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Biomedical subjects

W Scholz

Publications and source records attributed to W Scholz.

At least 19 recordsLinked to original sources
PubMed1992

Identification and characterization of the effector region within human C5a responsible for stimulation of IL-6 synthesis.

Human C fragment C5a is known to be a proinflammatory mediator and more recently shown to be a potent modulator of both humoral and cell-mediated immunity. We recently reported that natural and recombinant C5a induces the synthesis of IL-6-specific mRNA and secreted protein from human monocytes. Our studies using analogue peptides that are homologous to the carboxyl-terminal sequence of human C5a, indicate that the "effector" site for inducing IL-6 synthesis resides within the C-terminal region (C5a (70-74)) of the C5a molecule. C5a peptides containing the exact sequence of the natural factor were found to retain full agonist activity but exhibited low potency (0.01-0.1% of intact C5a). It was also shown that amino acid substitutions in the C5a peptides by aromatic/hydrophobic residues, outside the immediate effector site, resulted in analogue peptides with a substantial increase in potency relative to the most active natural peptide (C5a (56-74)). Moreover, these peptides approach the potency of natural C5a for induction of IL-6. Taken together, these results suggest that the inflammatory and immunoregulatory activities associated with C5a may, in part, be due to the synthesis of IL-6.

Amino Acid Sequence↗
PubMed1992

Na+/H+ exchange in porcine cerebral capillary endothelial cells is inhibited by a benzoylguanidine derivative.

Na+/H+ exchange activity has been examined in endothelial cells isolated from porcine brain capillaries. Intracellular pH (pHi) changes were monitored using a confocal laser scanning microscope and the pH-sensitive fluorescence indicator 2',7'-bis-(2-carboxyethyl)-5,6-carboxyfluorescein (BCECF). Acid load of the brain capillary endothelial cells was performed with a NH4Cl (20 mM) prepulse. In bicarbonate-free solutions pHi recovered within 3 to 10 min. Removal of extracellular Na+ ions demonstrated that H+ extrusion after an acid load of the cells was Na+ dependent. The Na+/H+ exchange could be completely blocked by EIPA (5-(N-ethyl-N-isopropyl)amiloride) as well as by the novel inhibitor 3-methylsulfonyl-4-piperidinobenzoyl guanidine hydrochloride (HOE 694) in concentrations of 1 to 10 microM, respectively. EIPA and HOE 694 in a concentration of 0.1 microM caused a partial block of Na+/H+ exchange.

Amiloride↗
PubMed1992

Airway pharmacology of the potassium channel opener, HOE 234, in guinea pigs: in vitro and in vivo studies.

The smooth muscle relaxant effects of the novel potassium channel opener, HOE 234, were investigated in guinea pig airways and compared with those of lemakalim (BRL 38227). Both agents evoked concentration-related reduction in spontaneous tracheal tone or in the tone induced by histamine, prostaglandin E2 or carbachol. HOE 234 was more potent, particularly against carbachol, and was considerably longer acting than lemakalim in a wash-out experiment. On testing for preventive efficacy against histamine-induced bronchoconstriction in anaesthetized animals a dose-related decrease of pulmonary resistance (RL) was observed. HOE 234 given either intravenously (i.v.) or by inhalation was longer acting and 3 and 6 times more potent than lemakalim. Administration of 30 micrograms/kg i.v. HOE 234 during continuous bronchoconstriction maintained by infusion of histamine decreased RL for more than 20 min whereas the effect of 100 micrograms/kg i.v. lemakalin disappeared within 4 min. These results show that HOE 234 is effective against contractile response induced by asthma mediators in guinea pig airways and compares favourably with lemakalim. Moreover it acts on acute existing bronchospasm and therefore has the potential to act against asthma attacks.

Animals↗
PubMed1992

Effects of Na+/H+ exchange inhibitors in cardiac ischemia.

To investigate a possible protective role of Na+/H+ exchange inhibition under ischemic conditions isolated rat hearts were subjected to regional ischemia and reperfusion. In these experiments all 6 untreated hearts suffered ventricular fibrillation on reperfusion. Addition of 1 x 10(-5) mol/l amiloride or 3 x 10(-7) mol/l 5-(N-ethyl-N-isopropyl)amiloride (EIPA) markedly decreased the incidence and duration of ventricular fibrillation or even suppressed fibrillation completely as in the case of 1 x 10(-6) mol/l EIPA. Both compounds diminished the activities of lactate dehydrogenase and creatine kinase in the venous effluent of the hearts during ischemia. At the end of the experiments tissue contents of glycogen, ATP and creatine phosphate were increased in the treated hearts as compared to control hearts. In an additional experiment the beneficial effects of Na+/H+ exchange inhibition during ischemia was confirmed in vivo with anaesthetized rats undergoing coronary artery ligation. In these animals amiloride or EIPA pretreatment caused a marked reduction of ventricular premature beats and ventricular tachycardia as well as a complete suppression of ventricular fibrillation. The concentration dependent inhibition of Na+ influx via Na+/H+ exchange by amiloride and EIPA was investigated in erythrocytes from hypercholesterolemic rabbits with Na+/H+ exchange activated by exposure to hyperosmotic medium. Furthermore the inhibition of Na+ influx by EIPA after intracellular acidification was studied in cardiac myocytes of neonatal rats. Both agents were effective in the same order of potency in the ischemic isolated working rat heart as in the erythrocyte model in which they inhibited Na+/H+ exchange.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiloride↗
PubMed1991

Fibronectin augments anti-CD3-mediated IL-2 receptor (CD25) expression on human peripheral blood lymphocytes.

The extracellular matrix (ECM) is composed of a number of macromolecules that promote cell adhesion, cell migration, and differentiation. Receptors for these molecules have been identified and belong to a superfamily of cell surface proteins, collectively known as the integrins. In this study, we show that the matrix protein fibronectin (FN) acts synergistically with immobilized anti-CD3 antibody to promote proliferation of total human peripheral blood lymphocytes (HPBL) in the absence of exogenous IL-2. Proliferation was inhibited by both the alpha 5 beta 1 and alpha 4 beta 1 recognition peptides. ARG-GLY-ASP (RGD), and GLU-ILE-LEU-ASP-VAL-PRO-SER-THR (EILDVPST), respectively. Expression of CD25 (IL-2 receptor) was significantly higher on cells cultured on anti-CD3 and FN, indicative of T-cell activation. Additionally, cells cultured on immobilized anti-CD3 and FN for 3 days showed increased adhesion to FN and increased forward light scatter/side scatter profile. Synthesis of both IL-1 and to a lesser extent IL-2 was elevated in supernatants from cultures containing both anti-CD3 and FN. These data are consistent with published reports which demonstrate that ECM proteins can act as costimulants of lymphocyte proliferation. Finally, our results show that cells cultured on anti-CD3 antibody and FN have an activated phenotype and that cytokines may be involved in this process.

Antibodies↗
PubMed1991

Effect of orotic acid on the generation of reactive oxygen and on lipid peroxidation in rat liver.

The pyrimidine precursor orotic acid (OA) is a constituent of dairy products and therapeutic drugs. Several recent publications point towards a tumor promoting activity of OA in rat liver. An increased production of reactive oxygen has been discussed as a possible mechanism, leading to lipid peroxidation and DNA single strand breaks. In view of contradictory results, this postulated prooxidative action of OA was reexamined with new experimental techniques. Weanling Sprague-Dawley rats were fed 1% OA in different diets for 4-35 days. The NADPH-mediated lipid peroxidation in liver homogenate and microsomes was determined in vitro by analysis of low-level chemiluminescence (CL) and the strongly correlated formation of malondialdehyde (MDA). In no case did treatment with OA result in an increase of lipid peroxidation in vitro nor did such treatment enhance the generation of reactive oxygen as measured by lucigenin CL. In accordance, the total cytochrome P-450 content as well as the activity of individual P-450 isoenzymes were unchanged. Treatment with OA did not elevate the MDA content of fresh liver homogenate when butylated hydroxytoluene (BHT) was present in the test system. However, when the antioxidant was omitted, increased levels of thiobarbituric acid reactive material were found which correlated with the triglyceride content. This could explain some published data that have been taken as indication for a prooxidative action of OA. Evidence against an increased lipid peroxidation in vivo is given by the analysis of ethane exhalation. Furthermore, no increase in DNA single strand breaks by OA treatment could be observed by the alkaline elution technique. These results do not support the hypothesis of a prooxidative activity of OA. The observed reversible decrease of the GSH/GSSG ratio is assumed to result from the reduced size of the phosphopyridine nucleotide pool due to purine deficiency and an increased consumption of NADPH by the enhanced reductive degradation of pyrimidines.

Administration, Oral↗
PubMed1991

Expression of CD26 (dipeptidyl peptidase IV) on resting and activated human T-lymphocytes.

CD26 is an activation antigen which is expressed on the surface of human T-lymphocytes. It has been characterized to be the dipeptidyl peptidase IV (DPP IV). Considerable amounts of CD26 are already present on resting T-lymphocytes. The expression of CD26 is enhanced by T-cell mitogens or antigens. A correlation of CD26 expression and of enhanced enzymatic activity was observed after T-cell activation. Our data indicate that not only the immunoreactivity, but also the enzymatic activity of CD26 are detectable on the cell surface. In addition, de novo expression of CD26 was demonstrated on CD26-negative T-cells after mitogenic or antigenic stimulation. CD26 expression is initiated during the G1 phase of the cell cycle. The expression occurs nearly simultaneously with HLA-DR, but later than CD25. Similar to CD25 and HLA-DR, CD26 is not a permanent marker on the surface of T-lymphocytes, but is down-regulated after 7 days of culture. When testing the influence of interleukin 1, interleukin 2, tumour necrosis factor, and interferon-gamma on the expression of CD26, no effect was found on unstimulated or on mitogen-stimulated T-lymphocytes. The binding of two different monoclonal antibodies against CD26 (anti-DPP IV and anti-Tal) to resting and activated T-lymphocytes revealed a different pattern of immunoreactivity. Resting T-lymphocytes reacted stronger with anti-DPP IV than with anti-Tal. However, binding of the two monoclonal antibodies to T-cell blasts did not show significant differences. These data indicate that CD26 may be expressed in differently modulated configurations on the surface of T-cells, which may be associated with a distinct status of activation and/or function.

Amino Acid Sequence↗
PubMed1991

Rapid determination of the elevated Na(+)-H+ exchange in platelets of patients with essential hypertension using an optical swelling assay.

Accumulating evidence suggests an increased activity of the Na(+)-H+ exchanger in essential hypertension. The present investigation aimed at developing a test for routine measurements. Platelet-rich plasma was added directly to a cuvette placed into an aggregometer containing 140 mmol/l sodium propionate medium (pH 6.7, 37 degrees C). The accumulation of intracellular sodium due to activation of Na(+)-H+ exchange results in an osmotic cell swelling, which is detectable as a decrease in optical density (OD). This reaction reflects activation of the Na(+)-H+ exchanger since we observed (1) a dose-dependent inhibition by amiloride (inhibition constant, Ki = 10 mumol/l) and ethylisopropylamiloride (Ki = 0.07 mumol/l) and (2) a dependence on extracellular sodium of the OD changes. Electron microscopy of sodium propionate-treated platelets revealed a general swelling and a distinct decrease in electron density of the cytosol without other significant alterations. Quantification of Na(+)-H+ exchange activities was accomplished by calculating rate constants of the recorded changes in OD. Application of this assay to 20 essential hypertensives and 32 normotensives demonstrated an increased activity of the Na(+)-H+ exchanger in essential hypertensives (rate constants 29.8 x 10(-3) per s versus 21.7 x 10(-3) per s).

Adult↗
PubMed1990

Phenobarbital enhances the formation of reactive oxygen in neoplastic rat liver nodules.

The effect of treatment of rats with the liver monooxygenase inducer phenobarbital on the formation of reactive oxygen in neoplastic liver nodules and the surrounding normal tissue was investigated. Liver nodules were induced by treatment of rats with diethylnitrosamine (single i.p. injection of 0.15 mumol/kg body weight on day 1 after birth) followed by chronic administration of phenobarbital-sodium (PB; 0.05% in diet) after weaning. Groups of rats were kept on PB until sacrifice or were withdrawn from the promoter 3-6 weeks prior to killing. Emission of chemiluminescence was used as a sensitive means to detect the formation of reactive oxygen in microsomal preparations from the various tissues incubated with NADPH and the chemiluminigenic detector lucigenin. In addition, a 2-dimensional photon counting system has been developed that permits the analysis of the spatial distribution of lucigenin-chemiluminigenic signals over liver tissue sections incubated with reduced phosphopyridine dinucleotides. In general, we observed increased levels of reactive oxygen formation in liver nodules when compared with the normal liver tissue. Highest levels were seen in nodules that stemmed from PB-induced rats. Studies on the expression and activity of cytochrome P-450 in liver nodules as well as experiments with specific inhibitors point towards a participation of the liver monooxygenase system in reactive oxygen formation, although additional metabolic pathways seem to be involved as well. The observed increases in reactive oxygen in liver nodules of PB-treated rats might be related to the promoting activity of this drug.

Acridines↗
PubMed1990

Synergistic induction of interleukin 2 receptor (TAC) expression on YT cells by simultaneous activation of distinct signal transduction pathways.

The human NK-like leukemic cell line YT was used to study interleukin 2 receptor (IL-2R; Tac) expression induced by activators of distinct signal transduction pathways. Tac expression was induced by active phorbol esters (12-O-tetradecanoylphorbol 13-acetate [TPA] and 4 beta-phorbol 12,13-didecanoate), which directly activate protein kinase C (PKC), as well as forskolin (FK), a stimulator of adenylate cyclase. A synergistic effect on Tac expression was obtained by simultaneous stimulation with optimal concentrations of phorbol esters and FK. Inactive phorbol esters (4 beta-phorbol, 4 alpha-phorbol 12,13-didecanoate) and the inactive analog of FK (1,9-dideoxyforskolin) had no effect on Tac expression. The active phorbol esters synergized also with interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF alpha) in Tac expression. Staurosporine, a potent inhibitor of PKC in vitro, inhibited Tac expression marginally in YT cells stimulated with FK, and enhanced Tac expression in cultures treated with TPA, TNF alpha, or IL-1. Based on the assumption that synergistic effects are observed when two agonists use different signaling pathways, these findings provide evidence that IL-1, TNF, and TPA use different pathways/regulatory elements to regulate Tac expression on the cell surface. Synergistic upregulation of Tac expression by simultaneous activation of distinct pathways may be an important mechanism to modulate the immune response.

Adenylyl Cyclases↗
PubMed1990

C5a-mediated release of interleukin 6 by human monocytes.

Recombinant human C5a (rC5a) was assessed for its ability to induce interleukin 6 (IL-6) production in human peripheral blood-derived mononuclear cell (PBMC) cultures. rC5a was observed to induce IL-6 production as measured by hybridoma growth promotion (B9.9 assay) and human B cell differentiation (SKW6.4 assay). Optimal IL-6 production was obtained after 24 hr stimulation with 0.1-0.5 micrograms/ml rC5a. In addition, natural human C5ades Arg and natural porcine C5a were able to induce a similar level of IL-6. The observed IL-6 activity appeared not to be due to endotoxin contamination since heat treatment (100 degrees C/15 min) inhibited rC5a induction of IL-6. The rC5a stimulation also induced an increase in steady-state IL-6 mRNA as determined by Northern blot analysis. Pretreatment of PBMC with leucine-methyl ester to deplete monocytes reduced the rC5a-induced IL-6 production to background levels. In addition, stimulation of purified T cell preparations with rC5a produced little IL-6 activity, suggesting that monocytes are the major source of IL-6 in this system. These results suggest that the inflammatory and immunoregulatory activities of C5a may in part be due to the stimulation of IL-6 release, a cytokine which possesses potent pleiotropic functions.

Complement C5a↗
PubMed1990

Interleukin-6 serum levels correlate with footpad swelling in adjuvant-induced arthritic Lewis rats treated with cyclosporin A or indomethacin.

To investigate the role of interleukin 6 (IL-6) in adjuvant-induced arthritis, serum from adjuvant-immunized Lewis rats treated with cyclosporin, indomethacin, or saline was evaluated for IL-6 activity. Inflammation was quantitated by measuring paw volume. We found that an increase in serum IL-6 activity parallels the kinetics of paw edema development in adjuvant-immunized rats. Daily treatment with 5 mg cyclosporin A/kg prevented the increase in paw volume and held serum IL-6 activity to levels observed in untreated (normal) rats. Daily treatment with 1 mg indomethacin/kg resulted in a 50% reduction in serum IL-6 levels and a significant decrease (approximately 50%) in paw volume on Day 17 compared to saline-treated rats. Linear regression analysis confirmed the positive correlation between mean paw volume and mean serum IL-6 activity (R2 = 0.783, P less than 0.01 on Day 17) in normal, arthritic, and cyclosporin A- or indomethacin-treated groups. These results are consistent with a role for IL-6 in the pathology of arthritis and suggest that serum IL-6 activity may be a useful parameter for monitoring disease activity.

Animals↗
PubMed1990

[Dynamic MRT after Gd-DTPA administration in kidney transplants: the susceptibility and T2 effects].

35 kidney transplanted patients (15 without pathological findings and 20 with histologically proven chronic rejection) were investigated with a combination of dynamic MR and bolus application of Gd-DTPA. The occurrence of susceptibility artifacts and T2 effects at the junction between papilla and renal calix were analysed. There are two groups of patients. The first one shows only artifacts due to susceptibility. The second group indicates the so-called "dark ring pattern" (susceptibility artifacts and T2 effects). These effects are discussed in terms of their dependence on concentration and their dependence on the degree of transplant malfunction. The appearance of "dark-ring patterns" and of susceptibility artifacts indicate the functional status of the glomerular filters.

Contrast Media↗
PubMed1989

Synergistic induction of interleukin 2 receptor (TAC) expression on YT cells by interleukin 1 or tumor necrosis factor alpha in combination with cAMP inducing agents.

This study demonstrates synergistic effects on Tac expression by interleukin 1 (IL-1) or tumor necrosis factor alpha (TNF alpha) in combination with the adenylate cyclase stimulator, forskolin (FK), as well as by IL-1 with TNF alpha in the human NK-like leukemic cell line YT. The maximal expression level (greater than 80% positive cells) obtained with FK plus IL-1 or FK plus TNF alpha could not be obtained by increasing the concentration of either agent alone. Furthermore, we demonstrate that Tac protein expression is correlated with increased steady-state Tac mRNA levels. Other agents that increase intracellular cAMP, such as prostaglandin E (PGE) or isobutyl-methylxanthine (IBMX), also synergized with IL-1 or TNF alpha (but not with FK). The findings suggest that cAMP plays a role in regulating Tac expression in YT cells, and that IL-1, TNF, and FK use distinct signal transduction mechanisms, all resulting in the same end point effect, namely, induction of Tac mRNA and cell surface protein expression.

1-Methyl-3-isobutylxanthine↗
PubMed1988

Lpr T cell hyporesponsiveness to mitogens linked to deficient receptor-stimulated phosphoinositide hydrolysis.

The T lymphocytes that expand with age in the peripheral lymphoid organs of autoimmune disease-prone mice homozygous for the lpr mutation display deficient activation and proliferation in response to mitogenic lectins or antigen. In the present study, an attempt was made to correlate the deficient agonist-induced proliferation of these lpr T cells with early transmembrane signaling events mediated by receptor-coupled phosphoinositide hydrolysis. lpr T cells were capable of binding the agonistic lectin, phytohemagglutinin, in a normal manner. In addition, they expressed on their surface the antigen-specific T cell receptor-CD3 complex, which is required for T cell activation, albeit at a lower density than that found on congenic +/+ T cells. Furthermore, lpr T cells contained normal levels of the Ca2+- and phospholipid-dependent enzyme, protein kinase C, and the enzyme was translocated from the cytosol to the particulate fraction upon phorbol ester treatment. On the other hand, the lpr T cells displayed a markedly deficient agonist-induced phosphoinositide hydrolysis in comparison with their congenic +/+ counterparts, as indicated by the minimal accumulation of the phosphoinositide-derived second messengers, inositol phosphates and diacylglycerol. The defective step(s) in transmembrane signaling was bypassed by a combination of phorbol ester plus Ca2+ ionophore, which reconstituted proliferative responses of lpr T cells to normal levels, suggesting that: (a) the phosphoinositide signaling pathway plays an obligatory role in T cell activation; and (b) signaling events subsequent to phosphoinositide hydrolysis are, for the most part, intact in lpr T cells. The deficient step(s) in lpr T cell activation precedes, therefore, the generation of phosphoinositide-derived second messengers and could be due to defective function of the T cell receptor-CD3 complex, GTP-binding proteins, and/or phosphoinositide-specific phosphodiesterase. It remains to be determined whether the deficient signaling event(s) in lpr T cells is a direct pathologic consequence of the lpr gene, or rather, reflects the immature status of a normally minor thymic subset that is aberrantly exported and expanded in lpr mice.

Animals↗