Biomedical subjects

G Feldmann

Publications and source records attributed to G Feldmann.

At least 55 records · Page 3Linked to original sources

PubMed1998

Identification of B10, an alkaline phosphodiesterase of the apical plasma membrane of hepatocytes and biliary cells, in rat serum: increased levels following bile duct ligation and during the development of cholangiocarcinoma.

Alkaline phosphodiesterase (APDE) is associated with the cellular plasma membrane of many organs. Several isoforms are also detected in normal human serum and their respective amounts vary in liver diseases but their significance is unknown. The aims of this study were: 1) to identify a serum form of B10, an APDE exclusively localized at the apical pole of the plasma membrane of rat hepatocytes and biliary cells; 2) to gain insight into its origin; and 3) to investigate its behavior, in two liver diseases in which an abnormal membrane expression of B10 has been reported, namely cholestasis and cholangiocarcinoma. A soluble form of B10 was immunoprecipitated from normal rat serum, which amounted to 13% of total serum APDE activity. By sodium dodecyl sulfate-polyacrylamide gel electrophoresis, the size of the serum enzyme was 125 kd, which is slightly lower than that found in the plasma membrane (130 kd). In bile, a 120-kd and a 130-kd form was found. A sixfold and fivefold increase of B10 APDE activity was observed in the serum of bile duct-ligated rats and in the Long-Evans Cinnamon (LEC) rats which spontaneously develop cholangiocarcinoma. The molecular size of the form present in serum was unchanged. A threefold increase was also observed in LEC rats which had not yet developed a cholangiocarcinoma. In conclusion, we identified a soluble form of B10 in normal rat serum. The increase in serum B10 in the experimental and pathological conditions investigated does not seem to result from passage of the biliary form to the serum but seems to be caused by increased cleavage of the membrane form. Its rise early during the onset of cholangiocarcinoma suggests that B10 in the serum might be a marker of carcinogenesis and/or be involved in the development of cholangiocarcinoma.

Animals↗

PubMed1998

Expression of integrins during liver organogenesis in humans.

Integrins play a pivotal role in organogenesis, by mediating the interactions between differentiating cells and the extracellular matrix. We analyzed the expression of integrins and their ligands during human liver organogenesis. The expression of beta1, beta3, and beta4 integrins and the distribution of several extracellular matrix proteins were studied by immunoperoxidase in fetal liver samples from 5 to 40 weeks' gestation. Hepatoblasts expressed only the beta1, alpha1, alpha5, alpha6, and alpha9 integrin chains. Fetal hepatocytes, emerging at the 8th week of gestation, initially retained the same combination of integrins, but presented a progressive decrease in their expression levels. After 15 weeks' gestation, the expression levels of beta1, alpha1, alpha5, and alpha9 reached levels comparable to those observed in the adult state. Alpha6 expression became undetectable after 30 weeks' gestation. As compared to hepatoblasts, intrahepatic biliary epithelial cells, differentiating at the 8th week of gestation in the ductal plate, were characterized by the progressive loss of alpha1, the marked induction of alpha6, and the de novo acquisition of the beta4, alpha2, and alpha3 integrin chains. The disappearance of integrin receptors for laminin on hepatocytes was associated with the rarefaction of laminin in the perisinusoidal matrix, whereas their induction on biliary epithelial cells was associated with laminin deposition at the point of contact with the ductal plate. In conclusion, integrins likely play an important role in the differentiation of the epithelial and endothelial cell populations of the liver.

Collagen↗

PubMed1998

CD31 expression in benign, borderline, and malignant epithelial ovarian tumors: an immunohistochemical and serological analysis.

OBJECTIVE: To evaluate (a) the expression of CD31 in benign, borderline, and maligant ovarian tumors; (b) the correlation between CD31 expression and the clinicopathological parameters; and (c) the diagnostic interest of serological soluble CD31 (sCD31) in patients with ovarian tumors. METHODS: The intratumoral microvessel density was evaluated by an immunohistochemical technique with the monoclonal antibody JC70 against CD31 at two dilutions in 20 benign, 20 borderline, and 20 malignant tumors of the ovary. Serological determinations of sCD31 with ELISA technique was performed in 35 patients with ovarian tumors (24 benign, 5 borderline, and 6 malignant tumors). RESULTS: The expression of CD31 was higher in ovarian carcinomas than in borderline and benign tumors (P < 0.001) irrespective of the dilutions of the antibody used. In ovarian carcinomas, a correlation was observed between CD31 expression and the stage of the disease, the histologic type, the degree of histological differentiation, and the survival of the patients. In borderline tumors, no correlation was noted between CD31 expression and the clinicopathologic parameters. No difference in serological levels of sCD31 was noted according to histologic types. CONCLUSION: CD31 immunostaining may have a prognostic relevance in ovarian carcinoma but seems to be of limited value in borderline tumors. Serological levels of sCD31 have no diagnostic interest in ovarian tumors.

Enzyme-Linked Immunosorbent Assay↗

PubMed1998

Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes.

BACKGROUND & AIMS: 4,4'-Diethylaminoethoxyhexestrol (DEAEH), amiodarone, and perhexiline cause steatohepatitis in humans. The mechanisms of these effects are unknown for DEAEH and have not been completely elucidated for amiodarone and perhexiline. The aim of this study was to determine these mechanisms. METHODS: Rat liver mitochondria, cultured rat hepatocytes, or rats were treated with these drugs, and the effects on mitochondrial respiration, beta-oxidation, reactive oxygen species formation, and lipid peroxidation were determined. RESULTS: DEAEH accumulated in mitochondria and inhibited carnitine palmitoyl transferase I and acyl-coenzyme A dehydrogenases; it decreased beta-oxidation and caused lipid deposits in hepatocytes. DEAEH also inhibited mitochondrial respiration and decreased adenosine triphosphate (ATP) levels in hepatocytes. DEAEH, amiodarone, and perhexiline augmented the mitochondrial formation of reactive oxygen species and caused lipid peroxidation in rats. CONCLUSIONS: Like amiodarone and perhexiline, DEAEH accumulates in mitochondria, where it inhibits both beta-oxidation (causing steatosis) and respiration. Inhibition of respiration decreases ATP and also increases the mitochondrial formation of reactive oxygen species. The latter oxidize fat deposits, causing lipid peroxidation. We suggest that ATP depletion and lipid peroxidation may cause cell death and that lipid peroxidation products may account, in part, for other steatohepatitis lesions.

Animals↗

PubMed1998

Expression and regulation of intercellular adhesion molecule-1 (ICAM-1) in organotypic cultures of rat liver tissue.

BACKGROUND/AIMS: The objective of the present study was to analyze the expression and regulation of intercellular adhesion molecule-1 (ICAM-1) in organotypic cultures of rat liver slices, which preserve the normal microenvironment of liver cells. METHODS: Rat liver slices were maintained in culture for 15 min to 24 h and examined for ICAM-1 expression by immunohistochemistry and Western blotting in basal conditions and after stimulation with 1000 IU/ml interferon-gamma (IFNgamma), 1000 IU/ml tumor necrosis factor-alpha (TNF alpha) and 50 microg/ml endotoxin. Immunohistochemical results were evaluated using a semiquantitative scoring system. RESULTS: In uncultured slices, ICAM-1 was not detected on hepatocytes. In unstimulated liver slices maintained in organotypic culture, ICAM-1 was induced at the surface of scattered hepatocytes (score at 15 min, 0.33+/-0.47 and at 24 h, 1.17+/-0.69). After 4 h of stimulation, a significant increase in ICAM-1 expression by hepatocytes and adjacent sinusoidal cells, but not by intra-hepatic biliary epithelial cells, was observed for IFNgamma (score: 2.35+/-0.47) and endotoxin (score: 2.67+/-0.47), but not with TNF alpha (score: 0.66+/-0.47). After 24 h of stimulation, a further increase in the extent of ICAM-1 expression by hepatocytes was observed for IFNgamma (score: 3.67+/-0.47) and endotoxin (score: 4.0+/-0.0), and a significant overexpression of ICAM-1 by hepatocytes was detectable after treatment with TNF alpha (score: 3.67+/-0.47). CONCLUSIONS: In rat liver organotypic cultures, TNF alpha, IFNgamma and endotoxin induce the expression of ICAM-1 in hepatocytes and adjacent sinusoidal endothelial cells, but not in portal tracts.

Animals↗

PubMed1998

Ki 67 expression in 35 borderline ovarian tumours: relations with clinicopathologic parameters and ploidy.

OBJECTIVE: To test the diagnostic and prognostic interest of Ki 67 expression and DNA ploidy in ovarian tumours. METHODS: The reactivity of tumour cells with the monoclonal antibody MIB 1 against Ki 67, was assessed by an indirect immunoperoxidase staining technique applied to 25 benign, 35 borderline and 20 malignant tumours of the ovary. In each cases, ploidy was analyzed by DNA flow cytometry. RESULTS: Ki 67 immunopositivity was detected in three benign tumours (12%), 14 borderline tumours (40%) and 14 ovarian carcinomas (70%). The mean and standard deviation of Ki 67 positive cells in benign, borderline and malignant tumours were: 1% +/- 8, 5% +/- 9.6 and 44.5% +/- 31 respectively. A difference in Ki 67 immunostaining was found between carcinomas and benign tumours (P < 0.0001), and between borderline and carcinomas (P = 0.001) but not between benign and borderline tumours. Evaluable DNA histograms from flow cytometry were generated in 77 cases (96.2%) of ovarian tumours. All 25 benign, 97.1% of 35 borderline and 44.5% of 20 malignant ovarian tumours were diploid. A difference was found between borderline and carcinomas (P = 0.001), but not between borderline and benign tumours. CONCLUSION: Ki 67 labelling was correlated with neither histologic and prognostic parameters, nor with survival, nor with DNA ploidy in borderline ovarian tumours.

Adult↗

PubMed1998

Fas-mediated apoptosis of hepatic cells.

While the fas/fas ligand system has been extensively investigated in immuno-competent cells, the place of this system in the physiology and pathophysiology of liver cells remains to be clarified. Although we know that fas is present at the surface of hepatocytes--the main hepatic cells--the role of this membranous protein in physiological conditions is not yet elucidated. However it is the localization of fas on the plasma membrane of hepatocytes which explains why these cells are mainly destroyed by apoptosis--in a picture resembling human fulminant hepatitis--when mice are administered with anti-fas antibodies or fas ligand. It is also established that fas is surexpressed in some human chronic liver diseases, such as those induced by hepatitis B or C virus, a situation which could explain the pathogenesis of some liver lesions occurring during these diseases, such as the apoptosis of hepatocytes in piecemeal necrosis. Finally the fact that caspases, a group of cysteine proteases activated in fas-induced apoptosis, opens the way to inhibition of these enzymes by synthetic peptides and to prevent and treat hepatocyte apoptosis. Demonstration of this possibility has been recently reported in animals presenting fulminant hepatitis induced by anti-fas antibodies.

Animals↗

PubMed1998

Long-term shake suspension and membrane vesicles of medullary thick ascending limb.

Cultured medullary thick ascending limb (MTAL) cells may lack some of the main carriers of fresh MTAL cells, such as apical Na+-K+(NH4+)-2Cl- cotransporter (BSC-1) and Na+/H+ exchanger (NHE-3). We have developed a technique to maintain rat MTALs several hours in suspension and in a good state of viability. Medullary thick ascending limbs were suspended in a 1:1 mixture of Ham's nutrient mixture F-12 and Dulbecco's modified Eagle's essential medium (HDMEM) supplemented with 25 mM HCO3- and gassed with 95% O2/5% CO2; the resulting mixture was placed in a rotary shaking water bath at 37 degrees C for 16 hours. As seen by electron microscopy, MTALs from the HDMEM-suspension retained a virtually normal tubular organization. Na+-K+(NH4+)-2Cl- cotransport activity and NHE consistent with both apical NHE-3 and basolateral NHE-1 activities were underscored both in intact cells by intracellular pH measurements and in a membrane fraction enriched in apical and basolateral membranes by 22Na+ uptake experiments. These results demonstrate that freshly harvested MTALs can be maintained in a well differentiated state for at least 16 hours; this preparation should make long-term in vitro studies of MTAL transport regulations possible.

Animals↗

PubMed1998

Soluble adhesion molecules in serum and cyst fluid from patients with cystic tumours of the ovary.

The potential of the soluble forms of the adhesion molecules ICAM-1 (sICAM-1), CD44std (sCD44std) and E-cadherin (sE-cadherin) was tested for the diagnosis of benign and malignant cystic epithelial tumours of the ovary. Concentrations of sICAM-1, sCD44 std and sE-cadherin were measured by enzyme-linked immunosorbent assay (ELISA) in the serum and cyst fluid obtained from 23 patients with luteal cysts, 29 with cystadenomas, nine with dermoid cysts, five with borderline tumours and 11 with carcinomas. Serum concentrations of sICAM-1, but not of sCD44std and sE-cadherin, were constantly elevated compared with normal controls. Cyst fluid concentrations of sICAM-1, sCD44std and sE-cadherin were elevated in borderline and malignant tumours compared with cystadenomas (P = 0.034, 0.006 and 0.001, respectively). In conclusion, our results suggest that serum concentrations of adhesion molecules have no diagnostic value in ovarian tumours, whereas cyst fluid concentrations may facilitate distinction between benign lesions and borderline or malignant tumours.

Adolescent↗

PubMed1998

Specificity of helper T-cells generated from macaques infected with attenuated simian immunodeficiency virus.

Deletion of the simian immunodeficiency virus (SIV) nef gene leads to an attenuated virus phenotype in vivo. We have previously shown that these viruses induce a potent cellular immune response in macaques. To extend these studies, we established virus-specific short-term T-cell lines from four rhesus macaques infected with a nef deletion mutant of SIV. These T-cell lines proliferated upon restimulation with whole SIV or SIV gp140 antigen in vitro. The proliferating cells were characterized as CD4+ helper T-cells (TH) and their antigen recognition was MHC class II DR-restricted. After antigenic stimulation, they transcribed mRNA for various TH1- and TH2-like cytokines. Using these SIV-specific cell lines, a variety of helper T-cell epitopes in the SIV Env protein were determined with overlapping peptides. TH epitopes were identified throughout the whole SIV Env including both constant and variable regions. Although the recognition of TH epitopes was heterogeneous among different animals, five more broadly reactive T-cell epitopes were identified. As expected, recognition was associated with the MHC class II DRB background of the animals. This is the first report on helper T-cell epitopes in SIV-infected monkeys. Such studies should be of considerable significance for AIDS/ vaccine research.

Amino Acid Sequence↗

PubMed1998

Expression of p53 protein in borderline epithelial ovarian tumors: a clinicopathologic study of 39 cases.

OBJECTIVE: To evaluate the expression of p53 protein in borderline ovarian tumors and its correlations with the clinicopathological parameters. STUDY DESIGN: p53 protein was detected by immunoperoxidase in 79 ovarian tumors (39 borderline, 20 malignant, 20 benign). p53 expression was compared to histological type, FIGO stage, age, presence of ascites, recurrence and patient survival. RESULTS: The median value of quantitative p53 immunopositivity was: 0.80+/-0.42 in ovarian cancers, 0+/-0.24 in borderline tumors and 0+/-0.16 in benign tumors (p=0.001). In borderline tumors, no correlation existed between p53 expression and the histological or clinical parameters. In malignant tumors, no correlation existed between the expression of p53 and patient survival. CONCLUSION: We found no correlation between p53 immunopositivity and clinicopathological parameters in carcinomas and borderline tumors of the ovary. p53 immunopositivity may help in distinguishing borderline tumors from ovarian cancers.

Adenocarcinoma, Mucinous↗

PubMed1997

Generation of herpes virus saimiri-transformed T-cell lines from macaques is restricted by reactivation of simian spuma viruses.

Herpes virus saimiri (HVS) transforms human T-cells in vitro to stable growth. These T-cell lines retain their immunological characteristics of the parent cells and do not release infectious virus. Recently, lymphocytes of Old World monkeys were efficiently transformed by HVS. In parallel to these studies we initiated transformation experiments by infecting peripheral blood cell cultures of 45 monkeys, 35 rhesus and 10 cynomolgus macaques. In only three cases, we obtained transformed T-cell lines. The transformed T-cells were largely double-positive for CD4 and CD8. They responded with increased proliferation to mitogenic or IL-2 stimulation and transcribed mRNA for IL-2, IL-4, and IL-10. However, most initiated T-cell cultures from macaques developed giant cells. The cytopathic agent was identified as simian foamy virus (SFV) as confirmed by PCR, immunofluorescence, and coculture experiments. Treatment of the T-cell cultures with AZT- and SFV-specific sera did only shortly prolong the life-span of the cultures. Therefore, the reactivation of SFV caused remarkable difficulties in the establishment of macaque T-cell lines by HVS. This seems to be a general problem since most animals from several breeding colonies are SFV-positive.

Animals↗

PubMed1997

Hepatocarcinogenesis in woodchuck hepatitis virus/c-myc mice: sustained cell proliferation and biphasic activation of insulin-like growth factor II.

Transgenic mice carrying the c-myc oncogene under control of woodchuck hepatitis virus (WHV) DNA sequences invariably develop hepatocellular carcinoma (HCC), despite a temporally limited expression of the transgene in the neonatal liver. To better characterize the different steps of the tumorigenic process, we analyzed the liver expression of the c-myc transgene and several growth-related genes by in situ hybridization and Northern blotting. In parallel studies, proliferated changes were investigated by detection of bromodeoxy-uridine-positive S-phase nuclei and apoptosis was evaluated by in situ nick end-labeling of DNA. During the neonatal period, high levels of c-myc messenger RNAs (mRNAs) were detected in all hepatocytes, and the expression of insulin-like growth factor II (IGF II) was frequently enhanced, correlating with increased cell proliferation. Despite elevated expression of the p53 gene, no change in liver cell apoptosis was observed. After weaning, c-myc transgene expression decreased to undetectable levels in all hepatocytes, whereas proliferation decreased but remained notably higher than in age-matched controls. The expression of c-fos, c-jun, and c-H-ras was highly variable during the preneoplastic period and in the tumors, with no consistent increase compared with controls. Resurgence of c-myc transgene expression was evidenced in all cells from hyperplastic lesions and carcinomas, accompanied with frequent focal reactivation of IGF II. Thus the strong proliferative stimulus induced by the combined effects of c-myc and IGF II in the neonatal liver might initiate a process characterized by persistent, dysregulated hepatocyte proliferation, in turn greatly increasing the risk of hepatocellular transformation.

Animals↗

PubMed1997

Apoptosis after ischemia-reperfusion in human liver allografts.

Little is known about the possible contribution of apoptosis to ischemia-reperfusion injury in human liver transplantation. Therefore, we studied postreperfusion surgical biopsy specimens of 16 human liver allografts using the TUNEL assay for in situ demonstration of apoptotic cells. In all patients, a variable proportion of hepatocytes and sinusoidal endothelial cells presented labeled nuclei. The mean +/- standard deviation percentages of positive hepatocytes were 18.7% +/- 12.2% in the whole section, 30.4% +/- 18.7% in the subcapsular region, 14.5% +/- 13.5% in the centrilobular zones, and 10.3% +/- 9.5% in the periportal zones. The percentage of positive hepatocytes were not correlated with the duration of cold ischemia but was higher in grafts harvested from donors with elevated preoperative aspartate aminotransferase (AST) levels. The percentage of positive hepatocytes was correlated with postoperative serum levels of AST (P = .015) and inversely correlated with postoperative serum levels of factor V (P = .019). Apoptotic biliary epithelial cells were detected in only 3 cases. In conclusion, apoptosis is a frequent event in postreperfusion biopsy specimens of liver allografts and probably contributes to preservation injury of hepatocytes.

Adenosine↗

PubMed1997

Expression of cadherins in benign, borderline, and malignant ovarian epithelial tumors: a clinicopathologic study of 60 cases.

We have analyzed the expression of E- and N-cadherins in benign, borderline, and maligant ovarian tumors, and we have correlated the pattern of cadherin expression with the standard clinicopathological parameters. An immunohistochemical technique has been applied to formalin-fixed, paraffin-embedded samples of 20 benign cystic tumors, 20 borderline tumors, and 20 cancers. Expression of E- and N-cadherins immunostaining were compared with the histological type, degree of histological differentiation, International Federation of Gynecology and Obstetrics (FIGO) stage, presence of ascites, occurrence of recurrence, and survival. E-cadherin was homogeneosuly expressed in benign tumors but was heterogeneously expressed or undetectable in most borderline and malignant tumors. In contrast, N-cadherin was detected in most benign and borderline tumors but was absent or heterogeneous in most carcinomas. The difference of expression of E-cadherin and N-cadherin between the three groups of ovarian tumors was statistically significant (respectively, P = .03 and P < .001). In ovarian carcinoma, patients with negative E-cadherin staining present a significantly shorter survival. No correlation was found between cadherin expression and clinicopathological parameters in borderline tumors. Our results suggest that alterations in E-cadherin and N-cadherin expressions are differentially involved in ovarian carcinogenesis and may have diagnostic and prognostic values.

Adult↗

PubMed1997

Interphase cytogenetic analysis reveals numerical chromosome aberrations in large liver cell dysplasia.

BACKGROUND/AIMS: Little is known about genetic alterations in large or small liver cell dysplasia. The aim of this study was to determine whether these lesions present numerical chromosome aberrations. METHODS: Eight patients with hepatocellular carcinoma on cirrhosis, five with large liver cell dysplasia and three with small liver cell dysplasia, were analysed by in situ hybridization with different centromeric nucleic acid probes specific respectively for chromosomes 1, 7, 17 and 18. In each case results were compared between dysplastic, tumoral and non-dysplastic cirrhotic cells. Four normal livers were also studied with the same method and served as cytogenetic controls. RESULTS: All cases of large liver cell dysplasia dysplayed a polysomic population for each investigated chromosome. A high variability of numerical chromosome aberrations was observed with a copy number of chromosomes which ranged from two to more than six. By contrast, only one case of small liver cell dysplasia showed chromosomal anomalies. Numerical aberrations of at least one chromosome were observed in six of the eight hepatocellular carcinoma while the non-dysplastic cirrhosis and normal liver always showed a diploid pattern. CONCLUSIONS: These results demonstrate that cellular modifications in large liver cell dysplasia coexist with an early acquisition of genomic alterations, supporting the view that these phenotypic changes are preneoplastic.

Adult↗

PubMed1997

The plasma membrane polarity of human biliary epithelial cells: in situ immunohistochemical analysis and functional implications.

BACKGROUND/AIMS: In transporting epithelia, like the biliary epithelium, most plasma membrane proteins present a polarized distribution, essential for the maintenance of the structural and functional properties of the epithelium. We therefore analyzed the expression of polarized plasma membrane proteins by human biliary epithelial cells in order to compare them with other transporting epithelial cells and to search for differences in plasma membrane protein expression between their different anatomical subsets. METHODS: We designed an in situ immunohistochemical study of the various anatomical compartments of the human biliary tract in order to assess the pattern of expression of selected polarized plasma membrane proteins, including integrin receptors, ectopeptidases, membrane transporters and GPI-linked proteins. RESULTS: All biliary epithelial cells expressed the same repertoire of integrins, except for integrin chain alpha5, restricted to the intra-hepatic compartments. All biliary epithelial cells expressed the following apical ectopeptidases: aminopeptidase-N, neutral-endopeptidase, dipeptidyl-peptidase IV. All biliary epithelial cells expressed the membrane transporter Na+ K+-ATPase, restricted to the basolateral domain, and the apical transporters CFTR and MDR-1. The apical AE2 anion exchanger was restricted to the small intra-hepatic bile ducts and the gallbladder. The GPI-linked protein protectin was basolateral in the intrahepatic bile ducts and apical in the gallbladder. CONCLUSIONS: The structural organization of the plasma membrane of biliary epithelial cells is very similar to that of other simple epithelia and exhibits a limited degree of heterogeneity.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1997

Effects of simvastatin, pentoxifylline and spironolactone on hepatic fibrosis and portal hypertension in rats with bile duct ligation.

AIMS/METHODS: Our aim was to study the antifibrotic and hemodynamic effects of simvastatin (SMV), pentoxifylline (PTX) and spironolactone (SPN), three drugs which may have antifibrotic and/or portal hypotensive properties, in a model of hepatic fibrosis and portal hypertension induced in rats by bile duct ligation. A blind study was performed in five groups of 53 Sprague-Dawley rats: sham, placebo (PL), SMV (2.5 mg x kg(-1) x J(-1)), PTX (50 mg x kg(-1) x J(-1)) and SPN (100 mg x kg(-1) x J(-1)). Drugs were administered by daily gavage over a 4-week period as soon as bile duct ligation was performed. At day 28, the following parameters were evaluated: area of hepatic fibrosis by image analysis after staining collagen with picrosirius and plasma concentrations of hyaluronate, splanchnic and systemic hemodynamics (radiolabeled microspheres). RESULTS: Portal venous pressure (PL: 15.5+/-1.5, SMV: 15.8+/-2.5, PTX: 15.9+/-1.8, SPN: 13.5+/-2.1 mmHg, p<0.05) and porto-systemic shunts (PL: 30+/-31, SMV: 18+/-27, PTX: 25+/-24, SPN: 5+/-4%, p<0.05) were significantly reduced in the SPN group; other hemodynamic parameters were not significantly altered. There was a significant correlation between portosystemic shunts and portal pressure (r(s)=0.47, p<0.01). The area of fibrosis was not significantly different among the four groups of bile duct ligated rats (PL: 8.7+/-3.9, SMV: 7.1+/-3.6, PTX: 7.8+/-2.7, SPN: 6.6+/-3.3%) but was higher than in sham rats (1.5+/-0.5%, p<0.001). Hyaluronate was significantly higher in bile duct ligated rats (from 374+/-162 to 420+/-131 microg/l, among the four groups) than in sham rats (52+/-16 microg/l, p<0.0001). CONCLUSIONS: In this model, none of the drugs prevented hepatic fibrosis. On the other hand, spironolactone decreased portal pressure and prevented porto-systemic shunts. Therefore, this drug may have beneficial effects in patients with early portal hypertension.

Animals↗