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Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis.

ABSTRACT: Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-beta1 (TGF-beta1) and thus a potential target for antifibrotic treatment strategies. CTGF is up-regulated in disorders such as atherosclerosis, scleroderma, and fibrosis of kidneys and lungs. We investigated the temporospatial expression patterns of CTGF and TGF-beta1 mRNA in rat livers with acute fibrogenesis (after a single dose of CCl(4)) and with advanced fibrosis (6 weeks after complete bile duct occlusion). Multiprobe ribonuclease protection assay revealed increasing TGF-beta1 and CTGF mRNA levels 6 hours after injection of CCl(4), with peak levels after 72 hours. In biliary fibrosis TGF-beta1 and CTGF mRNA levels increased fourfold and sevenfold, respectively (P: < 0.001). In situ hybridization combined with cell-specific markers revealed CTGF transcripts in desmin-positive cells after a single dose of carbon tetrachloride, whereas no transcripts were found in normal livers. In biliary fibrosis, however, proliferating bile duct epithelial cells were the predominant source of CTGF mRNA. We conclude that in rat liver fibrogenesis CTGF is up-regulated in close association with TGF-beta1 and that, contrary to a previous report, not solely hepatic stellate cells but activated bile duct epithelial cells are the main source of this profibrogenic factor.

SUBMITTER: Sedlaczek N

PROVIDER: S-EPMC1891909 | biostudies-literature | 2001 Apr

REPOSITORIES: biostudies-literature

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Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis.

Sedlaczek N N Jia J D JD Bauer M M Herbst H H Ruehl M M Hahn E G EG Schuppan D D

The American journal of pathology 20010401 4

Connective tissue growth factor (CTGF) is a downstream mediator of transforming growth factor-beta1 (TGF-beta1) and thus a potential target for antifibrotic treatment strategies. CTGF is up-regulated in disorders such as atherosclerosis, scleroderma, and fibrosis of kidneys and lungs. We investigated the temporospatial expression patterns of CTGF and TGF-beta1 mRNA in rat livers with acute fibrogenesis (after a single dose of CCl(4)) and with advanced fibrosis (6 weeks after complete bile duct o ...[more]

PMID: 11290541

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Project description:Background & aimsBiliary atresia (BA) results from a neonatal inflammatory and fibrosing obstruction of bile ducts of unknown etiology. Although the innate immune system has been linked to the virally induced mechanism of disease, the role of inflammasome-mediated epithelial injury remains largely undefined. Here, we hypothesized that disruption of the inflammasome suppresses the neonatal proinflammatory response and prevents experimental BA.MethodsWe determined the expression of key inflammasome-related genes in livers from infants at diagnosis of BA and in extrahepatic bile ducts (EHBDs) of neonatal mice after infection with rotavirus (RRV) immediately after birth. Then, we determined the impact of the wholesale inactivation of the genes encoding IL-1R1 (Il1r1-/-), NLRP3 (Nlrp3-/-) or caspase-1 (Casp1-/-) on epithelial injury and bile duct obstruction.ResultsIL1R1, NLRP3 and CASP1 mRNA increased significantly in human livers at the time of diagnosis, and in EHBDs of RRV-infected mice. In Il1r1-/- mice, the epithelial injury of EHBDs induced by RRV was suppressed, with dendritic cells unable to activate natural killer cells. A similar protection was observed in Nlrp3-/- mice, with decreased injury and inflammation of livers and EHBDs. Long-term survival was also improved. In contrast, the inactivation of the Casp1 gene had no impact on tissue injury, and all mice died. Tissue analyses in Il1r1-/- and Nlrp3-/- mice showed decreased populations of dendritic cells and natural killer cells and suppressed expression of type-1 cytokines and chemokines.ConclusionsGenes of the inflammasome are overexpressed at diagnosis of BA in humans and in the BA mouse model. In the experimental model, the targeted loss of IL-1R1 or NLRP3, but not of caspase-1, protected neonatal mice against RRV-induced bile duct obstruction.Lay summaryBiliary atresia is a severe inflammatory and obstructive disease of bile ducts occurring in infancy. Although the cause is unknown, activation of the innate and adaptive immune systems injures the bile duct epithelium. In this study we found that patients' livers had increased expression of inflammasome genes. Using mice engineered to inactivate individual inflammasome genes, the epithelial injury and bile duct obstruction were prevented by the loss of Il1r1 or Nlrp3, with a decreased activation of natural killer cells and expression of cytokines and chemokines. In contrast, the loss of Casp1 did not change the disease phenotype. Combined, the findings point to a differential role of inflammasome gene products in the pathogenic mechanisms of biliary atresia.

Project description:Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL), increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC-deficient (KitW-sh ) mice. Wild-type (WT) and KitW-sh mice were subjected to sham or BDL for up to 7 days and KitW-sh mice were injected with cultured mast cells or 1× phosphate-buffered saline (PBS) before collecting serum, liver, and cholangiocytes. Liver damage was assessed by hematoxylin and eosin and alanine aminotransferase levels. IBDM was detected by cytokeratin-19 expression and proliferation by Ki-67 immunohistochemistry (IHC). Fibrosis was detected by IHC, hydroxyproline content, and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and transforming growth factor-beta 1 (TGF-?1) expression/secretion were evaluated. Histidine decarboxylase (HDC) and histamine receptor (HR) expression were detected by qPCR and HA secretion by enzymatic immunoassay. To evaluate vascular cells, von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF)-C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and alpha-smooth muscle actin levels were measured. BDL-induced liver damage was reduced in BDL KitW-sh mice, whereas injection of MCs did not mimic BDL-induced damage. In BDL KitW-sh mice, IBDM, proliferation, HSC activation/fibrosis, and TGF-?1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW-sh mice. vWF and VEGF-C expression decreased in BDL KitW-sh mice. In KitW-sh mice injected with MCs, IBDM, proliferation, fibrosis, and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW-sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW-sh mice.MCs promote hyperplasia, fibrosis, and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies. (Hepatology 2017;65:1991-2004).

Project description:BACKGROUND:A history of abdominal biliary tract surgery has been identified as a relative contraindication for laparoscopic common bile duct exploration (LCBDE), and there are very few reports about laparoscopic procedures in patients with a history of abdominal biliary tract surgery. METHODS:We retrospectively reviewed the clinical outcomes of 227 consecutive patients with previous abdominal biliary tract operations at our institution between December 2013 and June 2019. A total of 110 consecutive patients underwent LCBDE, and 117 consecutive patients underwent open common bile duct exploration (OCBDE). Patient demographics and perioperative variables were compared between the two groups. RESULTS:The LCBDE group performed significantly better than the OCBDE group with respect to estimated blood loss [30 (5-700) vs. 50 (10-1800) ml; p?=?0.041], remnant common bile duct (CBD) stones (17 vs. 28%; p?=?0.050), postoperative hospital stay [7 (3-78) vs. 8.5 (4.5-74) days; p?=?0.041], and time to oral intake [2.5 (1-7) vs. 3 (2-24) days; p?=?0.015]. There were no significant differences in the operation time [170 (60-480) vs. 180 (41-330) minutes; p?=?0.067]. A total of 19 patients (17%) in the LCBDE group were converted to open surgery. According to Clavien's classification of complications, the LCBDE group had significantly fewer postoperative complications than the OCBDE group (40 vs. 57; p?=?0.045). There was no mortality in either group. Multiple previous operations (??2 times), a history of open surgery, and previous biliary tract surgery (including bile duct or gallbladder?+?bile duct other than cholecystectomy alone) were risk factors for postoperative adhesion (p?=?0.000, p?=?0.000, and p?=?0.000, respectively). CONCLUSION:LCBDE is ultimately the least invasive, safest, and the most effective treatment option for patients with previous abdominal biliary tract operations and is especially suitable for those with a history of cholecystectomy, few previous operations (<?2 times), or a history of laparoscopic surgery.

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Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis.

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Proliferating bile duct epithelial cells are a major source of connective tissue growth factor in rat biliary fibrosis.

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