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Biomedical subjects

H Redl

Publications and source records attributed to H Redl.

At least 19 recordsLinked to original sources
PubMed1999

Bacterial cell envelopes (ghosts) but not S-layers activate human endothelial cells (HUVECs) through sCD14 and LBP mechanism.

Bacterial cell-envelopes (called ghosts) and surface layers (S-layers) are discussed to be used as vaccines and/or adjuvants, consequently it is necessary to find out which immunomodulatory mediators are induced in human cells. The present work focuses on the effects of ghosts (Escherichia coli O26:B6), S-layers (Bacillus stearothermophilus) in comparison with LPS and antibiotic-inactivated whole bacteria (E. coli O26:B6) on human umbilical vein endothelial cells (HUVEC) with regard to the release of interleukin 6 (IL-6) and the expression of surface E-selectin and the role of lipopolysaccharide binding protein (LBP), soluble CD14 (sCD14) and serum for this activation. Endothelial cells responded to ghosts, whole bacteria and LPS with IL-6 release up to 15000 pg/ml and surface E-selectin expression, while in contrast the response to S-layers with IL-6 release up to 500 pg/ml was very weak. Compared to LPS, 10-100-fold higher concentrations of bacterial ghosts and whole bacteria were required to induce the cytokine synthesis and E-selectin expression. IL-6 release and E-selectin expression of HUVECs were reduced in the absence of serum and equivalent to unstimulated samples. We have also studied the role of CD14 and LBP for the activation of endothelial cells using antiCD14 and antiLBP antibodies (Ab). AntiCD14 and antiLBP Ab both inhibited IL-6 release and E-selectin expression in a dose dependent manner after stimulation with ghosts, whole bacteria and LPS but had no effect on S-layers stimulated cells. AntiCD14 Ab inhibited more effectively than antiLBP Ab. These findings suggest that bacterial ghosts but not S-layers activate HUVECs through sCD14 and LBP dependent mechanisms.

Acute-Phase Proteins↗
PubMed1999

4-Hydroxynonenal as a second messenger of free radicals and growth modifying factor.

Immunohistochemical analysis of the distribution of the lipid peroxidation product 4-hydroxynonenal (HNE) in the brain of baboons exposed to experimental hemorrhagic traumatic shock or sepsis showed that systemic oxidative stress and the thereby generated HNE affect the blood:brain barrier and the regulation of cerebral blood flow determining secondary brain damage. Similarly, HNE was determined during ischemia in the brain blood vessels of rats exposed to ischemia/reperfusion injury of the brain. After reperfusion, HNE disappeared from the blood vessels but remained in neurones and in glial cells. Since HNE modulates cell proliferation and differentiation (including proto-oncogene expression), it is postulated that HNE might have prominent local and systemic effects that are not only harmful but beneficial, too, determining the outcome of various pathophysiological conditions based on oxidative stress.

Aldehydes↗
PubMed1999

Protective effect of bactericidal/permeability-increasing protein (rBPI21) in baboon sepsis is related to its antibacterial, not antiendotoxin, properties.

OBJECTIVE AND SUMMARY BACKGROUND DATA: The recombinant fragment of bactericidal/permeability-increasing protein, rBPI21, has potent bactericidal activity against gram-negative bacteria as well as antiendotoxin (lipopolysaccharide [LPS]) action. On the basis of these activities, the authors sought to discover whether rBPI21 would be protective in baboons with live Escherichia coli-induced sepsis and whether the potential protective effects of rBPI21 (together with antibiotics) would be more closely related to its antibacterial or LPS-neutralizing effects. METHODS: In a prospective, randomized, placebo-controlled subchronic laboratory study, the efficacy of rBPI21 or placebo was studied over 72 hours in chronically instrumented male baboons infused with live E. coli under antibiotic therapy. RESULTS: Intravenous rBPI21 attenuated sepsis-related organ failure and increased survival significantly. Bacteremia was significantly reduced in the rBPI21 group at 2 hours after the start of the E. coli infusion, whereas circulating LPS was less affected. The in vivo formation of tumor necrosis factor was significantly suppressed by the rBPI21 treatment regimen. Microcirculation and organ function were improved. CONCLUSIONS: In baboon live E. coli sepsis, the salutary effect of rBPI21 results from a more prevalent antibacterial than antiendotoxin activity.

Animals↗
PubMed1999

Impaired energy metabolism in hearts of septic baboons: diminished activities of Complex I and Complex II of the mitochondrial respiratory chain.

Recent findings support the view that the bioenergetic part of septic organ failure is not caused by insufficient supply of oxygen but by disturbances of the mitochondrial function. Therefore, the aim of the present study was to investigate key enzymes of energy metabolism in septic hearts to answer the question whether or not impairment of mitochondrial or glycolytic enzymes occur under these conditions. For this purpose the well established model of septic baboons was used. Baboons under general anesthesia were made septic by infusion of Escherichia coli. Single challenge with infusion of high amounts of bacteria was compared with a multiple challenge protocol (less bacteria infused). Some animals obtained no E. coli (sham). The hearts of the baboons were removed after 72 h (survival: yes) or after death (survival: no) of the animals, frozen in liquid nitrogen, and stored at -80 degrees C until spectrophotometrical measurement of nine mitochondrial and glycolytic enzymes. A reduction of the activity of NADH:cytochrome-c-reductase (Complex I + III) to 67% and succinate:cytochrome-c-reductase (Complex II + III) to 45% was found in the hearts of surviving animals after infusion of high amounts of bacteria. After multiple challenge with lesser amounts of bacteria, no significant changes in enzyme activity were detectable. After lethal septic shock, activities of Complex I + III (12%) and Complex II + III (13%) as well as of phosphofructokinase (16%) were found to be strongly diminished. Decylubiquinol:cytochrome-c-reductase (Complex III, 59%), cytochrome-c-oxidase (51%), succinate dehydrogenase (60%), glucosephosphate isomerase (61%), lactate dehydrogenase (61%), and citrate synthase (120%) were less or unaffected. Similar but less pronounced effects were found after infusion of lesser amounts of bacteria. By means of inhibitor titrations of succinate: cytochrome-c-reductase, it was shown that the loss of activity is not caused by Complex III but by disturbances in Complex II. It is concluded that E. coli-induced sepsis causes decreased activities of Complex I and Complex II in baboon heart mitochondria in a dose-dependent manner.

Animals↗
PubMed1998

The inflammatory basis of trauma/shock-associated multiple organ failure.

Multiple alterations in inflammatory and immunologic function have been demonstrated in clinical and experimental situations after trauma and hemorrhage, in particular the activation of various humoral (e.g. complement, coagulation) and cellular systems (neutrophils, endothelial cells, macrophages). As a consequence of this activation process there is synthesis, expression and release of numerous mediators (toxic oxygen species, proteolytic enzymes, adherence molecules, cytokines), which may produce a generalized inflammation and tissue damage in the body. Mediators are responsible for ongoing interactions of different cell types and for amplification effects through their networks and feedback cycles, finally leading to a sustained inflammation and multiple organ damage in the body. In the setting of trauma/shock, many activators including bacterial as well as non-bacterial factors may be present that will induce local and systemic inflammatory responses. Although the potential role of bacteria/endotoxin translocation and its clinical relevance remains controversial, many lines of evidence support the concept that the gut may be the reservoir for systemic sepsis and subsequent MOF in a number of pathophysiologic states.

Bacterial Translocation↗
PubMed1998

Anti-TNF treatment of baboons with sepsis reduces TNF-alpha, IL-6 and IL-8, but not the degree of complement activation.

The activation of complement and the release of TNF-alpha, IL-6 and IL-8 are important pathogenic factors behind organ dysfunction in sepsis. The aim of this study was to determine whether infusion of anti-TNF antibodies alters complement activation and plasma concentrations of pro-inflammatory cytokines at high doses of Escherichia coli. Six baboons received intravenously 2 x 10(9) live E. coli bacteria per kg body weight (group 1), in addition five received pretreatment with 1 mg per kg body weight anti-TNF antibodies (group 2), and seven received 5 x 10(8) live E. coli bacteria per kg body weight (group 3). Two hours after the start of infusion of the bacteria, plasma concentrations of C3 activation products, C5a and the terminal SC5b-9 complement complex were increased in groups 1 and 2 (P < 0.05), but there was no significant difference between the groups. At 2 h the levels of TNF-alpha, IL-6 and IL-8 were lower in group 2 compared with group 1 (P<0.05). In group 2 compared with group 1 the TNF-alpha concentrations were, however, higher at 4, 8 and 24 h. The explanation for this phenomenon is probably that TNF-alpha binds to the anti-TNF antibody complex and is released slowly after it has been bound. The study showed that infusion of anti-TNF antibodies reduced the concentrations of TNF-alpha, IL-6 and IL-8, without any detectable influence on complement activation.

Animals↗
PubMed1998

Local and systemic reactions after lung contusion: an experimental study in the pig.

The present study was designed to investigate the consequences of isolated unilateral lung contusion on local alveolar and systemic inflammatory responses in an animal model in the pig. Isolated unilateral lung contusion was induced by bolt shot in eight mechanically ventilated animals under general anesthesia (sham: n=4). Plasma and bronchoalveolar lavage fluid were collected during a period of 8 h following lung contusion. Leukocytes, leukocyte neutral protease inhibitor (LNPI), terminal complement complex (TCC), thrombin-antithrombin-complex (TAT) as well as pulmonary microvascular permeability and surfactant function were determined. Within 30 min, lung contusion was found to cause a significant local and systemic increase in TCC and TAT concentrations and a systemic increase in LNPI concentrations. The latter was accompanied by a sequestration of leukocytes in the contused lung. Complement activation and leukocyte sequestration in the contused lung progressively increased during the investigation period. Although surfactant function decreased in the entire lung 30 min after contusion, TCC, TAT, and leukocyte sequestration was unchanged in the contralateral lung. The first indication of an involvement of the contralateral lung was obtained by an increase in leukocyte sequestration 8 h after lung contusion. Unilateral lung contusion initiates an early systemic activation of humoral and cellular defense systems. Involvement of the contralateral lung appears to be a secondary event caused by a systemic inflammatory reaction.

Animals↗
PubMed1997

IL-6 release after intestinal ischemia/reperfusion in rats is under partial control of TNF.

Although there is much evidence to substantiate the view that tumor necrosis factor (TNF) plays a pivotal role in the pathogenesis of multiple organ injury subsequent to intestinal ischemia/reperfusion (I/R), it is still unclear whether TNF is involved in triggering the release of other inflammatory mediators in this condition. The current study was designed to determine the potential effects of TNF blockade, by means of monoclonal antibody (TNF MoAb) treatment, on plasma interleukin 6 (IL-6) in rats after acute intestinal I/R injury. Anesthetized rats underwent 75-min occlusion of superior mesenteric artery followed by 6 hr of reperfusion. The animals were treated with TNF MoAb or control protein at a dose of 20 mg/kg i.v. 30 min before the onset of I/R. Similar IL-6 responses in both the portal and the systemic circulation were observed in animals subjected to intestinal I/R, who showed a progressive increase in plasma IL-6 concentration upon release of the clamp. In animals receiving TNF MoAb before I/R, the subsequent IL-6 release following reperfusion was significantly blunted compared to the levels in controls (P < 0.05). The present study demonstrates that the activation and/or release of IL-6 in the setting of acute gut I/R may, at least in part, be mediated via TNF-dependent mechanisms, providing further evidence that a complex interaction exists between TNF and IL-6.

Animals↗
PubMed1997

Complementary DNA (cDNA) sequence of baboon tumor necrosis factor alpha.

Baboons are less LPS-sensitive than humans, even though their immune response mechanisms are similar. Since TNFalpha is a central mediator of the LPS-response we cloned and sequenced the baboon TNFalpha cDNA and compared the resulting sequence with the human TNFalpha sequence. Analysis of the TNFalpha protein coding region indicated 97% homology and of the 3' UTF 89%. The predicted baboon TNFalpha amino acid sequence differed at 10 positions from the human sequence. "TA" rich motifs within the 3' UTR were 100% homologous.

Amino Acid Sequence↗
PubMed1997

Monoclonal antibody to endotoxin attenuates hemorrhage-induced lung injury and mortality in rats.

OBJECTIVES: To determine the possible role of enteric bacteria-derived endotoxin in the pathogenesis of the lung injury and mortality in rats following hemorrhagic shock and resuscitation. DESIGN: Prospective, randomized study. SETTING: Animal laboratory of an institute for research traumatology. SUBJECTS: Male Sprague-Dawley rats, weighing 450 to 480 g. INTERVENTIONS: Anesthetized rats were subjected to a prolonged hemorrhagic shock (mean arterial pressure of 30 to 35 mm Hg for 180 mins) followed by resuscitation. A murine monoclonal antibody to lipopolysaccharide from Escherichia coli and Salmonella, WN1 222-5, was administered at a total dose of 5 mg/kg i.v., starting at the onset of shock (WN1 group). The control group was treated similarly to the WN1 group but received saline at the same volume as WN1 222-5. MEASUREMENTS AND MAIN RESULTS: The 48-hr mortality rate was significantly reduced by WN1 222-5 treatment (28.6% in the treatment group vs. 78.6% in the control group; p = .0169). The characteristic lung injury in this model was significantly reduced in the WN1 group, as assessed by microscopic histopathologic examination increase in lung wet weight (7.60 +/- 0.47 g/kg in the control group vs. 5.14 +/- 0.31 g/kg in the WN1 group; p = .0002), and pulmonary neutrophilic infiltration (myeloperoxidase activity: 1835 +/- 567 mU/g wet weight in the control group vs. 891 +/- 212 mU/g wet weight in the WN1 group). CONCLUSIONS: These data suggest that a) endotoxin derived from enteric bacteria might play an important role in the pathogenesis of lung injury; and b) antiendotoxin agents, such as WN1 222-5, appear to protect against endogenous bacterial endotoxin-related disorders in severe hemorrhagic shock in rats.

Animals↗
PubMed1997

Interleukin-8 released into the cerebrospinal fluid after brain injury is associated with blood-brain barrier dysfunction and nerve growth factor production.

Interleukin (IL) 8 was measured in CSF of 14 patients with severe traumatic brain injury. IL-8 levels were significantly higher in CSF (up to 8,000 pg/ml) than serum (up to 2,400 pg/ml) (p < 0.05), suggesting intrathecal production. Maximal IL-8 values in CSF correlated with a severe dysfunction of the blood-brain barrier. Nerve growth factor (NGF) was detected in CSF of 7 of 14 patients (range of maximal NGF: 62-12,130 pg/ml). IL-8 concentrations were significantly higher in these patients than in those without NGF (p < 0.01). CSF containing high IL-8 (3,800-7,900 pg/ml) induced greater NGF production in cultured astrocytes (202-434 pg/ml) than samples with low IL-8 (600-1,000 pg/ml), which showed a smaller NGF increase (0-165 pg/ml). Anti-IL-8 antibodies strongly reduced (52-100%) the release of NGF in the group of high IL-8, whereas in the group with low IL-8, this effect was lower (0-52%). The inability of anti-IL-8 antibodies to inhibit the synthesis of NGF completely may depend on cytokines like tumor necrosis factor alpha and IL-6 found in these CSF samples, which may act in association with IL-8. Thus, IL-8 may represent a pivotal cytokine in the pathology of brain injury.

Adolescent↗
PubMed1997

Significance of TNF in hemorrhage-related hemodynamic alterations, organ injury, and mortality in rats.

To evaluate the role of tumor necrosis factor-alpha (TNF-alpha) in hemodynamic alterations, multiple organ damage, and mortality caused by hemorrhagic shock, we employed a monoclonal antibody to TNF-alpha (TNF-alpha MAb) in anesthetized rats subjected to prolonged hemorrhagic shock (mean arterial pressure of 30-35 mmHg for 180 min) followed by resuscitation over 50 min. Treatment of rats with 20.0 mg/kg TNF-alpha MAb 15 min after the end of resuscitation significantly decreased the total peripheral resistance index (P = 0.031) and provided remarkable protection from multiple organ damage compared with controls. The 48-h survival rate was significantly higher in the treatment group (73.3%) than in the control group (26.7%; P = 0.029). The results suggest that TNF-alpha induced by hemorrhagic shock in rats is an important mediator of pathophysiological alterations associated with cardiovascular abnormalities, multiple organ injury, and even lethality. Postresuscitation treatment with TNF-alpha MAb, even after an initial TNF-alpha formation had occurred, significantly attenuated the cardiovascular consequences and improved the survival rate. Thus monoclonal antibodies to TNF-alpha might provide new prospects in the treatment of hemorrhage-related disorders.

Animals↗