Papers by Dr. Albrecht Wendel
Hepatocyte apoptosis is crucial in several forms of liver disease. Here, we examined in different... more Hepatocyte apoptosis is crucial in several forms of liver disease. Here, we examined in different models of murine liver injury whether and how metabolically induced alterations of hepatocyte ATP levels control receptor-mediated apoptosis. ATP was depleted either in primary hepato-cytes or in vivo by various phosphate-trapping carbohydrates such as fructose. After the activa-tion of the tumor necrosis factor (TNF) receptor or CD95, the extent of hepatocyte apoptosis and liver damage was quantified. TNF-induced cell death was completely blocked in ATP-depleted hepatocyte cultures, whereas apoptosis mediated by CD95 was enhanced. Similarly acute TNF-induced liver injury in mice was entirely inhibited by ATP depletion with keto-hexoses, whereas CD95-mediated hepatotoxicity was enhanced. ATP depletion prevented mi-tochondrial cytochrome c release, loss of mitochondrial membrane potential, activation of type II caspases, DNA fragmentation, and cell lysis after exposure to TNF. The extent...
Sensitization by 5-Azacytidine towards death receptor – induced hepatic apoptosis
The FASEB Journal, 2009
Listeriosis can result in lethal pulmonary permeability edema, with reduced sodium uptake capacit... more Listeriosis can result in lethal pulmonary permeability edema, with reduced sodium uptake capacity and epithelial/endothelial hyperpermeability. This study investigated the effect of L. monocytogen...
Journal of Biological Chemistry, 1977
The effect of a divalent copper-tyrosine complex has been evaluated in rat liver microsome-cataly... more The effect of a divalent copper-tyrosine complex has been evaluated in rat liver microsome-catalyzed dealkylations. The copper complex, which is provided with superoxide dismutase activity, inhibits at micromolar concentrations aminopyrine, p-nitroanisol, and 7-ethoxycoumarin dealkylations. It has also been found that cumene hydroperoxide-supported p-nitroanisol demethylation, the formation of a 440 nm species, and the formation of superoxide radicals are inhibited by the divalent copper complex. On the other hand, 3-chloroperbenzoic acid has been found to support a copper complex-insensitive 7-ethoxycoumarin dealkylation. Oxygen uptake by rat liver microsomes is also inhibited by the copper complex. The data support the concept that the copper complex acts as a superoxide dismutase at the level of a cytochrome P-450 intermediate species, liganded with superoxide anions.
Journal of Biological Chemistry, 1993
Infection and Immunity, 1992
Tumor necrosis factor (TNF) toxicity was induced in vivo by intravenous administration of 15 micr... more Tumor necrosis factor (TNF) toxicity was induced in vivo by intravenous administration of 15 micrograms of recombinant murine TNF-alpha per kg to galactosamine-sensitized mice. Within 8 h, the animals developed a fulminant hepatitis. Intravenous administration of 0.5 mg of colchicine per kg at 19 and 4 h prior to TNF challenge protected the animals against hepatitis. Lipopolysaccharide (LPS)-stimulated, bone marrow-derived macrophages from C3H/HeN mice released significant amounts of TNF in vitro. When such macrophages were intravenously given to LPS-resistant galactosamine-sensitized C3H/HeJ mice, these animals died within 24 h. Preincubation of these transferred macrophages with colchicine did not suppress the LPS-inducible TNF release from these cells. Concordantly, administration of macrophages exposed to colchicine in vitro resulted in full lethality. However, in vivo pretreatment of C3H/HeJ mice with colchicine 19 and 4 h prior to the transfer of LPS-stimulated macrophages pre...
Infection and Immunity, 1999
The lungs are the remote organ most commonly affected in human peritonitis. The major goals of th... more The lungs are the remote organ most commonly affected in human peritonitis. The major goals of this study were to define the dose- and time-dependent relationship between graded septic peritonitis and systemic and pulmonary inflammatory responses in mice. BALB/c mice were treated with intraperitoneal polymicrobial inoculi and sacrificed at 3, 12, and 24 h. The treatment protocol resulted in distinct groups of animals with respect to mortality rate, kinetics, and concentrations of a broad spectrum of pro- and anti-inflammatory endogenous mediators, intrapulmonary bacterial accumulation, and static lung compliance. In sublethally infected mice, pulmonary bacterial proliferation was controlled. Levels of monocyte chemoattractant protein-1 (MCP-1), interleukin-10, interleukin-6, granulocyte colony-stimulating factor (G-CSF), and tumor necrosis factor (TNF) in plasma were elevated 3 h after infection exclusively. At 3 h, MCP-1, gamma interferon, and TNF were detected in extracts of pulmo...
Blood, 2000
In a double-blind, placebo-controlled, randomized study, 10 healthy men received either a single ... more In a double-blind, placebo-controlled, randomized study, 10 healthy men received either a single dose of 480 μg granulocyte colony-stimulating factor (G-CSF) or saline. Blood taken from the volunteers was stimulated with 10 μg/mL endotoxin and released cytokines were measured by enzyme-linked immunosorbent assay. Expression of G-CSF receptors on leukocytes was examined by flow cytometry and reverse transcriptase-polymerase chain reaction. Functional activity of these receptors was tested by challenging isolated leukocyte populations to release cytokines with endotoxin in the presence of G-CSF. The G-CSF treatment attenuated the release of the proinflammatory cytokines tumor necrosis factor (TNF)-, interleukin (IL)-12, IL-1β, and interferon (IFN)-γ in ex vivo lipopolysaccharide (LPS)-stimulated whole blood. In blood from untreated volunteers the presence of G-CSF in vitro also attenuated the LPS-stimulated release of these cytokines. G-CSF in vitro also attenuated TNF- release from...
Alternatives to Laboratory Animals, 2001
Preface This is the report of the forty-third of a series of workshops organised by the European ... more Preface This is the report of the forty-third of a series of workshops organised by the European Centre for the Validation of Alternative Methods (ECVAM). ECVAM's main goal, as defined in 1993 by its Scientific Advisory Committee, is to promote the scientific and regulatory acceptance of alternative methods which are of importance to the biosciences, and which reduce, refine or replace the use of laboratory animals. One of the first priorities set by ECVAM was the implementation of procedures which would enable it to become well informed about the state of the art of non-animal test development and validation, and the potential for the possible incorporation of alternative tests into regulatory procedures. It was decided that this would best be achieved by the organisation of ECVAM workshops on
Journal of Leukocyte Biology, 1996
In primary cultures of Kupifer cells and hepatocytes, human granulocytes potentiated toxicity of ... more In primary cultures of Kupifer cells and hepatocytes, human granulocytes potentiated toxicity of endotoxin about 1000-fold. Granulocyte elastase activity was found to correlate with toxicity. The serine protease inhibitors al-antitrypsin, eglin C, and aprotinin protected against toxicity. Tumor necrosis factor-a (TNF-a) induced cytotoxicity and elastase release, whereas neutralization ofTNF-a blocked both events. We conclude that TNF-a formed by Kupifer cells activates granulocytes. Experiments in cultures where cells were separated by membranes permeable to mediators indicated that cell contact is needed for toxicity. Scanning electron microscopy showed granulocytes adhering to and interdigitating with hepatocytes. Using liver cells from ICAM-1deficient mice had no effect on toxicity. However, neutralizing CD31 inhibited toxicity and elastase release but not granulocyte adhesion. Our findings demonstrate that adhesion of granulocytes is a necessary but not sufficient condition for the synergistic interaction of endotoxin-stimulated liver macrophages and granulocytes in the proteolytic killing of hepatocytes. .1. Leukoc.
Journal of Applied Physiology, 1994
This study was carried out to further clarify the role of eicosanoids in platelet-activating fact... more This study was carried out to further clarify the role of eicosanoids in platelet-activating factor (PAF)-induced pulmonary vasoconstriction, bronchoconstriction, and edema formation in the isolated perfused rat lung. Infusion of PAF into the isolated perfused rat lung caused vasoconstriction [mean effective concn (EC50) = 0.88 nmol], caused bronchoconstriction (EC50 = 0.71 nmol), and increased the capillary filtration coefficient (EC50 = 1.4 nmol). Two minutes after injection of 50 nmol PAF, a high thromboxane concentration (3,000 pg/ml) and a low peptidoleukotriene concentration (150 pg/ml) were found in the effluent perfusate. PAF-induced vaso- and bronchoconstriction were unaffected by the non-redox 5-lipoxygenase inhibitor ZM-230,487 but were markedly attenuated by inhibition of cyclooxygenase with acetylsalicylic acid or thromboxane-receptor antagonism with BM-13177. Dual inhibition of cyclooxygenase and 5-lipoxygenase had the most pronounced inhibitory effect on PAF-induced v...
Life Sciences, 1992
~,mrnRry The major low molecular weight thiol inside cells, the tripeptide glutathione (GSH), is ... more ~,mrnRry The major low molecular weight thiol inside cells, the tripeptide glutathione (GSH), is of importance for protection of the cell against oxidative challenge, for thiol homeostasis required to guarantee basic functions, and for defence mechanisms against xenobiotics. Since the pathophysiological significance of a perturbed GSH status in human disease is less clear, this review evaluates the consequences of/n viuo variations of GSH. Owing to intracellular GSH concentrations above 2 mM depletion of GSH as such has little metabolic consequences unless an additional stress is superimposed. The kinetic properties of GSH-dependent enzymes imply that loss of up to 90% of intraceUular GSH may still be compatible with cellular integrity. Mitochondrial GSH, which accounts for about 10% of total cellular GSH, may define the threshold beyond that toxicity commences. Thus, in cases of severe GSH-depletion a substitution of GSH as a therapeutic measure seems justified. Such a severe depletion of GSH has been described for some diseases such as liver dysfunction, AIDS or pulmonary fibrosis. I. Scope The intracellular redox balance of mammalian cells is maintained by a homeostatic mechanism which links small pools of coenzymes and cofactors to a large redox buffer with common chemical properties, i.e. the thiol system. The overwhelming part of intra-as well as extracellular soluble thiols is represented by the tripeptide glutathione (GSH) which occurs in any eukaryotic cell in high concentrations, i.e. 2-10 retool/1. The intactness of this glutathione system is essential for maintainment of physiological functions. The continuing research interest in glutathione is documented by a publication rate of two scientific papers per day with an increasing frequency of monographies published [Cited in ref. [1] and [2]).
Biochemical Journal, 1989
Single mouse livers were subfractionated by differential centrifugation and isopycnic centrifugat... more Single mouse livers were subfractionated by differential centrifugation and isopycnic centrifugation on sucrose or metrizamide gradients and separated into subcellular compartments. The fractionation procedure was highly reproducible and yielded essentially similar results in different preparations of livers from selenium-adequate (Se+) and selenium-deficient (Se-) mice that were fed on a Torula-yeast-based diet containing less than 10 parts per 10(9) of selenium for at least 16 weeks. Mice of both dietary groups were injected intraperitoneally with 370 kBq of L-[U-14C]leucine, and 48 h later 1.85 MBq of L-[4,5-3H]leucine was injected intraportally. After another 1 h, the livers were removed and subjected to subcellular fractionation. Incorporation of the 3H label into proteins of the subcellular fractions was taken as a measure of relative protein-synthesis rate. The ratio of the 3H to the 14C protein-bound label of the same fractions was used as an estimate of relative protein-deg...
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Papers by Dr. Albrecht Wendel