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Biomedical subjects

J Rosenbaum

Publications and source records attributed to J Rosenbaum.

At least 19 recordsLinked to original sources
PubMed1995

Fibroblast growth factor 2 and transforming growth factor beta 1 interactions in human liver myofibroblasts.

BACKGROUND & AIMS: During liver fibrogenesis, myofibroblastic liver cells proliferate and synthesize components of fibrosis. Fibroblast growth factor 2 (FGF-2) is expressed in vivo in myofibroblastic liver cells (MFLCs) during fibrogenesis, and exogenous FGF-2 is mitogenic for MFLCs. The aim of this study was to study the expression and role of endogenous FGF-2 in cultured human MFLCs. METHODS: FGF-2 and FGF-2 receptors were studied using immunoblotting. All RNA studies used ribonuclease protection. Growth of MFLCs was studied using [3H]thymidine incorporation and direct cell counting. RESULTS: MFLCs expressed FGF-2 and its receptors FGF receptor 1 and FGF receptor 2. An antibody to FGF-2 blocked the mitogenic effect of transforming growth factor beta 1 (TGF-beta 1) for MFLCs but not TGF-beta 1-induced increase in cellular fibronectin messenger RNA (mRNA). TGF-beta 1 increased levels of FGF-2 and FGF receptor mRNAs in MFLCs. We have previously shown that TGF-beta 1 also increased platelet-derived growth factor (PDGF) A chain mRNA in these cells and that anti-PDGF antibody blunted the mitogenic effect of TGF-beta 1. The present results show that anti-FGF-2 and anti-PDGF-AA are not additive and that FGF-2 and PDGF-AA are not sequentially induced by TGF-beta 1. CONCLUSIONS: FGF-2 mediates the mitogenic but not the profibrogenic effect of TGF-beta 1 for human MFLCs, and autocrine FGF-2 and PDGF-A interact in the mediation of the mitogenic effect of TGF-beta 1.

Analysis of Variance↗
PubMed1995

Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells. An endothelin B receptor-mediated pathway.

Ito cells play a pivotal role in the development of liver fibrosis associated with chronic liver diseases. During this process, Ito cells acquire myofibroblastic features, proliferate, and synthesize fibrosis components. Considering the reported mitogenic properties of endothelin-1 (ET-1), we investigated its effects on the proliferation of human Ito cells in their myofibroblastic phenotype. Both ET receptor A (ETA: 20%) and ET receptor B (ETB: 80%) binding sites were identified, using a selective ETA antagonist, BQ 123, and a selective ETB agonist, sarafotoxin S6C (SRTX-C). ET-1 did not stimulate proliferation of myofibroblastic Ito cells. In contrast, ET-1 inhibited by 60% DNA synthesis and proliferation of cells stimulated with either human serum or platelet-derived growth factor -BB (PDGF-BB). PD 142893, a nonselective ETA/ETB antagonist totally blunted this effect. SRTX-C was as potent as ET-1, while BQ 123 did not affect ET-1-induced growth inhibition. Analysis of the intermediate steps leading to growth-inhibition by ET-1 revealed that activation of mitogen-activated protein kinase by serum or PDGF-BB was decreased by 50% in the presence of SRTX-C. In serum-stimulated cells, SRTX-C reduced c-jun mRNA expression by 50% whereas c-fos or krox 24 mRNA expression were not affected. We conclude that ET-1 binding to ETB receptors causes a potent growth inhibition of human myofibroblastic Ito cells, which suggests that this peptide could play a key role in the negative control of liver fibrogenesis. Our results also point out that, in addition to its well known promitogenic effects, ET-1 may also exert negative control of growth on specific cells.

Adipocytes↗
PubMed1992

Are tiny polyps important when found on sigmoidoscopy in asymptomatic people?

To determine the occurrence of synchronous large bowel polyps located proximal to the sigmoid, in persons undergoing screening flexible sigmoidoscopy, we examined those who had diminutive polyps (less than or equal to 0.5 cm) as the only finding in the distal colon by further colonoscopy. One hundred one asymptomatic persons (mean age 61 +/- 13 years) had 143 diminutive polyps; a single polyp was found in 76%, and 64% of all polyps were located in the rectum. Thirty (21%) were hyperplastic and 86 (60%) were neoplastic, including 14 with moderate and one with severe dysplasia. The others were inflammatory (five) or unclassified (hot biopsy changes or normal mucosa, 14 polyps), and eight were lost before processing. Colonoscopy revealed that 16 (16%) of the 101 patients had 21 additional polyps proximally, mostly less than 1 cm in diameter. These included one hyperplastic and 18 neoplastic polyps, and two specimens showed hot biopsy changes. Age, histological type, number or location of the index diminutive polyps, were not associated with proximal lesions. We question whether immediate colonoscopy is justified in asymptomatic patients with only diminutive polyps at flexible sigmoidoscopy.

Adult↗
PubMed1990

Decreased toxicity of polymorphonuclear neutrophils toward hepatocytes isolated from rats with acute inflammatory reaction.

We have recently demonstrated that polymorphonuclear neutrophils were toxic to hepatocytes through a protease-mediated mechanism. Since synthesis of antiproteases is markedly increased during acute inflammatory reaction, the aim of this work was to investigate the toxicity of neutrophils against normal vs. inflammatory rat hepatocytes. Acute inflammatory reaction was induced by subcutaneous injection of turpentine 24 hr before the experiments. Hepatocytes from normal and turpentine-treated rats were isolated by collagenase digestion. They were incubated with human neutrophils stimulated by 1 mg/ml opsonized zymosan. Cytotoxicity was quantified by the percentage of alanine aminotransferase activity released by hepatocytes in culture medium after an 18-hr incubation period. By comparison to normal hepatocytes, inflammatory hepatocytes were more resistant to the toxicity of neutrophils. At a neutrophil/hepatocyte ratio of 20:1, the alanine aminotransferase activity releases were 53.7% +/- 5.4% (mean +/- 1 S.E.) and 27.4% +/- 4.8% for normal and inflammatory hepatocytes, respectively. Similarly, inflammatory hepatocytes were found to be less sensitive than normal hepatocytes to the toxic effect of purified neutrophil cathepsin G. In contrast, both types of hepatocytes exhibited the same sensitivity to H2O2 generated by a system consisting of glucose and glucose oxidase. Two arguments suggested that the resistance of inflammatory hepatocytes to protease toxicity was explained by an increased production of antiproteases by these cells: (a) when tested against cathepsin G and porcine pancreatic elastase activities, the protease inhibitory capacity of conditioned medium from inflammatory hepatocytes was higher than that of conditioned medium from normal hepatocytes; (b) conditioned medium from inflammatory hepatocytes markedly reduced the toxicity of stimulated neutrophils as that of cathepsin G.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1990

Interstrand duplexes in hnRNA: the occurrence of retrotransposon antisense sequences.

We have previously identified a class of non-polyadenylated hnRNA molecules (CLASS IA-) which hydrogen bond to polyadenylated hnRNA molecules. Characterization of clones from a Drosophila Class IA- cDNA library reveals that 18S rRNA and transcripts derived from intermediate repeat DNA constitute the bulk of such molecules. The most abundant non-ribosomal clone in the library derives from the antisense strand of the Copia retrotransposon and occurs in Drosophila Kc cell Class IA- hnRNA as non-polyadenylated transcripts of 10 and 15 kb.

Animals↗
PubMed1989

Demonstration of a basic fibroblast growth factor-like molecule in mouse hepatic endothelial cells.

We have investigated whether isolated mouse hepatic sinusoidal endothelial cells (HSEC) synthesized basic FGF. HSEC lysate was fractionated by heparin-Sepharose chromatography. A peak of mitogenic activity for Balb/c 3T3 fibroblasts was eluted with 3M NaCl. Several arguments suggested that the mitogenic factor was related to bFGF: a) its affinity for heparin; b) the loss of its mitogenic activity by heating at 65 degrees C, which was prevented in the presence of heparin; c) the abolition of its mitogenic activity in the presence of protamine sulfate; d) finally, its mitogenic effect was reduced in the presence of antibody to bFGF. These data demonstrate the presence of a bFGF-like molecule in HSEC. This molecule could be involved in the regulation of the neighboring Ito cell proliferation.

Animals↗
PubMed1989

Mouse hepatic endothelial cells in culture secrete a growth inhibitor for hepatic lipocytes and Balb/c 3T3 fibroblasts.

Hepatic lipocytes are sinusoidal cells in close contact to endothelial cells. They proliferate, switch to a fibroblastic phenotype and synthetize collagen during hepatic fibrosis. Since it is known that vascular endothelial cells can influence the proliferation of neighboring cells such as smooth muscle cells, we investigated the role of hepatic endothelial cells on the growth of lipocytes and Balb/c 3T3 fibroblasts. Concentrated conditioned medium from endothelial cells inhibited both [3H]thymidine incorporation and actual growth of lipocytes and Balb/c 3T3 fibroblasts. The inhibition was lost when conditioned medium was treated with heat or trypsin, or when medium was conditioned in the presence of cycloheximide. We conclude that hepatic endothelial cells secrete a proteic growth inhibitor for lipocytes and hepatic Balb/c 3T3 fibroblasts. This inhibitor could be of importance in limiting lipocyte proliferation in the liver and possibly in preventing hepatic fibrosis.

Animals↗
PubMed1988

Influence of ethanol consumption on maternal-fetal transfer of zinc in pregnant rats on day 14 of pregnancy.

The hypothesis that a biochemical lesion underlying the development of fetal alcohol syndrome is an ethanol-induced reduction in placental zinc transfer was tested. Placental zinc transfer was assessed in control and ethanol-fed dams on d 14-15 of pregnancy. Litters from ethanol-fed dams were characterized by a high resorption frequency and fewer live fetuses per litter than litters from control dams. In addition, fetuses from the ethanol-fed dams weighed less than control fetuses. However, despite the negative effects of ethanol intake on litter outcome, placental and fetal retention of 65Zn was similar in the two groups. Therefore, an ethanol-induced fetal zinc deficiency does not seem to have a role in the production of the gross structural malformations associated with fetal alcohol syndrome when adequate zinc is provided in the diet.

Animals↗
PubMed1988

Toxicity of phorbol myristate acetate-stimulated polymorphonuclear neutrophils against rat hepatocytes. Demonstration and mechanism.

Human polymorphonuclear neutrophils (PMN), when exposed to soluble or particulate stimuli, can destroy various types of cells. The purpose of the present work was to investigate the toxicity of phorbol myristate acetate (PMA)-stimulated PMN against hepatocytes. Neutrophils were incubated in basal conditions or after stimulation by 100 ng/ml PMA in the presence of rat hepatocytes isolated by collagenase digestion. Cytotoxicity was quantified by the percentage of alanine aminotransferase (ALAT) activity released by hepatocytes in the culture medium. Whereas unstimulated PMN had only minor effects, PMA-stimulated PMN induced, after a 16-hour incubation, a 29.5% ALAT activity release at a PMN/hepatocyte ratio of 20/1. At the same ratio, stimulated PMN induced a 1.5% and a 16.6% ALAT activity release at 1 and 4 hours, respectively. At 1 hour, electron microscopy showed intimate contacts between PMN and hepatocytes; hepatocytes appeared morphologically normal. Hepatocytic lesions were moderate at 4 hours and marked at 16 hours. Neutrophil-induced hepatocyte toxicity could not be explained by the production of reactive oxygen intermediates since: (a) hepatocyte toxicity was not prevented by either superoxide dismutase or by catalase; (b) PMN obtained from a subject with chronic granulomatous disease were as toxic as PMN obtained from a normal subject. By contrast, a proteinase-mediated mechanism could be implicated since: (a) the supernatant of stimulated PMN induced a 45.9% ALAT activity release, after 16 hours of incubation; (b) three neutral proteinase inhibitors (i.e., alpha 1-proteinase inhibitor, phenylmethylsulfonylfluoride, soybean trypsin inhibitor) as well as fetal calf serum decreased this toxic effect by 82, 86, 81 and 70%, respectively. These inhibitors had no or minor protective effect on the toxicity of stimulated PMN coincubated with hepatocytes. This could be explained by the existence of intimate contacts between PMN and hepatocytes impeding the action of antiproteinases. Our results suggest that PMA-stimulated PMN can damage hepatocytes through the release of proteinases and that the existence of close contacts between PMN and hepatocytes might play a major role in this toxic effect.

Animals↗
PubMed1988

Measurement and characterisation of circulating anti-endothelial cell IgG in connective tissue diseases.

We have detected circulating IgG antibodies that bind with high affinity to human umbilical vein endothelial cells in 74% of patients with systemic lupus erythematosus (SLE), 30% of those with scleroderma and 28% of those with rheumatoid arthritis. IgG binding was F(ab) mediated, and did not involve immune complexes. Anti-endothelial IgG were apparently unrelated to other circulating autoantibodies, including anti-cardiolipin or antiDNA IgG. Bound IgG from SLE or scleroderma patients was displaced by IgG from certain unrelated patients whereas others were ineffective. Anti-endothelial cell IgG from all sera tested were adsorbed by human dermal fibroblasts; erythrocytes and leucocytes each adsorbed a fraction of the activity. Purified IgG did not induce complement-mediated cytotoxicity. We conclude that a discrete group of IgG antibodies is common in connective tissue disease patients, reacts predominantly with endothelial cells and dermal fibroblasts, and may be important in the pathogenesis of vascular damage.

Arthritis, Rheumatoid↗
PubMed1987

Pharmacokinetics of erythromycin in patients with severe cirrhosis. Respective influence of decreased serum binding and impaired liver metabolic capacity.

Pharmacokinetic parameters were studied after i.v. infusion of erythromycin (500 mg) in five patients with alcoholic cirrhosis and six normal subjects. Serum AAG levels were 4.7 +/- 2.4 mumol l-1 in cirrhotics and 10.3 +/- 2.1 +/- mumol l-1 in normals. The unbound fraction (fu) of erythromycin was significantly higher in cirrhotic patients (58.3 +/- 17.7%) than in normal subjects (30.5 +/- 2.8%, P less than 0.01), and a negative correlation was found between fu values and serum AAG (r = -0.867, P less than 0.01). Due to increase in fu, volume of distribution (Vss) was significantly augmented in cirrhotics (85.5 +/- 23.8 l vs 57.6 +/- 14.8 l, P less than 0.05). Serum clearance of unbound erythromycin (CLu) was significantly reduced in cirrhotic patients (42.2 +/- 10.1 l h-1 vs 113.2 +/- 44.2 l h-1 in normal subjects, P less than 0.01). This led to marked elevation of serum concentrations of unbound drug and was entirely explained by the decrease of non renal (i.e. hepatic intrinsic) clearance (31.6 +/- 7.5 l h-1 in cirrhotics, 98.6 +/- 41.5 l h-1 in normals, P less than 0.02); renal clearance remained unchanged. It is concluded that in cirrhotic patients, low serum AAG levels and reduced liver metabolic capacity may lead to marked changes in pharmacokinetics of erythromycin, and that similar results might be expected for drugs which exhibit the same serum binding and pharmacokinetic behaviour as erythromycin.

Adult↗
PubMed1986

Modulation of endothelial cells growth induced by heparin.

We have previously shown that heparin was bound and internalized by cultured human endothelial cells. In this study, we have investigated the effect of heparin on endothelial cells growth. We found that heparin inhibited 3H-thymidine uptake as well as actual cell growth in a dose-dependent manner in the presence of low concentrations of human serum. Inhibition was maximal at 1% serum concentration and was abolished at 10%. Chasing experiments supported the role of membrane-bound heparin in this inhibition. Low molecular weight heparin fractions, or pentosan polysulfate, were equally effective in inhibiting 3H-thymidine uptake. On the other hand, the simultaneous addition of heparin and ECGS was synergic in stimulating 3H-thymidine uptake. These results suggest a modulatory role of heparin in endothelial cells growth.

Cell Division↗