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Biomedical subjects

U F Schade

Publications and source records attributed to U F Schade.

At least 19 recordsLinked to original sources
PubMed1999

Reduced B cell HLA-DR expression and natural killer cell counts in patients prone to sepsis after injury.

OBJECTIVE: To examine the influence of natural killer (NK) cells and HLA-DR molecules on B cells in the development of severe sepsis after injury. DESIGN: Prospective study. SETTING: Medical school, Germany. SUBJECTS: 46 severely injured (Injury Severity Score >16) patients. INTERVENTIONS: Blood samples were taken immediately after admission and subsequently for 14 days. MAIN OUTCOME MEASURES: HLA-DR expression on B cells and counts of B and NK cells measured by flow cytometry, and morphological estimation of large granular lymphocytes by microscopy. RESULTS: HLA-DR expression on circulating B cells was significantly reduced from days 6-14 after admission in 13 patients with subsequent severe sepsis compared with 33 patients who did not develop sepsis. In septic patients NK cell counts were significantly decreased from day 4 onwards (p < 0.05). CD16+/CD56+ cells correlated with the morphology of large granular lymphocytes. CONCLUSION: In severely injured patients reduced counts of NK cells and HLA-DR molecules on B lymphocytes seem to be part of an immune deviation that is associated with the development of severe sepsis.

Adolescent↗
PubMed1999

HLA-DR expression and soluble HLA-DR levels in septic patients after trauma.

OBJECTIVE: To determine if cellular and soluble HLA-DR molecules may be relevant in severely injured patients for the development of gram-positive or gram-negative sepsis. SUMMARY BACKGROUND DATA: HLA-DR molecules play a central role in the specific immune response to infection. The reduced HLA-DR expression on monocytes is considered to correlate with infectious complications and the development of sepsis. Data on the role of HLA-DR expression on T cells and soluble HLA-DR molecules are rare. METHODS: HLA-DR expression on monocytes and T cells was measured by flow cytometry. Plasma levels of soluble HLA-DR were studied by enzyme-linked immunosorbent assay. RESULTS: HLA-DR expression on circulating T cells, calculated as mean fluorescence intensity in channels, was reduced at day 1 after admission in 20 patients with subsequent severe sepsis compared with 46 patients without sepsis. The septic patients immediately after trauma had significantly lower soluble HLA-DR plasma levels than the nonseptic patients. At day 2 after admission, HLA-DR expression on monocytes was significantly lower in the severe sepsis group than in the patients without sepsis, and lasted until day 14 after injury. CONCLUSIONS: In severely injured patients, decreased levels of cellular and soluble HLA-DR appear as early indicators of an immune deviation associated with the development of severe sepsis. Moreover, immune alterations of different cell types may promote distinct kinds of septicemia.

Adolescent↗
PubMed1992

Cytokines involved in monocyte mediated tumor cell death and growth inhibition in serum-free medium.

In a serum-free culture system, the release of TNF, lI-1, lI-6, IFN-alpha, and IFN-beta during interaction of elutriated human monocytes (MO) with human tumor cells (TC) was studied by ELISA-technique. Contributions of these cytokines to inhibition of TC-growth and to induction of TC-death by supernatants (SU) gained from such MO/TC-interaction cultures were investigated using affinity chromatography for removal of individual cytokines. Although the TC used are relatively insensitive to recombinant human TNF, withdrawal of TNF causes 50% to 75% reduction of SU-induced TC-death rates, suggesting that susceptibility to TNF is raised during MO/TC-interaction by the other cytokines. Individual removal of other cytokines does not cause reduction of SU-mediated TC-death. However, combined withdrawal of lI-1 and IFN-alpha/beta causes in 2 of 4 TC-lines significant reduction of TC-death. Combined removal of TNF, IFN-alpha/beta, lI-1, and lI-6 leads to complete prevention of SU-mediated growth inhibitory and lytic effects, suggesting that besides these cytokines other signals are not involved significantly. SU-effects can be mimicked by appropriate combinations of authentic cytokines. The response of TC to SU- or cytokine-exposure is strikingly dependent on TC-density, leading at subconfluent TC-density exclusively to inhibition of growth and at postconfluent TC-density to induction of cell death. The principal effect of SU or cytokine combinations in this context seems to be the activation of growth inhibitory signal transduction pathways leading to TC-death in postconfluent TC-populations exclusively if growth stimulatory pathways are activated at the same time. Mouse L cells do not follow this reaction pattern: Their death is exclusively dependent on the presence of TNF in SU and they die upon SU-exposure at postconfluent as well as at subconfluent cell density.

Animals↗
PubMed1991

Differential protective activities of site specific lipoxygenase inhibitors in endotoxic shock and production of tumor necrosis factor.

Lipoxygenase inhibitors have been shown to exert beneficial effects in experimental models of endotoxin shock. In the present study it was found that lipoxygenase inhibitors prevented LPS, but not tumor necrosis factor alpha (TNF alpha)-evoked leukopenia in mice. These inhibitors protected against endotoxin lethality but not against TNF alpha induced lethality. When the protective potency of the specific 5-lipoxygenase inhibitors (MK 886, CGS 81585) was tested in endotoxin-induced leukopenia and shock, they were found to be ineffective. Site specificity of the inhibitors was assessed by comparison of their effects on the formation of LTC4 and the conversion of linoleic acid to 13-hydroxyoctadecadienoic acid (13-HODD) by macrophages. The 5-lipoxygenase inhibitors interfered with LTC4 formation in macrophages, however, they did not affect endotoxin-induced TNF alpha formation, neither in cell cultures nor in mice. The inhibitory strength of other, less specific lipoxygenase blockers to suppress TNF alpha formation correlated quantitatively with their ability to interfere with 13-HODD synthesis. From these findings it is concluded that lipoxygenase inhibitors interfere with endotoxic effects because they block TNF alpha formation. Since 5-lipoxygenase inhibitors neither prevented the formation of TNF alpha nor endotoxin leukopenia and lethality, it is suggested that a lipoxygenase product distinct from the leukotrienes is involved in TNF alpha synthesis. Based on the fact that a tight correlation exists between inhibition of TNF alpha synthesis and 13-HODD formation, activation of 15-lipoxygenase might be important for TNF alpha formation.

Animals↗
PubMed1991

Bacterial endotoxin: molecular relationships between structure and activity.

The significance of endotoxins in bacterial infection and their role as bacterial surface antigens (O antigens) have stimulated investigations into their chemical nature and the mechanisms of their biologic action during the last few decades. This article summarizes some of the recent results and emphasizes structure-activity relationships.

Animals↗
PubMed1991

Effects of pentoxifylline in endotoxinemia in human volunteers.

The following effects of pentoxifylline in endotoxinemia in man could be demonstrated: 1. Il-6 release and Il-6 mediated effects such as clinical responses and leukocytosis are not inhibited by POF treatment. 2. TNF-alpha release is suppressed which might be the most important result, because TNF seems to play the major role in the pathophysiological events of endotoxinemia. Furthermore, pentoxifylline is able to counteract the initial leukocytopenia caused by sticking of leukocytes in the microcirculation. 3. De-novo-synthesis of cytokines by monocytes ex vivo is totally abolished. This may possibly reflect the in vivo situation. In conclusion, beneficial effects of pentoxifylline in respiratory distress syndrome, multi-organ failure and septic shock are suggested. Furthermore, our data indicate that endotoxin-induced formation of Il-6 and TNF-alpha are regulated independently in vivo.

Endotoxins↗
PubMed1991

The role of lipoxygenases in endotoxin-induced cytokine production.

The LPS induced synthesis of tumor necrosis factor in macrophage cultures, as determined in a fibroblast cytolysis assay was found to be effectively blocked by inhibitors of lipoxygenases. Likewise, the presence of tumor necrosis factor in serum of D-galactosamine sensitized mice after challenge with endotoxin was suppressed by the lipoxygenase inhibitors. From LPS-treated macrophages 13-hydroxylinoleic acid, a lipoxygenase product was isolated, which is significantly increased after LPS treatment of the cells, covalently bound to cellular constituents and was found to counterbalance the suppression of TNF-synthesis by a lipoxygenase inhibitor when added to macrophages exogenously.

Animals↗
PubMed1990

In vivo evidence for protease-catalysed mechanism providing bioactive tumor necrosis factor alpha.

Mice pretreated by intravenous injection of 42 mg/kg of the serine protease inhibitor alpha 1-antitrypsin prior to a hepatotoxic dose of D-galactosamine/lipopolysaccharide (GalN/LPS) were fully protected against hepatitis. Pretreatment with alpha 1-antitrypsin with doses up to 300 mg/kg at different times failed to protect galactosamine sensitized animals against tumor necrosis factor alpha (TNF alpha)-induced hepatitis. No bioactive TNF alpha was detectable in serum of mice protected against GalN/LPS-induced hepatitis by pretreatment with alpha 1-antitrypsin. In contrast, abundant amounts of TNF were found in sera of GalN/LPS-treated control animals. It is concluded that a serine protease sensitive to alpha 1-antitrypsin provides bioactive TNF alpha by proteolytic cleavage of a TNF alpha precursor.

Alanine Transaminase↗
PubMed1990

Pentoxifylline increases survival in murine endotoxin shock and decreases formation of tumor necrosis factor.

Pentoxifylline (POF) was found to possess high protecting potential in murine endotoxin shock. POF was tested in endotoxic shock in normal, LPS-tolerant, LPS-hyperreactive, and D-galactosamine-sensitized mice. A dose of 50 mg/kg increased survival in normal and tolerant mice from 50% in LPS-controls to 90%, and in LPS-hypersensitized and D-galactosamine-sensitized mice from 20% in LPS-controls to 90%. POF did not interfere with the development of endotoxin tolerance. The protective effects of POF were dose-dependent and were observed, even when POF was given up to 4 h post endotoxin. POF was found to inhibit the appearance of TNF in serum of LPS-treated, D-galactosamine-sensitized mice and in the supernatants of LPS-stimulated, thioglycollate-induced mouse peritoneal macrophages.

Animals↗
PubMed1989

Lipoxygenase inhibitors suppress formation of tumor necrosis factor in vitro and in vivo.

Injection of endotoxin in D-galactosamine sensitized mice resulted in increased serum levels of tumor necrosis factor as determined in a fibroblast cytolysis assay. Concomitant injection of different lipoxygenase inhibitors decreased the titer of TNF. When the lipoxygenase inhibitors were tested in macrophage cultures stimulated with LPS, they prevented the production of TNF. Indomethacin, a blocker of cyclooxygenase was neither in vivo nor in vitro effective in the prevention of the endotoxin-induced synthesis of TNF. The involvement of superoxide anion in this effect was excluded by use of superoxide dismutase which did not influence the formation of TNF in macrophages.

Animals↗
PubMed1989

Mononuclear phagocytes and eicosanoids: aspects of their synthesis and biological activities.

Mononuclear phagocytes convert arachidonic acid and other unsaturated fatty acids from intracellular sources to a variety of oxygenated metabolites such as prostaglandins and leukotrienes which are secreted into the surrounding medium. Other oxidative products such as hydroxylinoleic acids are reacylated into cellular constituents. The underlying metabolic pathways are activated by numerous stimuli of exogenous or endogenous origin. Depending on the state of activation and cell differentiation, the organ of origin and the nature of the stimulus used, macrophages elaborate a distinct spectrum of oxidative arachidonic acid metabolites. The contribution of these metabolites to the proinflammatory properties of macrophages is twofold: As autocrine signals they modulate the synthesis of diverse macrophage products and they influence cellular functions of other cells such as T-lymphocytes.

Animals↗
PubMed1989

Lipoxygenase inhibitors suppress formation of tumor necrosis factor in vitro and in vivo.

The LPS induced synthesis of tumor necrosis factor in macrophage cultures, as determined in a fibroblast cytolysis assay was found to be effectively blocked by inhibitors of lipoxygenases. Likewise, the presence of tumor necrosis factor in serum of D-galactosamine sensitized mice after challenge with endotoxin was suppressed by the lipoxygenase inhibitors. Indomethacin, a blocker of cycclooxygenase was neither in vivo nor in vitro effective in the prevention of the endotoxin-induced synthesis of TNF. From LPS-treated macrophages we were able to isolate 13-hydroxylinoleic acid, a lipoxygenase product, which is significantly increased after LPS treatment of the cells, covalently bound to cellular constituents and may, therefore, be possibly involved in the formation of TNF.

Animals↗
PubMed1989

The role of prostacyclin in the protective effects of pentoxifylline and other xanthine derivatives in endotoxin action in mice.

The xanthine derivative pentoxifylline (POF, Trental) and its metabolically more stable structural analogues, HWA 138 and HWA 448, were compared for their capacity to prevent leukopenia provoked in mice by injection of bacterial lipopolysaccharide (LPS). It was found that HWA 138 and HWA 448 counteracted LPS-induced leukopenia more effectively than POF. Indomethacin diminished the action of HWA 138 and HWA 448, and the stable prostacyclin analogue CG-4203 (Taprosten) mimicked the effect of the xanthine derivatives. Since pentoxifylline and its structural analogues induced synthesis of PGI2 in endothelial cell cultures, it is suggested that its effect on LPS leukopenia is mediated by endogenous prostacyclin production. All of the xanthine derivatives tested and CG-4203 blocked the leukopenia induced by recombinant tumor necrosis factor, which is a major endogenous mediator for endotoxin toxicity.

Animals↗
PubMed1989

The effect of pentoxifylline in septic shock--new pharmacologic aspects of an established drug.

Pentoxifylline (Trental) is a well-known vasoactive drug with proven clinical efficacy in various circulatory disorders. It improves the microcirculation due to its rheologic effects on red blood cells, platelets, and plasmatic components, resulting in a decrease of whole blood viscosity. Surprisingly, it has been found that pentoxifylline will also be of great benefit in different models of animal sepsis, including both gram positive and gram negative bacteria. In these experiments, survival rates are significantly increased in the pentoxifylline group when compared with the controls, which is paralleled by a decrease in germ counts. By different experimental approaches it could be shown that this drug interferes with pathologic granulocyte-endothelium interactions which are closely related to septic symptoms, both downregulating intravasal granulocyte hyperreactivity as well as stimulating antiaggregatory activity of the vessel endothelium. Through this way, beneficial effects of pentoxifylline may be expected in various diseases related to infection, sepsis, and shock which, however, have still to be proven in detailed clinical studies.

Animals↗
PubMed1988

Stimulation of human and murine adherent cells by bacterial lipoprotein and synthetic lipopeptide analogues.

Lipoprotein from the outer membrane of Escherichia coli and its synthetically prepared N-terminal lipopeptide segments Pam3Cys-Ser-Ser-Asn-Ala and Pam3Cys-Ser, as well as lipoprotein from other Enterobacteriaceae, constitute potent polyclonal B lymphocyte activators. Here, we demonstrate that these compounds were also able to stimulate human and murine leukocytes: in murine macrophages, we could show the induction of interleukin 1 release by the mitogens, as measured in the thymocyte proliferation assay. Moreover, murine peritoneal exudate cells were stimulated to secrete prostaglandins E2 (PGE2) and F2 alpha (PGF2 alpha). The effect of Pam3Cys-Ser on the murine macrophage cell line P388D1 was also tested: the compound induced an increase in proliferation, as measured by a thymidine incorporation assay. In addition, the cell line could be induced to release IL 1 into the supernatant. Correspondingly, induction of IL 1 release could also be demonstrated in human mononuclear cells. Our results demonstrate that the two novel synthetic lipopeptides are potent stimulators for human monocytes and murine macrophages. These findings may be important for the elucidation of the role of these bacterial surface components in the course of bacterial infections.

Animals↗