Bio: Albrecht Wendel is an academic researcher from University of Konstanz. The author has contributed to research in topics: Tumor necrosis factor alpha & Apoptosis. The author has an hindex of 57, co-authored 185 publications receiving 10407 citations.
Papers published on a yearly basis
TL;DR: It is concluded that TNF-induced hepatocyte apoptosis is an early, general, and possibly causal event during experimental liver failure triggered by inflammatory stimuli.
Abstract: We investigated the role of hepatocyte apoptosis in four different murine models of acute inflammatory liver failure. Liver damage induced in D-galactosamine-sensitized mice by endotoxin infection was initiated by processes typical of apoptosis, ie, chromatin condensation, DNA fragmentation, and formation of intracellular apoptotic bodies. DNA was cleaved into oligonucleosomal fragments in the liver before a significant rise of alanine aminotransferase in plasma occurred. Passive immunization against tumor necrosis factor (TNF) completely inhibited the injury caused by endotoxin. Direct injection of recombinant TNF-alpha also caused DNA fragmentation followed by alanine aminotransferase release into the plasma. Pretreatment of mice with interleukin-1 beta, which is known to suppress TNF-induced lethality, completely prevented apoptosis and liver failure in this model. These results demonstrate the causal role of TNF in endotoxin-induced hepatic apoptosis. TNF-inducible hepatocyte apoptosis in vivo was not only observed in D-galactosamine-sensitized mice, but also when the alternative transcriptional inhibitor actinomycin D was used. In mice injected with the TNF-inducing T cell mitogen concanavalin A, hepatic apoptosis was even noticed without requirement of additional sensitizers. We conclude that TNF-induced hepatocyte apoptosis is an early, general, and possibly causal event during experimental liver failure triggered by inflammatory stimuli.
TL;DR: The findings of this study demonstrate that direct hepatotoxicity of TNF-alpha is associated with an apoptotic mechanism that becomes manifest under the metabolic condition of arrested transcription and functional translation.
Abstract: Freshly isolated mouse hepatocytes were essentially insensitive to TNF-alpha cytotoxicity. However, TNF-alpha induced a concentration-dependent cell death in hepatocytes that had been pretreated with the transcriptional inhibitors actinomycin D (ActD), D-galactosamine, or alpha-amanitin. Unlike RNA synthesis inhibition, a translational block in the presence of cycloheximide (CHX) or puromycin did not sensitive hepatocytes to TNF. On the contrary, these agents prevented hepatocytotoxicity induced by ActD/TNF. Pretreatment with peroxides or glutathione depletors had no significant influence on TNF cytotoxicity. In vivo treatment of mice with ActD/TNF caused hepatic failure, which was significantly reduced by co-treatment with CHX. These findings demonstrate that protein synthesis is required for this mechanism of cell death. To test whether TNF may trigger an endogenous suicide program in hepatocytes, we examined whether DNA fragmentation preceded cell death. In the culture system, hepatocellular DNA fragmentation in the presence of ActD/TNF was observed several hours before lactate dehydrogenase release and was inhibited by CHX. Similar results were obtained in vivo. Chromatin condensation and the formation of apoptotic bodies were observed in livers from mice treated with ActD/TNF and significant DNA fragmentation was detected as early as 4 h after challenge. At this time, organ total glutathione content and plasma transaminase levels were not significantly different from those of untreated controls. The findings of this study demonstrate that direct hepatotoxicity of TNF-alpha is associated with an apoptotic mechanism that becomes manifest under the metabolic condition of arrested transcription and functional translation.
TL;DR: In mouse liver microsomes, NADPH-dependent aminopyrine dealkylation was totally inhibited in the presence of 50 mumol/1 PZ 51, and in vivo experiments with Se-deficient mice showed that the Se-moiety of Pz 51 is not available for the synthesis of the selenoenzyme GSH-Px after dietary treatment or i.p. doses up to 25 mg Se.
Abstract: The anti-inflammatory compound 2-phenyl-1,2-benzoisoselenazol-3(2H)-on (PZ 51) catalysed GSSG formation from GSH in the presence of hydroperoxides in an NADPH/GSSG reductase system with the following rates (delta log GSH/min per molar selenium): 1.1 X 10(6) with H2O2, 1.2 X 10(6) with butylhydroperoxide, 1.7 X 10(6) with cumenehydroperoxide. The reaction catalysed by the sulphur analogue of PZ 51 was negligible. Similar results were obtained in a direct assay of GSH-Px activity based on GSH estimation by dithionitrobenzoate. The activation energy of the reaction was determined as 55 kJ/mol . deg in the presence of 30 mumol/1 PZ 51 compared to 36.5 kJ/mol . deg obtained in the presence of 1 nmol/1 pure GSH-Px isolated from bovine red blood cells. In mouse liver microsomes, NADPH-dependent aminopyrine dealkylation was totally inhibited in the presence of 50 mumol/1 PZ 51. In vivo experiments with Se-deficient mice showed that the Se-moiety of PZ 51 is not available for the synthesis of the selenoenzyme GSH-Px after dietary treatment or i.p. doses up to 25 mg Se as PZ 51 per kg body wt. After oral administration of labelled PZ 51, unlike with selenite, no radioactivity was incorporated into GSH-Px within 48 hr. The data suggest that several similarities between PZ 51 and the active site of GSH-Px exist, resulting in the capability of the compound to catalyse the GSH-Px reaction. An extracellular pharmacodynamic action of the drug seems likely.
TL;DR: It is concluded that artificial ventilation might cause pulmonary and systemic adverse reactions by inducing the release of mediators into the circulation.
Abstract: Artificial mechanical ventilation represents a major cause of iatrogenic lung damage in intensive care. It is largely unknown which mediators, if any, contribute to the onset of such complications. We investigated whether stress caused by artificial mechanical ventilation leads to induction, synthesis, and release of cytokines or eicosanoids from lung tissue. We used the isolated perfused and ventilated mouse lung where frequent perfusate sampling allows determination of mediator release into the perfusate. Hyperventilation was executed with either negative (NPV) or positive pressure ventilation (PPV) at a transpulmonary pressure that was increased 2.5-fold above normal. Both modes of hyperventilation resulted in an approximately 1.75-fold increased expression of tumor necrosis factor α (TNF α ) and interleukin-6 (IL-6) mRNA, but not of cyclooxygenase-2 mRNA. After switching to hyperventilation, prostacyclin release into the perfusate increased almost instantaneously from 19 ± 17 pg/ min to 230 ± 160 pg/m...
TL;DR: The TNF-R1 is not only necessary, but also sufficient for TNF signaling in murine hepatocytes, and the hepatotoxicity of TNF in D-galactosamine-sensitized mice is examined.
Abstract: The systemic inflammatory response is characterized by release of circulating TNF which may cause multiorgan failure including septic liver failure. We studied TNF signaling in an appropriate in vitro system with primary murine hepatocyte cultures from normal and genetically altered animals. Either one of the three different TNF species, huTNF-alpha, huTNF-beta, or muTNF-alpha (at concentrations > 1 ng/ml) induced direct hepatocytotoxicity preceded by DNA fragmentation in cells prepared from wild-type C57BL mice. TNF-induced cytotoxicity was preceded by oligonucleosomal DNA fragmentation. Further cellular responses to TNF exposure were induction of nitric oxide synthase and secretion of serum amyloid A. None of the above events occurred in hepatocytes lacking the gene for the 55-kDa TNF receptor (TNF-R1), even after stimulation with > 1 micrograms/ml TNF. However, selective stimulation of the TNF-R1 in wild-type hepatocytes with huTNF-alpha elicited a pattern of responses essentially similar to that seen with muTNF-alpha. We obtained analogous results when we examined the hepatotoxicity of TNF in D-galactosamine-sensitized mice, i.e., DNA fragmentation and liver failure was noted in wild-type mice, whereas TNF-R1-deficient mice were completely resistant. We conclude that the TNF-R1 is not only necessary, but also sufficient for TNF signaling in murine hepatocytes.
TL;DR: This review provides a comprehensive summary on the chemical properties of 4-hydroxyalkenals and malonaldehyde, the mechanisms of their formation and their occurrence in biological systems and methods for their determination, as well as the many types of biological activities described so far.
Abstract: Lipid peroxidation often occurs in response to oxidative stress, and a great diversity of aldehydes are formed when lipid hydroperoxides break down in biological systems. Some of these aldehydes are highly reactive and may be considered as second toxic messengers which disseminate and augment initial free radical events. The aldehydes most intensively studied so far are 4-hydroxynonenal, 4-hydroxyhexenal, and malonaldehyde. The purpose of this review is to provide a comprehensive summary on the chemical properties of these aldehydes, the mechanisms of their formation and their occurrence in biological systems and methods for their determination. We will also review the reactions of 4-hydroxyalkenals and malonaldehyde with biomolecules (amino acids, proteins, nucleic acid bases), their metabolism in isolated cells and excretion in whole animals, as well as the many types of biological activities described so far, including cytotoxicity, genotoxicity, chemotactic activity, and effects on cell proliferation and gene expression. Structurally related compounds, such as acrolein, crotonaldehyde, and other 2-alkenals are also briefly discussed, since they have some properties in common with 4-hydroxyalkenals.
TL;DR: This chapter presents a procedure for the preparation of glutathione peroxidase, which is regarded as a major protective system against endogenously and exogenously induced lipid peroxidation.
Abstract: Publisher Summary This chapter presents a procedure for the preparation of glutathione peroxidase, which is regarded as a major protective system against endogenously and exogenously induced lipid peroxidation. Two types of methods are used for determining the activity of glutathione peroxidase. One involves a direct measurement of unconsumed glutathione (GSH) at fixed time periods by polarographic GSH analysis' (Method 1), or by the dithionitrobenzoic acid method (Method 2). The second approach takes advantage of the capability of glutathione reductase, with nicotinamide adenine dinucleotide phosphate (NADPH), to regenerate GSH from oxidized GSH. The decrease in NADPH is continuously measured spectrophotometrically, while the GSH concentration in the enzymatic cycle remains essentially constant (Method 3). A convenient source for the preparation of glutathione peroxidase is bovine blood including the following steps: hemolysate; organic solvent precipitation; phosphate precipitation; absorption to phenyl-sepharose; and washing on diethylaminoethyl (DEAE)–sephadex, S-300 sephacryl, and hydroxylapatite column.
TL;DR: This paper presents experimental evidence for Increased Vascular Transmural Pressure Evidence for Alterations in Alveolar–Capillary Permeability Contributions of the Static and Dynamic Lung Volume Components to Ventilator-induced Edema High-volume Lung Edema Low Lung Volume Injury.
Abstract: Introduction: Ventilator-induced Lung Injury: Not Only Air Leaks Ventilation-induced Pulmonary Edema and Related Findings: A Historical Perspective Ventilation-induced Pulmonary Edema: Hydrostatic or Permeability Edema? Experimental Evidence for Increased Vascular Transmural Pressure Evidence for Alterations in Alveolar–Capillary Permeability Contributions of the Static and Dynamic Lung Volume Components to Ventilator-induced Edema High-volume Lung Edema Low Lung Volume Injury Effects of High-volume Ventilation on Abnormal Lungs Effects of High-volume Ventilation on Injured Lungs Interaction between Severe Alveolar Flooding and Mechanical Ventilation Effects of Resting the Lung on Ventilator-induced Lung Injury Possible Mechanisms of Ventilation-induced Lung Injury Mechanisms of Increased Vascular Transmural Pressure Mechanisms of Altered Permeability Clinical Relevance