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PubMed2000

Endotoxin, cytokines, and endotoxin binding proteins in obstructive jaundice and after preoperative biliary drainage.

BACKGROUND: Obstructive jaundice is associated with postoperative complications related to increased endotoxaemia and the inflammatory response. In animals obstructive jaundice is associated with endotoxaemia and cytokine induction, which are reversed by internal biliary drainage. AIMS: To study endotoxaemia and the subsequent inflammatory response in obstructive jaundiced patients and after endoscopic biliary drainage. METHODS: In 15 patients with malignant distal obstructive jaundice, inflammatory and bacteriological parameters were assessed before endoscopic stent placement and after three weeks endoscopic drainage. RESULTS: Drainage reduced bilirubin from 252.5 to 45.1 micromol/l. At baseline low level endotoxaemia was detected (4.3 pg/ml) which was not affected after drainage (4.5 pg/ml). Serum interleukin 8 (IL-8) and endotoxin binding proteins were increased in jaundice and reduced after drainage (IL-8 113.6 to 20.7 pg/ml; lipopolysaccharide binding protein 24.2 to 16.5 microg/ml; sCD14 17.4 to 7.6 microg/ml; bactericidal/permeability increasing protein 2.9 to 1.8 ng/ml). Levels of other cytokines, augmented in animals, were only slightly increased and not changed after drainage (tumour necrosis factor (TNF): 21.7 and 18.4 pg/ml; sTNFr p55/75: 2.9/7.0 and 2.7/5.6 ng/ml; IL-6: 4.2 and 6.1 pg/ml; IL-10: 4.5 and 2.7 pg/ml). Elastase and lactoferrin tended towards reduction after drainage. All bile cultures were positive after stenting. CONCLUSIONS: The effects of obstructive jaundice in humans on endotoxin and cytokines are different from those in animal models. Obstructive jaundice causes alterations in circulating endotoxin binding proteins and IL-8. Concentrations of other mediators (TNF, previously suggested as being responsible for systemic endotoxaemia effects) are low and not affected by drainage.

Bile Duct Neoplasms↗
PubMed1991

Spontaneous release of granulocyte colony-stimulating factor (G-CSF) by alveolar macrophages in the course of bacterial pneumonia and sarcoidosis: endotoxin-dependent and endotoxin-independent G-CSF release by cells recovered by bronchoalveolar lavage.

Because granulocyte colony-stimulating factor (G-CSF) is known to induce granulopoiesis and activate mature neutrophils, this factor could be important in determining the number and functional activity of neutrophils at sites of lung disease. The purpose of this study was to evaluate the ability of lung immune and inflammatory cells to produce G-CSF, and to seek evidence for the spontaneous production of this factor by cells recovered by lavage from controls and patients with lung diseases in which neutrophils may play a pathogenetic role. Lavage cells from controls produced little G-CSF spontaneously. Alveolar macrophages (AM), but not lymphocytes, produced large amounts following endotoxin stimulation. Lavage cells from patients with respiratory failure associated with bacterial pneumonia, but not those with respiratory failure from noninfectious causes, spontaneously released G-CSF (32 +/- 24 and less than 1 U/10(6) AM, respectively). Lavage cells from five of 15 patients with sarcoidosis and one of five patients with diffuse pulmonary fibrosis also spontaneously released G-CSF, which could not be explained by endotoxin exposure. The release of G-CSF by endotoxin-dependent and -independent mechanisms could play a role in the recruitment and activation of neutrophils in bacterial pneumonia and participate in the pathogenesis of some interstitial lung diseases.

Adult↗
PubMed1991

Plasma concentrations of endotoxin following jugular or portal injections of endotoxin and following gastrointestinal ischemia due to hemorrhage.

Endotoxin (LPS) was quantitated in canine plasma using the Limulus amebocyte lysate (LAL) chromogenic testing procedure. The assay was validated for sensitivity (25 pg/ml), recovery (90-110%), intra-assay precision (CV = 5.5), interassay precision (CV = 10), and stability of diluted, heat-treated, frozen samples (greater than or equal to 60 days). Canine plasma samples were analyzed for endotoxin following sublethal IV injections (cephalic and portal, bolus and slow infusion) of LPS. Pharmacokinetic analysis using the two-compartment open model on plasma LPS levels was possible for portal bolus, cephalic bolus, and portal slow infusion dogs. The results revealed that LPS given via cephalic bolus route had a lower clearance rate than LPS given via portal bolus route. Slow infusion of LPS into the portal vein revealed an increased distribution phase t1/2 in plasma and a slower elimination kel and beta rate than observed following a portal bolus injection of LPS. During a clinical endo(to)xemia, LPS enters the circulation slowly, and is therefore probably cleared more slowly; the prolonged low level of LPS may be responsible for many pathophysiological changes observed. Low levels of endotoxin were detected in plasma following hemorrhage, indicating that intestinal ischemia results in low levels of LPS leaking into the circulation.

Animals↗
PubMed1978

[Study of the structure and function of endotoxins with the aid of enzymes. 2. Modification of Salmonella paratyphi B endotoxin with lysozyme and lipase].

Endotoxin preparations from the S. paratyphi B cultures, isolated by various methods, were treated with lysozyme (splitting of beta-1,4-glycoside links of lipid A) and lipase of the pancreas (splitting of complex ester links of glycerophosphatides). Lysozyme and, to a lesser extent, lipase, were capable of partial depression of the toxic endotoxin function. The process of enzymatic detoxication coursed selectively, without influencing the serological and immunological activity of the preparations. Suppositions are put forward on the complicated nature of the toxic endotoxin function manifestation and possibility of provision of detoxication effect by specific actions differing by the point of application.

Antitoxins↗
PubMed1993

Anti-endotoxin monoclonal antibodies protect by enhancing bacterial and endotoxin clearance.

In this study, we sought to determine the mechanism(s) by which a type-specific anti-lipopolysaccharide monoclonal antibody (an IgG directed against the O-antigen polysaccharide region of Salmonella minnesota lipopolysaccharide) and its F(ab')2 fragments protect during gram-negative bacterial peritonitis and endotoxemia in mice. During peritoneal infection, (1) IgG significantly decreased mortality, bacteremia, and endotoxemia at all time points compared with saline solution pretreatment and (2) F(ab')2 fragments reduced mortality at 24 hours but not thereafter, and had no effect on bacteremia but reduced endotoxemia compared with saline solution pretreatment. In the endotoxin model, IgG pretreatment significantly reduced mortality compared with saline solution pretreatment, while F(ab')2 fragments had no significant effect on mortality. No difference in endotoxemia was observed in mice that received IgG, F(ab')2 fragments, or saline solution pretreatment during endotoxemia. These results suggest that type-specific anti-lipopolysaccharide monoclonal antibodies protect by Fc-mediated clearance of both bacteria and endotoxin.

Animals↗
PubMed2006

Endotoxin detection in a competitive electrochemical assay: synthesis of a suitable endotoxin conjugate.

A biotin-lipopolysaccharide (biotin-LPS) conjugate was synthesized from LPS smooth from Salmonella minnesota, yielding a conjugate with a biotin/LPS ratio equal to 1:1 and endotoxic activity of 0.08 EU ng(-1). The conjugate was used in an amperometric competitive assay to determine endotoxins with endotoxin-neutralizing protein (ENP) as the recognition element. The assay is performed on a modified electrode, involving the covalent binding of carboxymethyl dextran (CMDex) to a cystamine-modified gold electrode and then the covalent binding of the recognition protein, ENP, to CMDex. The assay is carried out by incubating the modified electrode in an LPS sample to which biotin-LPS was added. Both species compete for the recognition sites on the modified surface. After the incubation stage and a careful rinsing, the electrode is immersed in a solution containing neutravidin-horseradish peroxidase conjugate (N-HRP), which binds to the sites containing biotin-LPS on the electrode. The system is rinsed and a current signal is generated by the addition of hydrogen peroxide and a redox mediator. The assay is able to detect LPS from Salmonella minnesota at concentrations as low as 0.1 ng ml(-1), equivalent to 0.07 EU ml(-1).

Biotin↗
PubMed1990

Dexamethasone prevents the induction by endotoxin of a nitric oxide synthase and the associated effects on vascular tone: an insight into endotoxin shock.

The relationship between vascular tone and the induction by endotoxin of a nitric oxide (NO) synthase was studied in vitro in rings of rat thoracic aorta. In rings with and without endothelium there was a time-dependent induction of NO synthase accompanied by both spontaneous and L-arginine-induced relaxation and by reduced contractility to phenylephrine. These effects, which were attributable to the presence of endotoxin in the Krebs' buffer, were attenuated by cycloheximide, polymyxin B and inhibitors of NO synthase. Furthermore, dexamethasone inhibited the induction of NO synthase and the consequent effects on vascular tone. These findings indicate that prevention of the induction of NO synthase by glucocorticoids may be an important component of their therapeutic action.

Amino Acid Oxidoreductases↗
PubMed2003

Extracorporeal endotoxin removal for the treatment of sepsis: endotoxin adsorption cartridge (Toraymyxin).

Toray Industries Inc. has developed an endotoxin removal cartridge (Toraymyxin) composed of a polymyxin B immobilized, fibrous adsorbent. Toraymyxin has been listed as a blood purification medical device for endotoxin removal to be reimbursed by the Japanese national health insurance since 1994. Toraymyxin can be applied to patients with endotoxemia or suspected gram-negative infection, which fulfilll the conditions of Systemic Inflammatory Response Syndrome (SIRS) and have septic shock demanding vasopressor infusion. Since 1994, over 30,000 patients have received this treatment. The safety of this device has been confirmed and improvement of hemodynamic dysfunction has been shown to be a major benefit. Infection resulting from an acute abdominal condition requiring surgery has been shown to be one of the good indications for Toraymyxin. Further studies are now ongoing to establish Toraymyxin treatment as one of the options to treat sepsis and septic shock patients and to clarify the mechanisms involved in this therapy.

Adsorption↗
PubMed1992

Effectiveness of a human monoclonal anti-endotoxin antibody (HA-1A) in gram-negative sepsis: relationship to endotoxin and cytokine levels.

Gram-negative sepsis is caused by endotoxin-induced release of tumor necrosis factor (TNF) and other cytokines. HA-1A is a human monoclonal antibody that binds specifically to endotoxin. HA-1A should prevent death in endotoxemic patients and reduce serum levels of TNF and interleukin-6 (IL-6). This hypothesis was tested in 82 septic patients who were randomly allocated to receive a single intravenous 100-mg dose of HA-1A or placebo. Pretreatment endotoxemia was detected in 27 patients (33%). Death occurred within 28 days of treatment in 8 (73%) of 11 placebo recipients and in 5 (31%) of 16 HA-1A recipients (P = .02). The median decrease in serum TNF level 24 h after treatment was 12 ng/L in patients given HA-1A and 0 ng/L in placebo recipients (n = 65; P = .04). For IL-6, this was 204 ng/L in patients given HA-1A and 44 ng/L in placebo recipients (n = 67; P = .4). Thus, HA-1A reduces mortality in septic patients with endotoxemia and lowers serum TNF levels.

Adult↗
PubMed1986

Detection of endotoxin in mice by measurement of endotoxin-induced changes in plasma concentrations of zinc and of the acute-phase protein serum amyloid P-component.

Preparations of six bacterial endotoxins reduced plasma concentrations of zinc and increased concentrations of the acute-phase protein serum amyloid P component (SAP) in mice. The changes were sufficiently sensitive to permit use of either response in tests for endotoxin and hence for pyrogenic contamination.

Acute-Phase Proteins↗
PubMed2003

Inhibition of endotoxin response by e5564, a novel Toll-like receptor 4-directed endotoxin antagonist.

Alpha-D-glucopyranose,3-O-decyl-2-deoxy-6-O-[2-deoxy-3-O-[(3R)-3-methoxydecyl]-6-O-methyl-2-[[(11Z)-1-oxo-11-octadecenyl]amino]-4-O-phosphono-beta-D-glucopyranosyl]-2-[(1,3-dioxotetradecyl)amino]-1-(dihydrogen phosphate), tetrasodium salt (E5564) is a second-generation synthetic lipodisaccharide designed to antagonize the toxic effects of endotoxin, a major immunostimulatory component of the outer cell membrane of Gram negative bacteria. In vitro, E5564 dose dependently (nanomolar concentrations) inhibited lipopolysaccharide (LPS)-mediated activation of primary cultures of human myeloid cells and mouse tissue culture macrophage cell lines as well as human or animal whole blood as measured by production of tumor necrosis factor-alpha and other cytokines. E5564 also blocked the ability of Gram negative bacteria to stimulate human cytokine production in whole blood. In vivo, E5564 blocked induction of LPS-induced cytokines and LPS or bacterial-induced lethality in primed mice. E5564 was devoid of agonistic activity when tested both in vitro and in vivo and has no antagonistic activity against Gram positive-mediated cellular activation at concentrations up to 1 microM. E5564 blocked LPS-mediated activation of nuclear factor-kappaB in toll-like receptor 4/MD-2-transfected cells. In a mouse macrophage cell line, activity of E5564 was independent of serum, suggesting that E5564 exerts its activity through the cell surface receptor(s) for LPS, without the need for serum LPS transfer proteins. Similar to (6-O-[2-deoxy-6-O-methyl-4-O-phosphono-3-O-[(R)-3-Z-dodec-5-endoyloxydecl]-2-[3-oxo-tetradecanoylamino]-beta-O-phosphono-alpha-D-glucopyranose tetrasodium salt (E5531), another lipid A-like antagonist, E5564 associates with plasma lipoproteins, causing low concentrations of E5564 to be quantitatively inactivated in a dose- and time-dependent manner. However, compared with E5531, E5564 is a more potent inhibitor of cytokine generation, and higher doses retain activity for durations likely sufficient to permit clinical application. These results indicate that E5564 is a potent antagonist of LPS and lacks agonistic activity in human and animal model systems, making it a potentially effective therapeutic agent for treatment of disease states caused by endotoxin.

Animals↗
PubMed1990

Endotoxin-induced auto-immunity in mice. III. Comparison of different endotoxin preparations.

Six different endotoxin preparations derived from Escherichia coli and Salmonella typhimurium subspecies were compared as to their potencies to provoke auto-immune phenomena in mice. The numbers of spleen cells forming antibodies to bromelain-treated isologous erythrocytes or anti-DNA antibodies, the serum levels of these auto-antibodies, and the circulating immune complex titres were determined. As far as comparison on a weight base was concerned, S. typhimurium Re-mutant lipopolysaccharide appeared to be the most active preparation in inducing auto-antibody formation. Upon comparison of amounts with equal activity in the limulus amoebocyte lysate assay, however, S. typhimurium lipid A turned out to be the most potent. The contribution of O-type specific polysaccharides, phosphate groups, and the lipid A moiety to the potencies of the endotoxin preparations is discussed.

Animals↗
PubMed2004

Endotoxin recognition molecules MD-2 and toll-like receptor 4 as potential targets for therapeutic intervention of endotoxin shock.

Gram-negative sepsis is the major cause of deaths in intensive care units of hospitals and continues to increase worldwide due to the increased frequency of invasive procedures and therapy leading to immunosuppression. This syndrome is characterized by endothelial damage, coagulopathy, loss of vascular tone, tissue hypoperfusion, and multiple-organ failure. They are caused by uncontrolled, overwhelming inflammatory responses, which are triggered by microbial products. Amongst these products, endotoxin also called LPS (lipopolysaccharide), a constituent of the outer membrane of Gram-negative bacteria, is known to play a central role by eliciting immune responses leading to production of proinflammatory cytokines. Our understanding of LPS recognition has increased dramatically over the last several years by identification of Toll-like receptor 4 (TLR4) and MD-2 as LPS recognition molecules. TLR4 is a mammalian homologue of drosophila Toll. The extracellular domain of TLR4 is associated with a molecule called MD-2. Mice lacking either TLR4 or MD-2 do not respond to LPS and are resistant to endotoxin shock. Here, the potential for TLR4-MD-2 as target molecules for therapeutic intervention is discussed.

Animals↗
PubMedDate not supplied

Protective effect of radio-detoxified endotoxin (Tolerin) on the ultrastructure of pancreas in experimental endotoxin shock of rats.

The ultrastructural changes of pancreas exocrine cells were studied after the intravenous administration of endotoxin (LPS) or radio-detoxified endotoxin (150 kGy 60Co-gamma irradiated: RD-LPS or Tolerin). The LPS (1 mg/rat) induces an autolytic destruction in the membranes of the mitochondria of the pancreas exocrine cells. The RD-LPS given in similar dose does not produce any autolytic change. However, a small dose (100/micrograms/rat) of RD-LPS (Tolerin) as a pretreatment can protect the autolytic destruction of the mitochondria induced by LPS. This may be attributed to the membrane stabilizing effect of RD-LPS.

Animals↗
PubMed2006

[Study on the expression, purification and the anti-endotoxin activity of human endotoxin binding peptide and its mutant].

OBJECTIVE: To express endotoxin binding peptide and its mutant in E coli DH5alpha and detect the antiendotoxin activity of the purified peptides. METHODS: (1 ) E coli DH5at containing pinpointXa3-EBP and pinpointXa3-mEBP was activated by IPTG to express biotin fusion protein. The fusion proteins were purified, and then digested by factor Xa for isolation of EBP and mEBP. The target peptide was purified with affinity chromatography and reversed-phase HPLC. Sequences of 10 amino acids at N-terminal were used for identification of mEBP. (2) PBMCs were isolated from blood of normal people, and they were stimulated with 5 mg/L FITC-LPS plus 2.0,5. 0 and 12. 5 mg/L EBP or mEBP. Then the mean fluorescent intensity was detected. PBMC was also stimulated with 1 mg/L LPS plus 2.0, 5.0 and 12.5 mg/L EBP or mEBP for 5 hours for the detection of the TNF-alpha and IL-6 level in the supernatant. (3) Thirty-five Kunming mice were randomized into normal control ( n = 5, with intraperitoneal injection of 0. 2 ml isotonic saline) , model group(n = 5, with intraperitoneal injection of LPS and 20% TBSA full-thickness burns), and treatment group (n = 15, with intraperitoneal injection of 5 mg/kg PMB or 10 mg/kg EBP or mEBP after burns). The serum contents of TNF-a and IL-6, and TNF-alpha mRNA level in hepatic tissue in each group were determined 6 hours after treatment. RESULTS: ( 1 ) EBP and mEBP were obtained after Xa digestion of biotin fusion protein, with purity reaching above 98% . The sequence of 10 amino acid at N-terminal was in accord with what expected. (2) The fluorescent intensity was decreased followed by an increase in mEBP or EBP concentration. Compared with normal PMBC, IL-6 and TNF-alpha level in the supernatant were obviously lowered in 1 mg/L LPS + 12.5 mg/L EBP group and I mg/L LPS +2. O0 , 5. 0, 12. 5 mg/L mEBP groups ( P < 0.01). (3) The serum level of IL-6 and TNF-ca in the therapeutic groups were obviously lower than that in model group ( P < 0.01 ) , and the levels of these cytokines were significantly lower in 10 mg/kg mEBP group than that in 10 mg/kg EBP group ( P <0. 01) , but they were similar to that in 5 mg/kg PMB treatment group ( P >0.05). (4) Relative optical density of TNF-alpha. mRNA in control, model, 10 mg/kg mEBP, 10 mg/kg EBP and 5 mg/kg PMB groups was 0.25, 0.93, 0.51 , 0.77 and 0.43, respectively. CONCLUSION: Endotoxin binding peptides can be obtained by procaryon expression. Both EBP and mEBP have anti-LPS activity, but mEBP is more effective.

Animals↗
PubMed1986

Comparison of adjuvanticity and autoantibody inducing capacity of endotoxin and radio-detoxified endotoxin in mice.

Endotoxin (LPS) and radio-detoxified endotoxin (RD-LPS: 150 kGy 60Co-gamma irradiated) preparations were compared in mice (C57Bl X CBA: F1/Rapo) for capacity to enhance the immune response against sheep red blood cells and to induce the production of antibody against autologous (bromelain-treated) erythrocytes. As RD-LPS retains its capacity to stimulate immune response against heterologous antigen, it may be used as an immuno-adjuvant. The LPS preparation gave rise to a significant increase of autoreactive cells. However, RD-LPS activated the autoantibody forming cells only to a very small degree.

Adjuvants, Immunologic↗
PubMed1986

[Detection of endotoxins in radiopharmaceutical preparations--II. Comparison of the sensitivity of methods using the rabbit and the Limulus amoebocyte lysate for the detection of endotoxins].

The rise of the rabbit internal temperature after i.v. injection of an endotoxin solution is proportional to concentration. Gelation of Limulus amoebocyte, when in presence of an endotoxin solution, is also related to concentration. We compared the sensitivity of these two methods. With our experimental procedure, the rabbit is sensitive to a 0.40 ng/mL solution and the Limulus amoebocyte lysate to a 0.14 ng/mL solution. The rabbit sensitivity increase is related to the per kilogramme injected volume, whereas sensitivity is not related to the volume to check in the case of the lysate.

Animals↗
PubMed1994

Endotoxin-binding synthetic peptides with endotoxin-neutralizing, antibacterial and anticoagulant activities.

Endotoxin(lipopolysaccharide = LPS), cell wall component of gram-negative bacteria, activates monocytes and macrophages to release cytokines, reactive nitrogen intermediates (RNI), and to generate tissue factor(TF) which initiate coagulation. We have purified 7kDa and 18kDa cationic antibacterial proteins (CAP-7 and CAP-18) with LPS-binding and LPS-neutralizing activities from rabbit granulocytes using as an assay the agglutination of erythrocytes coated with Re-LPS. From protein sequencing, CAP-7 was identified as the C-terminal 37 amino acid fragment of CAP-18. Synthetic peptide #197 (identical sequence to CAP-7, Gly1-Try37) and #36-1 (a truncation of CAP consisting of 32 amino acid residues, Gly1-Ala32) showed LPS-binding activity. Each peptide inhibited LPS-induced tissue factor(TF) generation by murine peritoneal macrophages, even added 1-3 hours after stimulation of cells with LPS. C57BL/6 mice treated with #197 were significantly protected from lethal LPS challenge. Peptide #36 also blocked the LPS-induced lethality. These peptides had antibacterial activity to gram-negative bacteria, such as E.coli, S.typhimurium, K.pneumonia, Ps.aeruginosa and also to gram-positive S.aureus (Methicillin sensitive and resistant strains). Both peptides inhibited TF- and Xa-induced plasma clotting. Using synthetic chromotogenic substrates, both CAP7 peptides blocked the coagulation cascade at two sites, activation of factor X to Xa and conversion of Factor II (prothrombin) to factor IIa (thrombin). In vivo treatment of peptide #197 prevented acute lethality in mice injected with tissue factor (rabbit brain thromboplastin). Two other peptides, #32(Gly1-Phe9) and #50(Ile13-Typ37) failed to demonstrate LPS-binding, LPS-neutralizing, antibacterial and anticoagulant activities. The active peptides but not the inactive peptide maintain a putative heparin binding domain at their N-termini. This heparin binding domain is participate in the LPS-binding, LPS neutralizing, antibacterial and anticoagulant activities of CAP7. These active peptides may have a therapeutic potential for treatment for DIC due to sepsis and endotoxin shock.

Amino Acid Sequence↗