Biomedical subjects

Chantal Housset

Publications and source records attributed to Chantal Housset.

25 records · Page 2Linked to original sources

PubMed2002

Peribiliary myofibroblasts in biliary type liver fibrosis.

Biliary type liver fibrosis develops as part of the wound healing response to bile duct injury in chronic cholestatic liver diseases. The origin of myofibroblasts accumulating together with extracellular matrix around proliferating bile duct structures (referred to as ductular reaction) in the setting of cholestatic injury, has been investigated mostly in the rat bile duct ligation model. Evidence indicates that hepatic stellate cells undergo a myofibroblastic transition following bile duct ligation and that myofibroblastic hepatic stellate cells disclose chemoattraction towards bile duct structures in cholestatic liver. On the basis of morphological studies, nevertheless, the origin of peribiliary myofibroblasts has also been attributed to the activation and proliferation of portal fibroblasts. Bile duct epithelial cells of the ductular reaction actively contribute to the promotion and regulation of biliary type liver fibrogenesis. They synthesize and release a number of paracrine mediators such as transforming growth factor-beta, connective tissue growth factor, platelet-derived growth factor-BB, and endothelin-1 that target different liver cell types, including hepatic stellate cells and portal fibroblasts. Through these interactions, bile duct epithelial cells and peribiliary myofibroblasts cause periportal fibrosis in cholestatic and also probably other types of liver diseases.

Animals↗

PubMed2002

Hepatocyte growth factor and c-Met inhibition by hepatic cell hypoxia: a potential mechanism for liver regeneration failure in experimental cirrhosis.

Hepatic resection in cirrhotic patients is associated with impaired liver regeneration and poor clinical outcome. Because experimental cirrhosis is associated with hepatic cell hypoxia, we herein investigated whether hypoxia might alter the mechanisms of liver regeneration in the cirrhotic liver. Cirrhosis was induced by diethylnitrosamine in rats. Immunohistochemistry was performed to assess hepatocellular hypoxia and proliferation 24 hours after a two-thirds partial hepatectomy (PH) in cirrhotic and control rats. Cultured hepatocytes and myofibroblastic hepatic stellate cells were submitted to hypoxia using anaerobic jars. Hepatocyte growth factor (HGF) and c-Met expressions were determined by reverse transcriptase-polymerase chain reaction, Northern blot, and Western blot. In control rats, hypoxia was restricted to perivenular hepatocytes, and PH induced a marked increase in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression remained unchanged. In cirrhotic rats, hypoxia was detected virtually in all of the hepatocytes, and PH induced no significant change in hepatocyte proliferation and in liver HGF expression, whereas c-Met expression was decreased as compared to normal livers. In vitro, the expression of HGF in myofibroblastic hepatic stellate cells and of c-Met in hepatocytes underwent a dramatic decrease under hypoxia. Our results suggest that hepatocellular hypoxia causes inhibition of HGF (and of c-Met)-mediated proliferation and thereby might contribute to liver regeneration failure in cirrhotic liver.

Animals↗

PubMed2002

Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan.

BACKGROUND/AIMS: Bosentan, a dual endothelin ET(A/B) receptor antagonist, may cause dose-dependent reversible cholestatic liver injury. We herein tested whether bosentan or metabolites, both eliminated in bile, induce alterations in bile secretion. METHODS: Bile flow and output of bile constituents were monitored in pentobarbital-anesthetized rats with biliary fistulas. Normal and TR(-) rats with a genetic defect in mrp2, received bosentan intravenous injections. RESULTS: Bosentan bolus intravenous injections of 0.1-10mg/kg triggered a dose-dependent increase in biliary bilirubin excretion. In addition, doses (> or =10mg/kg) caused a sustained increase in canalicular bile salt-independent bile flow, combined with significant increases in the concentration and output of glutathione and of bicarbonate in bile. In rats receiving bosentan (> or =10mg/kg), both under basal conditions and under intravenous taurocholate perfusion (2micromol/min/kg), phospholipid and cholesterol secretions were profoundly inhibited and uncoupled from bile salt secretion. In TR(-) rats, the choleretic effect of bosentan was reduced to non-significant levels. The stimulation of bilirubin secretion and the uncoupling of phospholipid from bile salt secretion were absent, whereas that of cholesterol was maintained. CONCLUSIONS: Bosentan alters canalicular bile formation in major part via mrp2-mediated mechanisms. Intermittent uncoupling of lipid from bile salt secretion may contribute to bosentan hepatic adverse reaction.

Animals↗

PubMed2002

Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sclerosing cholangitis.

BACKGROUND/AIMS: Because biliary tract lesions that resemble those of primary sclerosing cholangitis (PSC) may occur in cystic fibrosis (CF), we examined the prevalence and influence of CF transmembrane conductance regulator (CFTR) gene mutations in PSC patients. METHODS: Genomic DNA was analyzed in 29 consecutive PSC patients and in 115 healthy control individuals. A scanning method followed by direct DNA sequencing was used to scan the CFTR coding regions. RESULTS: Four patients (13.8%) were heterozygous for a CFTR mutation, including a new putative severe CF-causing mutation (N782K), and three mild defects (L997F, D1270N, and S1235R). The comparison of PSC patients with healthy controls showed no significant difference in the frequency of CFTR mutations (P=0.415). In addition, two patients (6.9%) were heterozygous for the IVS8-5T allele, which is not significantly different from the 5-6%-prevalence in the general population. Unusual clinical features including a severe outcome in childhood, with a lethal outcome at age 22, and biliary aspergillosis were recorded in patients with a CFTR mutation. CONCLUSIONS: The proportion of CF carriers is not significantly higher in PSC patients than in the general population. The possibility that CFTR mutations may contribute to a severe clinical course in PSC patients is worth further examining.

Adolescent↗

PubMed2002

Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis.

Cirrhosis consists of hepatocyte nodules surrounded by a highly vascularized fibrous tissue. We previously showed that the development of biliary cirrhosis in the rat is associated with the occurrence of hepatocellular hypoxia and the induction of hepatic angiogenesis. We herein examined the occurrence of hypoxia in an experimental model of diethylnitrosamine (DEN)-induced cirrhosis. We also determined whether hypoxia directly affects the expression of vascular endothelial growth factor (VEGF), of VEGF receptors (Flt-1, Flk-1), and of type I and type IV collagens in activated hepatic stellate cells (HSCs) and the expression of VEGF in hepatocytes. Our results show that in DEN-treated rats, although the progression of liver fibrosis is associated with hepatocellular hypoxia and angiogenesis, VEGF and Flt-1 expressions in the liver are increased and correlated with the density of microvessels. In vitro, hypoxia induces the expression of VEGF, Flt-1, and type I collagen in activated HSCs and that of VEGF in hepatocytes. In addition, we show that hypoxia-induced type I collagen expression in HSCs may occur independently of transforming growth factor beta1 (TGF-beta1) overexpression. In conclusion, the present study provides further evidence that hepatocellular hypoxia and angiogenesis progress together with fibrogenesis after liver injury and that hypoxia directly contributes to the progression of liver fibrosis.

Alkylating Agents↗

PubMed2002

Liver disease in pediatric patients with cystic fibrosis is associated with glutathione S-transferase P1 polymorphism.

Liver disease in patients with cystic fibrosis (CF) is inconstant and has not yet been clearly related to any specific risk factor. While the expression of cystic fibrosis transmembrane conductance regulator (CFTR) is restricted to the biliary epithelium in the liver, recent findings indicate that CFTR modulates reduced glutathione (GSH) transport and that CFTR dysfunction creates an imbalance in the antioxidant defense. Among liver detoxifying enzymes, the glutathione S-transferases (GSTs) play a key role in the protection against oxidative stress. Because oxidative injury contributes to the development of liver disease, we hypothesized that 2 members of the GST superfamily, GSTM1 and GSTP1, which are expressed in the biliary epithelium, could influence the hepatic status in patients with CF. The potential impact of GSTM1 and GSTP1 gene polymorphisms was assessed in 106 children with CF (mean age, 11.5 years). Based on polymerase chain reaction/restriction fragment length polymorphism analysis, we found that the frequency of GSTP1-Ile(105)/Ile(105) genotype was significantly higher in patients with CF with liver disease than in those without (P <.03). Among the youngest patients, aged 6 years, GSTP1-Ile(105)/Ile(105) genotype was associated with a 8-fold increase in the risk of liver disease compared with other GSTP1 genotypes (P =.002). No association between the GSTM1 genotype and liver status was documented. In conclusion, GSTP1-Ile(105)-encoding allele contributes to hepatic dysfunction in CF. Identification of this polymorphism may have prognostic value and prompt early treatment in patients with CF with an increased risk of liver disease.

Adolescent↗

PubMedDate not supplied

[Cystic liver diseases. Genetics and cell biology].

In 50% of cases, polycystic liver disease is associated with autosomal dominant polycystic kidney disease, which is caused by mutations in the PKD1 and PKD2 genes that encode polycystin-1 and -2, respectively. These proteins form a polycystin-1/2 complex on the plasma membrane, including that localized on the surface of primary cilia, where they act as mechanosensors. Polycystin-1 acts as a (mechano)receptor of environmental signals, and polycystin-2 as a calcium channel mediating intracellular transduction. Isolated autosomal dominant polycystic liver disease is caused by mutations in PRKCSH that encodes hepatocystin, a protein of the endoplasmic reticulum, which may participate in the N-glycosylation and maturation of proteins addressed to the cell surface. Congenital hepatic fibrosis whether it is accompanied by bile duct dilatations (Caroli's syndrome) or not, may be associated with autosomal recessive polycystic kidney disease, which is caused by mutations in PKHD1 that encodes fibrocystin, a protein of primary cilia. Genetic defects in fibrocystin cause ciliary dysfunction, presently considered as a major pathogenic event in cystogenesis. Excessive cell proliferation, a hallmark of cystic biliary epithelium, occurs in combination with deregulation of the epidermal growth factor (EGF) and probably also estrogen receptors. EGF receptor antagonists inhibit kidney and liver cyst development in animal models, and are currently under investigation in phase I and II clinical trials in patients with autosomal dominant polycystic kidney disease.

Caroli Disease↗