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H Redl

Publications and source records attributed to H Redl.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1996

Mediators of injury and inflammation.

Mediators play a key role in the development of systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome, and multiple organ failure of vital organs. In this short review, we update our knowledge on these mediator networks. First, we summarize the stimuli that occur during severe trauma (intraoperative stress), including polymorphonuclear neutrophil-derived tissue-damaging substances, complement activation products, and adherence molecules such as selectins. The gut in shock is discussed as an important intermediate step in the transition from noninfectious to infectious SIRS. Second, we describe the mediators, including cytokines, nitric oxide, phospholipase A2, platelet-activating factor, and procoagulatory substances, that are released during sepsis. The release of mediators depends primarily on the severity of the trauma, shock, or sepsis and secondarily on the activation of the various cascades of mediators during posttraumatic/postoperative complications. The mediators are thus of decisive importance regarding the intensity of organ damage and the outcome.

Humans↗
PubMed1996

Animal models as the basis of pharmacologic intervention in trauma and sepsis patients.

With limited resources and the current concerns about using animals for research purposes, the needs must be clear when setting up trauma and sepsis experiments for pharmacologic interventions. Such interventions are performed typically for four reasons: (1) to study the pathophysiologic role of certain mediators (which can be influenced by pharmacologic agents); (2) to study the therapeutic efficacy of treatment strategies; (3) to study the overall safety of new drugs under trauma/sepsis conditions, which are adjunct studies to standard toxicology; (4) to test new diagnostic procedures in a defined trauma or sepsis setting. Intervention in the inflammatory response may be performed at several levels: (1) at the primary induction site (e.g., by antilipopolysaccharide or by preventing complement activation); (2) at the intermediate mediator level (e.g., by antitumor necrosis factor); (3) at the final mediator level (e.g. , by block of polymorphonuclear neutrophil elastase, and (4) at the target (e.g., by membrane stabilization or enhanced antioxidant defense).

Animals↗
PubMed1996

Systemic inflammatory response syndrome after cardiac operations.

BACKGROUND: A systemic inflammatory response after open heart operation may be responsible for hyperdynamic circulatory instability and organ dysfunction. To what extent mediator release is involved needs to be clarified. METHODS: Ten patients with postoperative hyperdynamic circulatory dysregulation (group I) requiring application of alpha-constrictors and 10 patients with routine cardiac procedures and stable postoperative hemodynamic indices (group II) were analyzed for mediator release and metabolic and hemodynamic changes until the third postoperative day. RESULTS: Group I patients showed a significantly increased cardiac index and decreased systemic vascular resistance after bypass (cardiac index, group I: 5.2 +/- 1.2 L.min-1.m-2, group II: 2.5 +/- 1.6 L.min-1.m-2; systemic vascular resistance, group I: 495 +/- 204 dyne.s. cm-5, group II: 1,356 +/- 466 dyne.s.cm-5) and at 3 hours (cardiac index, group I: 4.4 +/- 0.8 L.min-1.m-2, group II: 2.9 +/- 0.6 L.min-1.m-2; systemic vascular resistance, group I: 567 +/- 211 dyne.s.cm-5, group II: 1,053 +/- 273 dyne.s.cm-5). Significantly higher serum levels of interleukin-6 were assessed in group I (postbypass, group I: 6,812 +/- 9,293 pg/mL, group II: 295 +/- 303 pg/mL; 3 hours, group I: 3,474 +/- 5,594 pg/mL, group II: 286 +/- 296 pg/mL). Concentrations of elastase, tumor necrosis factor, soluble tumor necrosis factor receptor, and interleukin-8 were elevated in group I (not significant). Early postoperative levels of soluble E-selectin and soluble intercellular adhesion molecule were also higher in group I (not significant). Continuously increased levels of endotoxin could be detected in only 3 of 10 patients in group I. Severe lactic acidosis (> or = 5 mmol/L) occurred in group I only. CONCLUSIONS: Postoperative hyperdynamic instability after open heart operations appears to be associated with a certain pattern of mediator release. In particular, interleukin-6 appears to be involved in circulatory dysregulation and metabolic derangement.

Acidosis, Lactic↗
PubMed1996

Comparison of endothelial activation during endotoxic and posttraumatic conditions by serum analysis of soluble E-selectin in nonhuman primates.

Because the presence of E-selectin, which is one of the adhesion molecules on the endothelium, cannot be determined directly in vivo except by invasive biopsy techniques, the only available kinetic information concerning its activity is the serum level of the soluble form. Therefore we tried to measure soluble E-selectin levels and compare the degree of endothelial activation in a trauma and endotoxic situation, where endothelial activation is supposed to occur. To perform these studies, an enzyme-linked immunosorbent assay with two monoclonal antibodies was set up and used in (1) a model of endotoxic shock in baboons (n = 8) (1.5 mg/kg Escherichia coli endotoxin as a 10-minute intravenous infusion), (2) a hemorrhagic traumatic shock model in baboons (n = 6), where trauma was simulated by infusion of zymosan-activated serum and hemorrhage. Soluble E-selectin was released in vivo after the application of endotoxin, and it reached a peak level after 24 hours (13.82 +/- 5.38 ng/ml). In baboons with hemorrhagic shock, much lower levels (5.03 +/- 1.98 ng/ml) of soluble E-selectin were found. A lower soluble E-selectin level indicates a lower level of endothelial activation after experimental hemorrhagic traumatic shock (with endotoxin translocation from the gut) as compared with endotoxic shock probably caused by much lower endotoxin levels in traumatic shock.

Animals↗
PubMed1996

Evaluation of a soluble E-selectin enzyme-linked immunosorbent assay under posttraumatic conditions.

The up-regulation of E-selectin, one of the adhesion molecules on the endothelium, is an important event in the mediation of the inflammatory response. Because the presence of E-selectin cannot be determined directly in vivo except by invasive biopsy techniques, the only available information concerning its activity is the serum level of the soluble form. Therefore we tried to measure soluble E-selectin levels in trauma and sepsis situations, where endothelial activation is supposed to occur. We have investigated the soluble E-selectin levels in a group of patients undergoing the trauma associated with cardiac surgery and the use of extracorporeal circulation, some of whom developed a systemic inflammatory response syndrome (SIRS). We have also confirmed that our enzyme-linked immunosorbent assay (ELISA) will detect the levels of soluble E-selectin that are produced as a result of the exposure of cultured human umbilical endothelial cells to even low levels of endotoxin. The data presented in this paper indicate that in patients with SIRS after extracorporeal circulation, the levels of circulating soluble E-selectin are numerically higher but---at least in this group of patients---not statistically significantly different from the levels in patients who have undergone the surgery. These results suggest that the measurement of serum levels of soluble E-selectin is not a reliable method for monitoring the onset of SIRS in patients having undergone surgical trauma, although we have confirmed that our ELISA will detect the levels of soluble E-selectin that are produced as a result of the exposure of cultured human endothelial cells to even low levels of endotoxin.

Adult↗
PubMed1996

Monoclonal antibody to tumor necrosis factor-alpha attenuates hemodynamic dysfunction secondary to intestinal ischemia/reperfusion in rats.

OBJECTIVE: To evaluate the effects of monoclonal antibody to tumor necrosis factor (TNF)-alpha on the hemodynamic alterations and survival rate in rats subjected to intestinal ischemia/reperfusion. DESIGN: Prospective, randomized study. SETTING: Animal laboratory of an institute for research in traumatology. SUBJECTS: Male Sprague-Dawley rats, weighing 430 to 460 g. INTERVENTIONS: Anesthetized rats underwent 75 mins of superior mesenteric artery occlusion followed by 6 hrs of reperfusion. The animals were treated intravenously with either TNF-alpha monoclonal antibody (TN3, 20 mg/kg) or the control protein (albumin, 20 mg/kg) 30 mins before the onset of ischemia. MEASUREMENTS AND MAIN RESULTS: Pretreatment with TNF-alpha monoclonal antibody significantly attenuated the decreases in blood pressure and cardiac index (p < .01) compared with controls, for < or = 6 hrs after reperfusion. Stroke volume remained stable in the TNF-alpha monoclonal antibody-treated group and was significantly higher than in the control group at 0.5, 5, and 6 hrs after reperfusion (p < .05 at 0.5 and 5 hrs and p < .01 at 6 hrs). No differences in vascular resistance index values were observed between the two groups at any point in time (p > .05). After intestinal ischemia/reperfusion injury, both the portal and systemic TNF concentrations in the control animals were completely neutralized by TNF-alpha monoclonal antibody treatment. The 72-hr survival rate was significantly (p < .01) better in the treatment group (90%, 9/10) than in the control group (20%, 2/10). CONCLUSIONS: These results suggest that intestinal ischemia/reperfusion injury can lead to increased TNF release into both the portal and the systemic circulation, which may be an important factor contributing to the development of hemodynamic dysfunction. Pretreatment with TNF-alpha monoclonal antibody significantly attenuates the cardiovascular consequences and improves the survival rate after acute intestinal ischemia/reperfusion injury.

Animals↗
PubMed1996

Comparison of the efficacy of pentoxifylline and albifyllin (HWA 138) on endotoxin-induced cytokine production, coagulation disturbances, and mortality.

We have evaluated two different xanthine derivatives, pentoxifylline (POF) and albifyllin (HWA), in rat endotoxemia for their ability to reduce 1) cytokine formation, 2) coagulation disturbances, and 3) mortality. The animals were injected with lipopolysaccharide (LPS) (15 mg/kg i.p.) and received HWA or POF (25, 50, or 100 mg/kg) or saline 30 min before LPS administration. The plasma tumor necrosis factor levels were significantly reduced and in a similar manner by pretreatment with HWA or POF in vivo as well as in vitro. Neither the coagulation disturbance nor the characteristic leukopenia that follow an LPS challenge were significantly influenced by the xanthine derivatives. At a dose of 100 mg/kg, the 6 day mortality was significantly reduced by HWA to 36% but only attenuated by POF to 55% as compared to 80% in the control group. The similar effect of both agents on cytokine formation and coagulation disturbances indicate that, at least to a substantial degree, other mechanisms may account for the significant protection of rats against endotoxin-induced mortality by HWA only. HWA 138 may, therefore, be a new powerful agent against endotoxin-related disorders and mortality.

Animals↗
PubMed1996

Pteridine and nitrite/nitrate formation in experimental septic and traumatic shock.

Bacterial lipopolysaccharides (LPS) induce the activity of guanosine triphosphate (GTP)-cyclohydrolase I (GTP-CHI), the first enzyme in the biosynthesis of tetrahydrobiopterin (H4bip) from GTP in endothelial cells and macrophages. In these and other cells, LPS also acts costimulatory with cytokines, i.e., mainly tumor necrosis factor-alpha (TNF-alpha). H4bip is the cofactor for nitric oxide synthase (NOS). We were interested in comparing the pteridine and nitrate levels in two baboon models: a hyperdynamic sepsis model and a hemorrhagic traumatic shock model. Our results show a similar response of pteridines (H4bip, neopterin) and nitrite/nitrate levels to an immune stimulus. LPS, which peaks rapidly, induces a sustained increase in pteridine levels in septic animals. Since hemorrhagic animals show very little response in terms of cytokine production, it was not possible to measure the induction of neopterin and nitrite/nitrate. This information could aid our understanding of the regulatory mechanisms in various forms of experimental shock.

Animals↗
PubMed1996

Effects on complement activation and cytokine (TNF-alpha and IL-8) release of infusion of anti-TNF-antibodies or a xanthine derivative (HWA 138) in septic baboons.

BACKGROUND: Sepsis and septic shock lead to activation of the complement cascade and to the release of pro-inflammatory cytokines. METHODS: The effects of E coli infusion and of infusion of anti-TNF antibodies and a xanthine derivative (HWA 138) on complement activation and cytokine release was evaluated in 17 baboons. All animals received 5 x 10(8) live bacteria per kg body weight. Five animals received only bacteria, five received in addition 0.5 mg per kg body weight of anti-TNF-antibody, and seven received an infusion of 6 mg per kg body weight of HWA 138 in addition to the bacteria. RESULTS: In baboons receiving 5 x 10(8) live E coli per kg body weight increased plasma levels of TCC, TNF-alpha and IL-8 were found. The release of TNF-alpha was lower in the group receiving HWA 138 at 2 h after the infusion. In baboons receiving an infusion of anti-TNF antibody the concentration of IL-8 was lower at 2 and 4 h than in animals receiving just E coli or HWA 138. CONCLUSION: Infusion of anti-TNF-antibody before E coli infusion will decrease the formation of IL-8. Infusion of HWA 138 before the E coli infusion will also inhibit the formation of TNF-alpha.

Animals↗
PubMed1996

Significance of NO in hemorrhage-induced hemodynamic alterations, organ injury, and mortality in rats.

In an attempt to evaluate the role of nitric oxide (NO) in pathophysiological alterations and multiple organ damage caused by hemorrhagic shock, we employed NG-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthase, in anesthetized rats subjected to a prolonged hypovolemic insult (30-35 mmHg for 180 min). Infusion of 2.0 mg/kg L-NMMA at the end of resuscitation diminished the fall in mean arterial pressure (MAP) and significantly increased the cardiac index and stroke volume, together with remarkable protection from multiple organ damage compared with the controls. The 48-h survival rate was significantly improved from 26.7% in the control group to 68.8% in the treatment group (P < 0.05). In contrast, the high dose of 20.0 mg/kg L-NMMA resulted in a strong blood pressure response, but a marked reduction in cardiac index and stroke volume concomitant with an increased total peripheral resistance index within the observation period, and tended to increase damage to various organs at 2 h after treatment. In addition, marked elevation in both endotoxin and tumor necrosis factor levels were observed in animals subjected to shock insult. The results suggest that NO induced by hemorrhagic shock in rats is an important mediator for pathophysiological alterations associated with cardiovascular abnormalities, multiple organ dysfunction, and even lethality. Regulation of NO generation and use of NO inhibitors might provide new aspects in the treatment of hemorrhage-related disorders, whereas the administration of L-NMMA would be either deleterious or salutary in a dose-dependent manner.

Animals↗
PubMed1996

Endogenous modulators of TNF and IL-1 response are under partial control of TNF in baboon bacteremia.

Tumor necrosis factor (TNF) and interleukin (IL)-1 are two cytokines for which naturally occurring inhibitors have been identified. The present study was undertaken to evaluate the extent to which scavenging of TNF in bacteremia attenuates the plasma levels of IL-1 receptor antagonist (IL-1ra) and soluble TNF receptors (sTNFR). Ten male baboons received 2 x 10(9) colony-forming units/kg live Escherichia coli over 2 h and were subjected to either placebo or anti-TNF antibody (anti-TNF Ab) treatment (1 mg/kg CDP571, Celltech, UK) 2 h before E. coli infusion (observation time: 72h). IL-1ra (range: 50-100 ng/ml) and sTNFR (range: 55kDa, 20-25 ng/ml; 75 kDa, 30-35 ng/ml) release was more sustained than that of IL-1 and TNF and was significantly attenuated by anti-TNF treatment, as were the circulating levels of IL-1, IL-8, and monocyte chemotactic peptide-1 (MCP-1) in the anti-TNF Ab group. We conclude that the increase in circulating natural cytokine modulators observed in nonhuman primate bacteremia is under the partial control of endogenous TNF because it was influenced by anti-TNF pretreatment. This attenuation is comparable to the anti-TNF effect on the chemokine MCP-1.

Animals↗
PubMed1995

Thrombomodulin release in baboon sepsis: its dependence on the dose of Escherichia coli and the presence of tumor necrosis factor.

This study was designed to test whether thrombomodulin is shed in septic baboons and whether shedding is blocked by antibody to tumor necrosis factor (anti-TNF). Live Escherichia coli were injected intravenously into 24 baboons according to one of the following regimens: 5 x 10(8) or 2 x 10(9) cfu/kg (n = 6/8), 2 x 10(9) cfu/kg with placebo (n = 5), or pretreatment with 1 mg/kg anti-TNF 2 h before E. coli injection (n = 5). E. coli administration resulted in a significant release of thrombomodulin in a dose-dependent manner; however, thrombomodulin release was significantly attenuated (180 to 40 ng/mL) by anti-TNF pretreatment. This is parallel to the reduction of neutrophil activation (elastase). These results provide evidence for an E. coli dose-related and TNF-dependent thrombomodulin release into the plasma of septic baboons and suggest a possible role of anti-TNF in protection of the endothelium.

Alanine Transaminase↗