated with non-obstructive liver fibrosis. "
[Show abstract][Hide abstract] ABSTRACT: Background
Extensive bile duct proliferation is a key feature of the tissue reaction to clinical and experimental forms of liver injury. Experimental infection of mice by Schistosoma mansoni is a well-studied model of liver fibrosis with bile duct hyperplasia. However, the regulatory mechanisms of bile duct changes are not well understood. In this study we report the reproducible isolation of long-term cultures of cholangiocytes from mice livers with schistosomal fibrosis.
We have isolated a cholangiocyte cell line from Schistosoma-induced liver granulomas using a combination of methods including selective adhesion and isopyknic centrifugation in Percoll.
The cell line was characterized by morphological criteria in optical and transmission electron microscopy, ability to form well differentiated ductular structures in collagen gels and by a positive staining for cytokeratin 18 and cytokeratin 19. To our knowledge, this is the first murine cholangiocyte cell line isolated from schistosomal fibrosis reported in the literature.
After 9 months and 16 passages this diploid cell line maintained differentiated characteristics and a high proliferative capacity. We believe the method described here may be a valuable tool to study bile duct changes during hepatic injury.
[Show abstract][Hide abstract] ABSTRACT: To determine whether protoporphyric liver injury affects hepatic dendritic cells (DC) and Kupffer cells, we examined liver tissues of griseofulvin-induced protoporphyric mice using histological and immunohistochemical methods. After 1 week of griseofulvin feeding, the protoporphyric liver showed prominent hepatomegaly and a gradual in- crease in histopathological changes such as hepatocellular hypertrophy, focal necrosis and brown pigment deposits. After 4 weeks of treatment, marked ductular reaction was observed in the liver tissue. Immunohistochemical analyses indicated that the den- sity of NLDC-145-positive hepatic DC gradually decreased during griseofulvin feeding. However, the index of the number of DC in the whole liver appeared to fall sharply after 6 weeks. In contrast, the density of F4/80-positive Kupffer cells gradually increased during griseofulvin feeding. In the spleen and lung, no significant differences were noted in the distribution of NLDC-145-positive DC between experimental and control mice. These results suggested that griseofulvin-induced protoporphyria leads to a specific decrease in the density of hepatic DC due to hepatomegaly until 4 weeks of treatment and is substantial after 6 weeks. This substantial decrease of hepatic DC might have been induced by some alterations in protoporphyric liver injury including ductular reaction at a later stage in this experiment. Since hepatic DC were reduced in number, they seemed to have no significant relation to the progression of griseofulvin- induced protoporphyric liver injury. However, the decrease of hepatic DC might affect the cellular immune response in protoporphyria.
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