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Biomedical subjects

D Steinberg

Publications and source records attributed to D Steinberg.

At least 217 records · Page 12Linked to original sources
PubMed1982

Hypersensitivity pneumonitis in strain II guinea pigs. I. Histologic features.

A model of hypersensitivity pneumonitis (HP) in syngeneic animals would allow experiments designed to determine immunopathogenesis of HP. Strain II guinea pigs were treated with Micropolyspora faeni and challenged with intratrachael M. faeni. Lung histology 4 days thereafter was quantitatively evaluated. Intratrachael administration of M. faeni caused interstitial and intraalveolar collections of mononuclear and polymorphonuclear cells. Sensitized (pretreated with M. faeni) animals' lungs had more extensive pathology than unsensitized animals. 3 weeks after challenge with M. faeni, pulmonary histopathology regressed to granulomatous interstitial infiltration, similar to that found in chronic HP in humans. We conclude that the pulmonary histopathologic response of sensitized strain II guinea pigs to intratrachael M. faeni resembles human HP.

Alveolitis, Extrinsic Allergic↗
PubMed1982

Hypersensitivity pneumonitis in strain II guinea pigs. II. Immunologic features.

A model of hypersensitivity pneumonitis (HP) in syngeneic animals would allow experiments designed to determine immunopathogenesis of HP. Strain II guinea pigs were treated with Micropolyspora faeni and challenged with intratracheal M. faeni. Skin test, serum antibody, hilar lymph node lymphocyte proliferation and bronchoalveolar macrophage migration inhibition (MMI) response to M. faeni antigen were determined. Sensitized animals had positive delayed skin tests, serum antibody and bronchoalveolar cell MMI, but not M. faeni-induced hilar node lymphocyte proliferation. We conclude that this model is suitable for examination of the importance of various mechanisms which might be important in HP.

Alveolitis, Extrinsic Allergic↗
PubMed1982

Effects of insulin and glucose on very low density lipoprotein triglyceride secretion by cultured rat hepatocytes.

The effect of insulin on hepatic triglyceride synthesis and secretion is controversial. Previously, we have described a cell culture system of adult rat hepatocytes that synthesize and secrete very low density lipoprotein (VLDL) triglycerides with small and irreproducible effects of insulin on triglyceride metabolism. To study the primary effects of insulin on hepatic triglyceride metabolism a method was developed utilizing fibronectin-coated culture dishes that allowed adhesion, spreading, and maintenance of hepatocytes for 2-3 d in the absence of serum and insulin. This culture system allowed mass measurements of both cellular and secreted VLDL triglycerides for long time periods after the addition of physiological concentrations of insulin to hormone-free culture medium. In the absence of insulin and after an initial 4 h in culture, the medium was replenished and triglyceride mass was measured at the end of 18-h incubations. VLDL triglyceride accumulated in the culture medium at a linear rate over this time-course with increasing accumulation as the medium glucose concentration was raised from 2.5 to 25 mM glucose (1.77+/-0.24 to 3.09+/-0.76 mug triglyceride/mg cell protein per h). There was no apparent significant lipolysis or hepatocellular reuptake of secreted VLDL triglycerides. In the absence of insulin cellular triglyceride levels were unchanged between 3 and 24 h in culture while insulin (50-500 muU/ml) significantly increased cellular triglyceride content at all glucose concentrations tested (0-25 mM). The addition of insulin to the culture medium progressively reduced the rate of VLDL triglyceride secretion accompanied by an increase in cellular triglyceride at insulin concentrations > 50 muU/ml. Most or all of the observed increase in cell triglyceride content could in all experiments be accounted for by the insulin-induced inhibition of VLDL secretion. Incorporation of [2-(3)H]glycerol into cellular and VLDL triglycerides as a function of insulin concentration was also measured. Glycerol incorporation data at 20-22 h after plating of the cells closely paralleled the insulin-induced changes in cellular and VLDL triglyceride as determined by mass analysis. The observed effects of insulin occurred at concentrations close to the physiological range and suggest that the direct hepatic effect is to suppress VLDL secretion although the net effect in vivo will clearly reflect many additional accompanying changes.

Albumins↗
PubMed1982

Nonenzymatic glucosylation of low-density lipoprotein alters its biologic activity.

Human low-density lipoprotein (LDL) was glucosylated by incubation in vitro with glucose (20-80 mM) with or without addition of cyanoborohydride. The incorporation of covalently bound glucose was linear over time, and amino acid analysis showed the presence of glucosyllysine residues. The glucosylated LDL (glc LDL) moved more rapidly than normal LDL on agarose electrophoresis. The rate of degradation of 125I-labeled glucosylated LDL (glc LDL) by cultured human fibroblasts was reduced compared with that of native I-LDL, the difference increasing with extent of glucosylation. Effects were seen with blockage of as few as 6-15% of the LDL lysine residues; high-affinity degradation was completely lost when one-third of the lysine residues were blocked. Conjugation of LDL with glucose-6-phosphate also blocked high-affinity uptake and degradation. Whereas native LDL uptake inhibited the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase and stimulated acyl coenzyme A:cholesterol acyltransferase activity, glc LDL had no effects on these enzymes. The fractional catabolic rate of glc LDL in guinea pigs was reduced. Degradation of glc LDL by mouse peritoneal macrophages was not significantly faster than that of native LDL. Finally, the presence of glc LDL in human plasma was demonstrated. Preliminary data show that 1.3% of lysine residues in normal LDL and 2-5.3% of lysines in diabetic LDL were glucosylated. Since, like other plasma proteins, LDL undergoes glucosylation in diabetes, its turnover and sites of catabolism may differ from normal and this may be relevant to the accelerated atherosclerosis of diabetes.

Amino Acids↗
PubMed1982

Activated alveolar macrophages: IgG and complement receptors.

Receptors for IgG and C on PM populations can be modulated by activation. AM populations constantly exposed to environmental particulates may not be subject to changes of IgG and C receptors after activation. We compared normal and activated rabbit AMs and PMs. Activation was accomplished by treatment with intravenous BCG or intratracheal Micropolyspora faeni. We examined the ability of these AM populations to attach to (form rosettes) and phagocytize SRBC coated with varying concentration of IgG or C. Compared to normal AMs, activated AM populations formed more rosettes with SRBC coated with IgG or C and phagocytized more via the IgG receptor. PMs from BCG-treated rabbits did not form more rosettes with IgG- or C-coated SRBC but demonstrated more IgG-mediated phagocytosis than did normal PMs. C-mediated phagocytosis occurred in AM populations from only five of 25 BCG-treated rabbits and two of 20 normal rabbits. The TG broth-induced rabbit PM also exhibited a low level of C and IgG-mediated phagocytosis compared to the mouse TG broth-induced PM. We conclude that rabbit AM IgG and C receptors can be altered by events that activate AMs. C-mediated phagocytosis is much lower in rabbit macrophages (both AMs and PMs) than in activated mouse PM populations. IgG-mediated phagocytosis can be used as an index of rabbit AM activation.

Animals↗
PubMed1982

Cytosine arabinoside with daunorubicin or adriamycin for therapy of acute myelocytic leukemia: a CALGB study.

A randomized comparison of the relative efficacy and toxicity of daunorubicin (DNR) at 30 or 45 mg/sq m or adriamycin (ADM) at 30 mg/sq m, given on the first 3 days of a 7-day continuous infusion of cytosine arabinoside (ara-C) at 100 mg/sq m/day, shows the outcome to be dependent on anthracycline, dose, and patient age. DNR 45 is significantly better than DNR 30 or ADM 30 for inducing complete remissions (CR) in patients younger than 60 yr, (72%, 59%, 58% CRs, respectively). DNR 30 is better than DNR 45 or ADM 30 for inducing CR in patients older than 60 yr (47%, 31%, 35%, respectively). There was a corresponding shift in the induction mortality for the age, dose, and anthracycline groups. Adriamycin was significantly more toxic to the gastrointestinal tract than daunorubicin. The duration of complete remission, with cyclic courses of maintenance therapy, was independent of the patient's age, the dose, or choice of anthracycline used in induction, and of whether the maintenance courses were given every 4 wk or every 8 wk.

Adolescent↗
PubMed1981

Neutral cholesterol esterase activity in macrophages and its enhancement by cAMP-dependent protein kinase.

Cholesterol esterase with optimal activity at pH 6.8 was found in the 40,000 X g supernatant fraction prepared from rabbit alveolar macrophages, thioglycolate-elicited mouse peritoneal macrophages, and the J774 macrophage cell line. The neutral cholesterol esterase activity in these three types of macrophages was of the same order of magnitude as that in the 40,000 X g supernatant fraction of adrenal, heart, and liver but considerably lower than that in adipose tissue. The enzyme prepared from J774 cells was activated about 60% by preincubation with cAMP and Mg-ATP; half-maximal activation was obtained at 2.5 X 10(-7) M cAmP. The activation was completely blocked by a specific protein inhibitor of cAMP-dependent protein kinase. These findings suggest that cytoplasmic cholesterol esters stored in macrophages can be mobilized for release by action of the neutral enzyme described and, further, that this process may be regulated by factors that affect intracellular cAMP levels.

Animals↗
PubMed1981

Low density lipoprotein receptor deficiency in cultured hepatocytes of the WHHL rabbit. Further evidence of two pathways for catabolism of exogenous proteins.

We have studied hepatocytes cultured from Watanabe-heritable hyperlipidemic (WHHL) rabbits, animals that display striking elevation of plasma low density lipoprotein (LDL), spontaneous atherosclerosis, and an absence of LDL receptor activity in cultured fibroblasts. Degradation of LDL by WHHL hepatocytes differed from degradation by normal hepatocytes in several ways: 1) degradation by normal hepatocytes as a function of LDL concentration was curvilinear with a saturable component, while degradation by WHHL hepatocytes was a linear function of concentration; 2) degradation of 125I-labeled LDL by mutant cells was not decreased by excess unlabeled LDL, while degradation by normal cells was; 3) degradation of LDL by normal cells was inhibited by colchicine and chloroquine while degradation by the mutant cells was not; 4) both cell types catabolized LDL at nearly equal rates, but activity of 3-hydroxy-3-methylglutaryl-CoA reductase was suppressed only in the normal cells. These differences are analogous to those previously reported in describing the qualitatively different pathways for receptor-dependent and receptor-independent catabolism of lactosylated and native human LDL in rat hepatocytes. Thus, hepatocytes from WHHL rabbits lack LDL receptor activity. The peripheral and hepatic LDL receptors most likely are products of the same gene or depend for their activity on a single gene product.

Animals↗
PubMed1981

Studies on the rate of efflux of cholesterol from cultured human skin fibroblasts.

The cholesterol content of normal human skin fibroblasts was increased (approximately doubled) by incubating cells in the presence of a high concentration of low density lipoprotein. Cholesterol efflux from these cells was then studied as a function of time and as a function of acceptor concentration. High density lipoprotein from which essentially all of the cholesterol had been removed by heptane extraction was used as a model acceptor (cholesterol-depleted high density lipoprotein). Using a sensitive enzymatic assay, it was possible to measure the increase in medium cholesterol and the decrease in cell cholesterol content simultaneously. Release was approximately a linear function of time for at least 6-12 h. A maximal rate of release was obtained at 20 micrograms of protein/ml (50% of excess stored sterol released in about 12 h); increasing the acceptor concentration 10-fold (to 200 micrograms/ml) failed to increase efflux rate. Comparison of the rates of fall of free and ester cholesterol levels suggested that hydrolysis of the ester may be rate-limiting when cholesterol-depleted high density lipoprotein is used as the acceptor. The results imply that above saturating concentrations of acceptor, acceptor-cell interaction is no longer limiting and that the rate of efflux of cholesterol under such conditions depends on intracellular processes necessary to make cholesterol available to the acceptor (e.g. hydrolysis of cholesterol esters and transfer of cholesterol from intracellular sites to the plasma membrane). Whether or not the concentrations of acceptor bathing cells in vivo is normally rate-limiting remains to be determined.

Blood↗
PubMed1981

Underlying mechanisms in atherosclerosis.

A brief resume of advances in atherosclerosis research over the past 30 years is presented, emphasising the multidisciplinary origins of those advances. A somewhat more detailed review of progress in the lipoprotein field is presented as an example illustrative of the pace of research related to atherosclerosis. Finally, an attempt is made to identify some of the research areas that promise to yield valuable new insights in the next 30 years.

Arteries↗
PubMed1981

Effect of a high carbohydrate diet on apoprotein-B catabolism in man.

We have previously demonstrated that while VLDL-TG production increased in subjects fed high CHO diets, VLDL apo-B production did not change. To further define the effects of high CHO diets on apo-B metabolism in man, we studied the catabolism of this apoprotein in VLDL, IDL, and LDL in three hypertriglyceridemic subjects during control and high CHO diets. 125I-VLDL was injected intravenously into subjects and 18 blood samples obtained over the following 48-hr period. VLDL, IDL, and LDL were isolated by sequential ultracentrifugation at each time point and the specific radioactivity of apo-B in each lipoprotein class was determined. A multicompartmental analysis was utilized to analyze the three radioactivity curves obtained in each study. The major change in apo-B catabolism during the high CHO diet involved the conversion of VLDL apo-B to LDL apo-B. During the control diet, 40%--62% of VLDL apo-B was converted to LDL apo-B while during the high CHO period, only 16%--42% of VLDL apo-B was converted to LDL. The reduction in conversion resulted from two separate processes. First, direct catabolism of VLDL apo-B without conversion to higher density lipoprotein classes increased during the high CHO diet. Second, although during the control period approximately 25% of VLDL apo-B was converted directly to LDL apo-B (without passing through the IDL density range), essentially no VLDL apo-B degradation occurred via this route during the high CHO period. Thus, although the rate of VLDL apo-B secretion into plasma was the same during both diet periods, significant alterations in the routes of catabolism of apo-B occurred on the high CHO diet.

Apolipoproteins↗