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Biomedical subjects

D Kunz

Publications and source records attributed to D Kunz.

At least 73 records · Page 4Linked to original sources
PubMed1997

[Bilateral laparoscopic transperitoneal adrenalectomy in pheochromocytoma].

Laparoscopic transperitoneal and endoscopic extraperitoneal adrenalectomy are two safe options in minimally invasive surgery associated with a very low morbidity. Comparative studies with the conventional access to the adrenal gland demonstrated the advantages of the endoscopic technique. The anterior transperitoneal approach yields a better exposure of the anatomic structures and allows the surgeon to orient himself more easily, while at the same time he may perform additional laparoscopic maneuvers. In two cases of bilateral pheochromocytoma a bilateral laparoscopic adrenalectomy was performed simultaneously by employing the transperitoneal approach. The duration of surgery was approximately 210 and 270 min, respectively, with an intraoperative blood loss of about 350 and 400 ml. There were no complications following this procedure. Already on the 1st postoperative day, the patients could be fully mobilized. Furthermore, immunological data obtained perioperatively support the minimal invasiveness of this technique.

Adrenal Gland Neoplasms↗
PubMed1997

[Laparoscopic transperitoneal adrenalectomy--technique and personal experiences].

Laparoscopic transperitoneal and endoscopic extraperitoneal adrenalectomy are two safe options in minimally invasive surgery associated with very low morbidity. The anterior transperitoneal approach we prefer yields a better exposure of the anatomic structures and allows the surgeon to orient himself more easily. In addition, various other laparoscopic maneuvers may be performed synchronously. We report on our own experience with eight laparoscopic transperitoneal adrenalectomies performed in four cases unilaterally and in two additional cases bilaterally during April, 1996, and January, 1997, in six patients aged 20 to 56 years. The indications were in four cases pheochromocytoma (operated on bilaterally in two cases), and in the remaining two cases adrenal Cushing's syndrome. The duration of surgery was approximately 240 min for bilateral adrenalectomy and 166 min for unilateral adrenalectomy, respectively, with an intraoperative blood loss of about 50 to 400 ml. Except for haematoma of the abdominal wall there were no other postoperative complications. The serum levels of interleukin 6 and 10 underline the minimal invasiveness of this technique, since there were only small increases of interleukin 6 and interleukin 10.

Adrenal Gland Neoplasms↗
PubMed1996

Molecular cloning of the rat inducible nitric oxide synthase gene promoter.

The inducible nitric oxide synthase (iNOS) is not constitutively expressed but is induced in many types of mammalian cells by cytokines and bacterial endotoxins. Previously, we have reported the most interesting feature of rat iNOS gene that is up-regulated by cyclic AMP at transcriptional level as demonstrated by nuclear run-on assay. We now have isolated and sequenced the rat iNOS gene promoter and determined the transcription start site. Moreover, we have constructed a rat iNOS promoter-chloramphenicol acetyltransferase (CAT) fusion gene and analyzed its inducibility by interleukin 1 beta and cyclic AMP in transiently transfected Swiss 3T3 fibroblasts.

3T3 Cells↗
PubMed1996

Tetranactin inhibits interleukin 1 beta and cAMP induction of group II phospholipase A2 in rat renal mesangial cells.

Renal mesangial cells express secretory phospholipase A2 in response to two principal classes of activating signals that may interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines, such as interleukin 1 beta, and agents that elevate cellular levels of cAMP. Treatment of mesangial cells with tetranactin, a cyclic antibiotic produced by Streptomyces aureus with a molecular structure similar to cyclosporin A inhibits interleukin 1 beta- and cAMP-dependent group II phospholipase A2 secretion in a dose-dependent manner with IC50 values of 43 and 33 nM, respectively. However, tetranactin does not directly inhibit group II phospholipase A2 activity. Western blot analyses of mesangial cell supernatants reveal that the inhibition of phospholipase A2 activity is due to suppression of phospholipase A2 protein synthesis. This effect is preceded by the reduction of phospholipase A2 mRNA steady-state levels as shown by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells. Thus, tetranactin is a potent inhibitor of group II phospholipase A2 expression in cytokine- and cAMP-stimulated mesangial cells and represents a new class of group II phospholipase A2 inhibitors with IC50 values in the low nanomolar range. This compound may be useful in the therapy of diseases associated with increased group II phospholipase A2 secretion.

Analysis of Variance↗
PubMed1996

Molecular mechanisms of dexamethasone inhibition of nitric oxide synthase expression in interleukin 1 beta-stimulated mesangial cells: evidence for the involvement of transcriptional and posttranscriptional regulation.

Inducible nitric oxide synthase (iNOS; EC 1.14.13.39) is expressed in rat glomerular mesangial cells upon exposure to the inflammatory cytokine interleukin 1 beta (IL-1 beta). We have reported that nanomolar concentrations of dexamethasone suppress IL-1 beta-induced iNOS protein expression and production of nitrite, the stable end product of NO formation, without affecting IL-1 beta-triggered increase in iNOS mRNA levels. We now have studied the mechanisms by which dexamethasone suppresses IL-1 beta-stimulated iNOS expression in mesangial cells. Surprisingly, nuclear run-on transcription experiments demonstrate that dexamethasone markedly attenuates IL-1 beta-induced iNOS gene transcription. However, this is counteracted by a prolongation of the half-life of iNOS mRNA from 1 h to 2.5 h by dexamethasone. Moreover, dexamethasone drastically reduces the amount of iNOS protein by reduction of iNOS mRNA translation and increased degradation of iNOS protein. These results indicate that glucocorticoids act at multiple levels to regulate iNOS expression, thus providing important insights into the treatment of inflammatory diseases.

Animals↗
PubMed1996

Therapeutic strategies for the inhibition of inducible nitric oxide synthase--potential for a novel class of anti-inflammatory agents.

In recent years, NO, a gas previously considered a potentially toxic chemical, has become established as a diffusible universal messenger mediating cell-cell communication throughout the body. In mammals, NO is a recognized mediator of blood vessel relaxation that helps to maintain blood pressure. In the central nervous system NO acts as a non-conventional neurotransmitter and participates in the establishment of long-term plasticity required for memory formation. In addition, NO is responsible for some parts of the host response to sepsis and inflammation and contributes to certain disease states. A number of strategies have emerged with regard to a pharmacological control of pathological NO overproductions. This review will discuss these novel therapeutic approaches that may provide new means for clinical medicine.

Animals↗
PubMed1996

Inhibition by tetranactin of interleukin 1 beta- and cyclic AMP-induced nitric oxide synthase expression in rat renal mesangial cells.

1. We have investigated whether tetranactin, a cyclic antibiotic produced by Streptomyces aureus with a molecular structure related to cyclosporin A, influences inducible nitric oxide synthase (iNOS; EC 1.14.13.39) induction in rat glomerular mesangial cells. 2. Previously we have shown that iNOS is expressed in renal mesangial cells in response to two principal classes of activating signals comprising inflammatory cytokines such as interleukin 1 (IL-1) or tumour necrosis factor alpha and agents that elevate cellular levels of cyclic AMP. Treatment of mesangial cells with IL-1 beta or the membrane-permeable cyclic AMP analogue, N6, 0-2'-dibutyryladenosine 3',5'-phosphate (Bt2 cyclic AMP) for 24 h induces iNOS activity measured as nitrite levels in cell culture supernatants by 44 fold or 33 fold, respectively. Incubation of mesangial cells with tetranactin inhibits IL-1 beta- and cyclic AMP-dependent production of nitrite in a dose-dependent fashion with IC50 values of 50 nM and 10 nM, respectively. 3. Western-blot analyses of mesangial cell extracts reveal that the inhibition of nitrite synthesis by tetranactin is due to a suppression of iNOS protein levels. This effect is preceded by a reduction of iNOS mRNA steady state levels as demonstrated by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells. 4. Thus, tetranactin is a potent inhibitor of iNOS expression in cytokine- and cyclic AMP-stimulated mesangial cells and represents a new class of iNOS inhibitors with IC50s in the low nanomolar range. This compound may be useful in the therapy of diseases associated with pathological NO overproduction due to iNOS expression.

Animals↗
PubMed1995

Interleukin 1 beta-induced expression of nitric oxide synthase in rat renal mesangial cells is suppressed by cyclosporin A.

The expression of inducible nitric oxide synthase (iNOS) is triggered in rat renal mesangial cells by exposure to the inflammatory cytokine interleukin 1 beta (IL-1 beta). Here we report that cyclosporin A (CsA) a potent immunosuppressive drug, inhibits IL-1 beta dependent iNOS expression in renal mesangial cells. Addition of CsA dose dependently suppresses IL-1 beta-induced nitrite formation (IC50 = 0.9 microM). Western- and Northern blot analyses of mesangial cell extracts reveal that the inhibition of IL-1 beta-induced nitrite formation by CsA is due to decreased iNOS protein and iNOS mRNA steady state levels. Using nuclear run on experiments we show that the transcription rate of the IL-1 beta-induced iNOS gene is reduced. Furthermore, by electrophoretic mobility shift analysis we demonstrate reduced DNA-binding of the nuclear factor NF kappa B, an essential component of the IL-1 beta-dependent upregulation of iNOS gene transcription. The data presented in this report suggest that the cellular machinery involved in the IL-1 beta dependent transcriptional upregulation of the iNOS gene in mesangial cells is a target for the action of CsA.

Animals↗
PubMed1995

Pyrrolidine dithiocarbamate differentially affects cytokine- and cAMP-induced expression of group II phospholipase A2 in rat renal mesangial cells.

Renal mesangial cells express group II phospholipase A2 in response to two principal classes of activating signals that may interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha) and agents that elevate cellular levels of cAMP such as forskolin, an activator of adenylate cyclase. Using pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of nuclear factor NF kappa B, we determined its role in cytokine--and cAMP--triggered group II PLA2 expression. Micromolar amounts of PDTC suppress the IL-1 beta- and TNF alpha-dependent, but not the forskolin-stimulated group II PLA2 activity in mesangial cells. Furthermore, PDTC inhibited the increase of group II PLA2 mRNA steady state levels in response to IL-1 beta and TNF alpha, while only marginally affecting forskolin-induced PLA2 mRNA levels. Our data suggest that NF kappa B activation is an essential component of the cytokine signalling pathway responsible for group II PLA2 gene regulation and that cAMP triggers a separate signalling cascade not involving NF kappa B. These observations may provide a basis to study the underlying mechanisms involved in the regulation of group II PLA2 gene expression.

Animals↗
PubMed1995

Oxygraphic evaluation of mitochondrial function in digitonin-permeabilized mononuclear cells and cultured skin fibroblasts of patients with chronic progressive external ophthalmoplegia.

For quantitative elucidation of maximal mitochondrial oxidation capacities in human mononuclear cells, cultured human skin fibroblasts and human thrombocytes the optimal amount of digitonin for plasma membrane permeabilization was determined to be 5, 10, and 0.1 micrograms/10(6) cells, respectively. Using these concentrations the rate of respiration of permeabilized cells with the mitochondrial substrates succinate (+ rotenone) or glutamate + malate can be stimulated between two- and fourfold by ADP and inhibited by carboxyatractyloside. The maximal respiratory activities of well-characterized preparations of permeabilized mononuclear cells of five patients with chronic progressive external ophthalmoplegia were compared to healthy controls and a 30 to 50% decrease of the ADP-stimulated respiration rates with glutamate + malate and succinate + rotenone was detected. This is an indication for the presence of the mitochondrial defect in respiratory active blood cells. Additionally, for two of these patients the mitochondrial defects were proven to be detectable by the determination of maximal oxygen consumption rates of digitonin-permeabilized cultured skin fibroblasts. Therefore, the determination of maximal oxidation capacities of a well-defined cell population using strictly standardized conditions of digitonin permeabilization is judged as a useful and sensitive method for the elucidation of mitochondrial function in extramuscular tissue.

Adolescent↗
PubMed1995

Effects of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta) on neutrophil elastase release.

The proinflammatory cytokine interleukin-6 (IL-6) and its potential opponent, transforming growth factor-beta (TGF-beta 1), have been discussed as being involved in the regulation of inflammatory processes following trauma and infections. The aim of this study was to investigate the effect of these cytokines on the regulation of neutrophil degranulation. The posttraumatic time courses of the plasma concentrations of IL-6, and the elastase-alpha 1-proteinase-inhibitor complex as marker of degranulation in patients undergoing severe trauma were found to be highly correlated, whereas TGF-beta 1 levels were determined to be not significantly altered. The close temporal correlation of IL-6 and elastase levels could be confirmed by investigation of exudates derived from the surgical area. To prove these in vivo findings, the effect of IL-6 and TGF-beta 1 on the degranulation of isolated neutrophils of healthy donors was investigated in vitro. Pathological high IL-6 concentrations were found to be capable of inducing a significant release of lysosomal elastase in a concentration-dependent manner, whereas the degranulation was unaffected by TGF-beta 1. In conclusion, these data suggest an involvement of IL-6 in the regulation of neutrophil degranulation under pathological conditions. However, TGF-beta 1 seems to have no direct regulatory effects besides its described chemotactic function on neutrophils.

Cell Degranulation↗
PubMed1994

Dexamethasone differentially affects interleukin 1 beta- and cyclic AMP-induced nitric oxide synthase mRNA expression in renal mesangial cells.

Inducible nitric oxide synthase (iNOS) is expressed in renal mesangial cells in response to two principal classes of activating signals that interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin (IL)-1 beta or tumour necrosis factor alpha and agents that elevate cellular levels of cyclic AMP (cAMP). We examined whether dexamethasone differentially affects iNOS induction in response to IL-1 beta and a membrane-permeable cAMP analogue, N6,O-2'-dibutyryladenosine 3',5'-phosphate (Bt2cAMP). Nanomolar concentrations of dexamethasone suppress IL-1 beta- as well as Bt2cAMP-induced iNOS protein expression and production of nitrite, the stable end product of nitric oxide (NO) formation. In contrast, dexamethasone prevents induction of iNOS mRNA in response to Bt2cAMP without affecting IL-1 beta-triggered increase in iNOS mRNA levels. These data suggest that dexamethasone acts at different levels, depending on the stimulus used to suppress iNOS induction in mesangial cells.

Amino Acid Oxidoreductases↗
PubMed1994

Two distinct signaling pathways trigger the expression of inducible nitric oxide synthase in rat renal mesangial cells.

The expression of nitric oxide synthase (NOS; EC 1.14.13.39) is induced in rat glomerular mesangial cells by exposure to the inflammatory cytokine interleukin 1 beta (IL-1 beta) or cAMP-elevating agents. Stimulation with IL-1 beta alone leads to an approximately 40-fold increase in NOS activity and nitrite synthesis, whereas the elevation of cAMP with forskolin, cholera toxin, salbutamol, or dibutyryl-cAMP for 24 h resulted in a 2- to 12-fold increase in NOS activity. Moreover, the combinations of IL-1 beta with each of the cAMP-elevating agents greatly enhanced NOS activity in a synergistic fashion. Northern-blot analysis demonstrated a single band of approximately 4.5 kb for the NOS mRNA in rat mesangial cells. IL-1 beta increased NOS mRNA levels in a dose- and time-dependent fashion with a peak of NOS mRNA at 24 h. Dibutyryl-cAMP also increased NOS mRNA levels in mesangial cells in a dose- and time-dependent manner. Furthermore, combination of IL-1 beta and forskolin revealed a strong synergy with maximal mRNA levels 12 h after stimulation. Nuclear run-on transcription experiments suggest that IL-1 beta and cAMP synergistically interact to increase NOS gene expression at the transcriptional level. Furthermore, message stability studies established that NOS mRNA induced by cAMP has a longer half-life than the IL-1 beta-induced message. Moreover, cAMP exposure markedly prolonged the half-life of NOS mRNA from 1 h to 3 h. These data suggest that the level of NOS mRNA is controlled by at least two different signaling pathways, one involving cAMP and the other being triggered by cytokines such as IL-1 beta. The two pathways act synergistically and thus potently up-regulate the expression of inducible NOS in rat mesangial cells.

Amino Acid Oxidoreductases↗
PubMed1994

Pyrrolidine dithiocarbamate differentially affects interleukin 1 beta- and cAMP-induced nitric oxide synthase expression in rat renal mesangial cells.

Inducible nitric oxide synthase (NOS) is expressed in renal mesangial cells in response to two principal classes of activating signals that interact in a synergistic fashion. These two groups of activators comprise inflammatory cytokines such as interleukin 1 (IL-1) or tumour necrosis factor alpha and agents that elevate cellular levels of cAMP. We have used pyrrolidine dithiocarbamate (PDTC), a potent inhibitor of nuclear factor kappa B (NF kappa B), to determine its role in IL-1 beta- and cAMP-triggered NOS expression. Micromolar amounts of PDTC suppress IL-1 beta-, but not cAMP-stimulated nitrite production, the stable end product of NO formation in mesangial cells. Furthermore, PDTC completely inhibited the increase of NOS mRNA in response to IL-1 beta, while only marginally affecting cAMP-induced NOS mRNA levels. Our data suggest that NF kappa B activation is an essential component of the IL-1 beta signalling pathway responsible for NOS gene activation and that cAMP triggers a separate signalling cascade not involving NF kappa B. These observations may provide a basis for the synergistic stimulation of NOS expression by cytokines and cAMP in mesangial cells.

Amino Acid Oxidoreductases↗
PubMed1994

Expression of nitric oxide synthase in rat glomerular mesangial cells mediated by cyclic AMP.

1. Treatment of rat mesangial cells with interleukin 1 beta (IL-1 beta) or tumour necrosis factor alpha (TNF alpha) has been shown to induce a macrophage-type of nitric oxide (NO) synthase. Here we report that adenosine 3':5'-cyclic monophosphate (cyclic AMP) is another mediator that triggers induction of NO synthase in mesangial cells. 2. Incubation of mesangial cells with the beta-adrenoceptor agonist, salbutamol, forskolin or cholera toxin, which all activate adenylate cyclase and increase intracellular cyclic AMP concentration, increased nitrite formation in a dose-dependent manner. Likewise, the addition of the membrane-permeable cyclic AMP analogue, N6, 0-2'-dibutyryladenosine 3',5'-phosphate (Bt2 cyclic AMP) or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine enhanced NO synthase activity in a dose-dependent manner. 3. There was a lag period of about 8 h before a significantly enhanced secretion of nitrite could be detected upon exposure of cells to forskolin and for maximal stimulation, forskolin had to be present during the whole incubation period. 4. Treatment of mesangial cells with actinomycin D, cycloheximide or dexamethasone completely suppressed forskolin-stimulated NO-synthase activity, thus demonstrating that transcription and protein synthesis are necessary for nitrite formation. 5. Bt2 cyclic AMP, the most potent inducer of nitrite production, increased NO synthase mRNA levels in mesangial cells in a time- and dose-dependent fashion. Dexamethasone completely inhibited the increase of NO synthase mRNA in response to Bt2 cyclic AMP. 6. Combination of Bt2 cyclic AMP and IL-1 beta or TNF alpha revealed a strong synergy in terms of nitrite formation. Time-course studies indicated that cyclic AMP needed to be increased during the whole period of IL-1 Beta stimulation for maximal nitrite production.7. These observations suggest that cyclic AMP controls NO synthase expression in mesangial cells.Furthermore, the signalling cascades triggered by IL-1 Beta and TNF alpha synergize with the cyclic AMP pathway to stimulate NO synthase activity.

Adenylyl Cyclases↗
PubMed1993

Cyclosporin derivatives inhibit interleukin 1 beta induction of nitric oxide synthase in renal mesangial cells.

Treatment of mesangial cells with recombinant human interleukin 1 beta dose dependently increased nitrite formation due to the induction of a macrophage-type of nitric oxide (NO) synthase. Addition of cyclosporin A, cyclosporin G or cyclosporin H dose dependently inhibited interleukin 1 beta-induced nitrite generation. Half-maximal inhibition was observed at concentrations of 0.9 microM, 2.0 microM and 3.8 microM of cyclosporin A, cyclosporin G and cyclosporin H, respectively. Time-course studies indicated that cyclosporin A could be added up to 6 h after the interleukin 1 beta stimulus and still caused maximal inhibition of nitrite production. Furthermore, interleukin 1 beta increased NO synthase mRNA levels in mesangial cells and this effect was potently suppressed by all three cyclosporin derivatives. As cyclosporin H has no immunosuppressive activity, these data indicate that the inhibitory effect of the cyclosporin derivatives on NO synthase expression is not related to the immunosuppressive action of the drugs. This suggestion is further substantiated by the observation that the potent immunosuppressants rapamycin and FK506 did not alter interleukin 1 beta-induced NO synthase mRNA levels or nitrite generation in mesangial cells. In summary, these data demonstrate that cyclosporin derivatives potently modulate the L-arginine-NO pathway in renal mesangial cells.

Amino Acid Oxidoreductases↗
PubMed1993

Aminopeptidase N (CD13, EC 3.3.4.11.2) occurs on the surface of resting and concanavalin A-stimulated lymphocytes.

Using different approaches evidence is provided that aminopeptidase N (APN, EC 3.4.11.2, CD13) is expressed on the surface of resting and stimulated human lymphocytes. 1) 50% of total Ala-pNA hydrolysis of viable cells was found to be due to the ectoenzyme APN as revealed by titration with the new inhibitor probestin in comparison to purified APN from human kidney (Ki value 6.5 nM). After stimulation with ConA an increase of Ala-pNA hydrolysis was observed from 8 pkat up to 15 pkat/10(6) cells. 2) This correlated with an increase of APN (CD13) surface expression as detected by antibody surface labeling of unstimulated (5-12% CD13 positive cells) and stimulated lymphocytes (28-36% CD13 positive lymphocytes) using polyclonal and monoclonal antibodies. 3) In vivo APN was found to be expressed on the surface of up to 50% lymphocytes isolated from the synovial fluid of rheumatoid patients.

Aminopeptidases↗