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PubMed1992

Endotoxin concentration in neutropenic patients with suspected gram-negative sepsis: correlation with clinical outcome and determination of anti-endotoxin core antibodies during therapy with polyclonal immunoglobulin M-enriched immunoglobulins.

We carried out a study in patients with severe neutropenia from hematologic malignancy and suspected gram-negative sepsis to evaluate the clinical significance of endotoxin concentrations in plasma before and during a therapeutic intervention with a human polyclonal immunoglobulin M (IgM)-enriched immunoglobulin preparation (Pentaglobin; Biotest, Dreieich, Germany). Twenty-one patients with acute leukemia or non-Hodgkin's lymphoma entered the study upon the development of clinical signs of gram-negative sepsis and received the IgM-enriched immunoglobulin preparation every 6 h for 3 days (total dose, 1.3 liter with 7.8 g of IgM, 7.8 g of IgA, and 49.4 g of IgG), in addition to standardized antibiotic treatment. Concentrations of endotoxin and IgM and IgG antibodies against lipid A and Re lipopolysaccharide (LPS) in plasma were determined by a modified chromogenic Limulus amebocyte lysate test and semiquantitative enzyme linked immunosorbent assay, respectively, before each immunoglobulin infusion and during the following 25 days. Seventeen patients were endotoxin positive; in five of these patients, gram-negative infection was confirmed by microbiologic findings. Prior to therapy, endotoxemia correlated significantly with the occurrence of fever, and a quantitative correlation between the endotoxin concentration and body temperature was found during the individual course of infection in 8 of the 17 patients. Overall mortality from endotoxin-positive sepsis was 41% (7 of 17) and 64% (7 of 11) in patients with symptoms of septic shock. Nonsurvivors had significantly higher maximum concentration of endotoxin in plasma compared with those of survivors at the first study day (median of 126 versus 34 pg/ml; P < 0.05) and during the whole septic episode (median of 126 versus 61 pg/ml; P < 0.05). In survivors, immunoglobulin therapy resulted in a significant decrease in endotoxin levels in plasma within the initial 18-h treatment period, from a pretreatment median value of 28 pg/ml to a value of 8 pg/ml (P< 0.05). In the seven patients who died from uncontrollable infection, no effect of therapy on endotoxin levels in plasma was observed. IgM and IgG antibodies against lipid A and Re LPS increased significantly under immunoglobulin treatment, with significant correlations between antibodies against lipid A and Re LPS. These data strongly suggest a prognostic significance of the endotoxin levels in plasma and a potential effect of treatment with a polyclonal IgM-enriched immunoglobulin preparation. Further studies are needed to substantiate these findings and to assess the impact on the clinical course by way of a prospective placebo-controlled clinical trial.

Adult↗
PubMed1992

[Plasma endotoxin measured by the combination of new perchloric acid pretreatment method and endotoxin specific assay in liver cirrhosis].

Using with the newly modified perchloric acid pretreatment method and endotoxin specific assay (Endospecy), the plasma endotoxin in the patients with liver cirrhosis was investigated. The mean value of plasma endotoxin in control (n = 20) was below 9.8 pg/ml. The plasma endotoxin level in liver cirrhosis was 5.7 +/- 5.3 pg/ml (n = 70, mean +/- SD), and 20% of the patients (15 cases) showed above 9.8 pg/ml. Endotoxin level significantly correlated with the severity of liver function based on the Child-Turcotte classification (p less than 0.01). Plasma endotoxin positively correlated with total bilirubin (r = 0.417) and ICG clearance test (r = 0.298) and negatively correlated with prothrombin time (%) (r = 0.497) and HDL-cholesterol (r = 0.578) in the patients with liver cirrhosis. There was no correlation between esophageal varices and plasma endotoxin level. Plasma endotoxin was slightly detected in the patients with decompensated cirrhosis, and these data suggest that plasma endotoxin level in cirrhosis is not so elevated.

Bilirubin↗
PubMed1982

Binding of 125I-labeled endotoxin to bovine, canine, and equine platelets and endotoxin-induced agglutination of canine platelets.

Endotoxin from Escherichia coli O127:B8, Salmonella abortus-equi and S minnesota induced clumping of some canine platelets (PLT) at a final endotoxin concentration of 1 microgram/ml. Endotoxin-induced clumping of canine PLT was independent of PLT energy-requiring processes, because clumping was observed with canine PLT incubated with 2-deoxy-D-glucose and antimycin A. The PLT responded to adenosine diphosphate before, but not after, incubation with the metabolic inhibitors. Endotoxin induced a slight and inconsistant clumping of bovine and equine PLT at high (mg/ml) endotoxin concentration. High-affinity binding sites could not be demonstrated on canine, bovine, and equine PLT, using 125I-labeled E coli O127:B8 endotoxin. Nonspecific binding was observed and appeared to be due primarily to an extraneous coat on the PLT surface that was removed by gel filtration. The endotoxin that was bound to PLT did not appear to modify PLT function. An attempt to identify plasma proteins that bound physiologically relevant amounts of endotoxin was not successful. The significance of the endotoxin-induced clumping or lack of it on the pathophysiology of endotoxemia is discussed.

Agglutination↗
PubMed1994

Macrophage endotoxin tolerance: effect of TNF or endotoxin pretreatment.

Macrophages pretreated with low-dose endotoxin [lipopolysaccharide (LPS1)] have an altered response to subsequent endotoxin (LPS2) stimulation, a process known as endotoxin tolerance. In this study we investigated whether the LPS1 pretreatment effects were mediated primarily via tumor necrosis factor (TNF alpha). Murine peritoneal macrophages were pretreated in vitro with either TNF alpha or LPS1 and the effects on mediator production in response to a second endotoxin exposure, LPS2, were compared. Mediators in macrophage supernatant were measured using specific bioassays [TNF, interleukin-1 (IL-1), and IL-6] or enzymatic immunoassays [prostaglandin E2 (PGE2) and TNF]. Macrophage production of all mediators was stimulated by endotoxin in the absence of LPS1 pretreatment. Pretreatment with LPS1 completely inhibited LPS2-triggered TNF release whereas preexposure to TNF alpha had no effect. In contrast, LPS1 pretreatment significantly augmented IL-1 and PGE2 release in response to LPS2, whereas pretreatment using either high- or low dose TNF alpha did not. TNF, stimulated by an initial exposure to endotoxin, LPS1, is not solely responsible for the observed alterations in macrophage mediator release following a subsequent endotoxin stimulus (LPS2). Thus, the data suggest that endotoxin tolerance is mediated primarily by factors other than TNF.

Animals↗
PubMed1984

Are the decreases in hepatic cytochrome P-450 and other drug-metabolising enzymes caused by indomethacin in vivo mediated by intestinal bacterial endotoxins? 16,16-Dimethylprostaglandin F2 alpha prevents decreases in hepatic drug-metabolising enzymes due to exogenous endotoxin.

Administration of either indomethacin (8.5 mg/kg) or E. coli endotoxin (3.5 mg/kg) to rats caused significant decreases in a variety of drug-metabolising enzyme activities. Either agent markedly decreased biphenyl 4-hydroxylase by 72-80% and caused lesser decreases (21-64%) in cyt. P-450, aminopyrine N-demethylase, ethoxyresorufin O-deethylase (EROD), benzyloxyphenoxazone O-debenzylase (BPOD), cyt. b5, NADPH-cyt. c reductase, NADH-cyt. b5 reductase, epoxide hydrolase (EH) and glucuronyl transferase (GT). The decreases in GT (21-22%) were significantly less than in cyt. P-450 (45-57%). Sulphotransferase was not affected by either indomethacin or endotoxin. The overall pattern of relative decreases in the different enzymes was similar for either indomethacin or endotoxin. Four activities, however, were affected to a significantly greater extent by indomethacin than by endotoxin at 2-6 mg/kg: EROD, BPOD, cyt. b5 and EH. Additionally, hepatic glutathione was decreased by indomethacin but not by endotoxin. Indomethacin or endotoxin caused similar but not identical decreases in selected protein bands in the "cyt. P-450 region" of microsomal SDS-polyacrylamide gel electrophoretograms. Concomitant administration of 16,16-dimethylprostaglandin F2 alpha afforded significant (50-100%) protection against all the above-mentioned effects of indomethacin or endotoxin. The effects of indomethacin on cyt. P-450 were lessened by concomitant administration of a mixture of neomycin, polymyxin B and bacitracin. Throughout the study there was a close correlation between the extent of decrease in hepatic cyt. P-450 and the degree of intestinal ulceration caused by indomethacin. It was concluded that bacterial endotoxins liberated into the portal blood as a result of indomethacin-induced ulceration of the small intestine probably only partially mediated the effects of indomethacin on hepatic drug-metabolising enzymes. The protection afforded by 16,16-dimethylprostaglandin F2 alpha could have been due to both the prevention of ulceration and to a direct cytoprotective effect on the liver.

Animals↗
PubMedDate not supplied

High in vitro endotoxin responsiveness of macrophages from an endotoxin-resistant wild rodent species, Sigmodon hispidus.

It has been reported that macrophages primarily mediate endotoxin shock and cell death by synthesizing and releasing cytokines, largely tumor necrosis factor (TNF) and interleukin-1 (IL-1). However, macrophages from some laboratory mouse strains such as C3h/HeN are unresponsive to endotoxin both in vivo and in vitro. We found members of a wild rodent species, Sigmodon hispidus, to also be extremely resistant to bacterial endotoxin challenge. Intravenous administration of up to 100,000 micrograms/kg body mass of Escherichia coli O26:B6 endotoxin did not cause lethality in adult S. hispidus. In contrast to the endotoxin-resistant mouse strain, peritoneal macrophages derived from S. hispidus were responsive to in vitro endotoxin challenge as measured by high levels of TNF and IL-1 activity in supernatants of macrophage cultures. Thus, in vitro macrophage responsiveness to endotoxin does not always indicate high host sensitivity to endotoxin challenge.

Animals↗
PubMed2004

Evaluation of the bacterial endotoxin test for quantification of endotoxin contamination of porcine vaccines.

We investigated the application of the bacterial endotoxin test for the quantification of the endotoxin contamination of various commercial porcine vaccines. In endotoxin-spiked samples, Freund's complete adjuvant and aluminum hydroxide gel adjuvant failed to interfere with the results of the endotoxin test, and both recovery ratios were within the permissible range mentioned in the Japanese Pharmacopoeia. At the various dilutions tested, none of the adjuvants in commercial porcine vaccines caused noteworthy interference in the test. In addition, none of the 39 samples of porcine vaccines approved in Japan induced an interfering effect in the endotoxin test. Our findings suggest that the bacterial endotoxin test using endotoxin-specific Limulus amoebocyte lysate (LAL) can detect endotoxin contamination in commercial porcine vaccines containing either oil or aluminum adjuvants.

Aluminum Hydroxide↗
PubMed2001

Endotoxin release and endotoxin neutralizing capacity during colonoscopy.

In 38 patients who underwent elective colonoscopy, endotoxin and endotoxin neutralizing capacity (ENC) were determined by use of the limulus--amebocyte--lysate test. A control group of 10 patients, prepared for colonoscopy, were sampled in the same manner as the study group prior to endoscopy. Elevated endotoxin plasma levels were only found when comparing the plasma levels before endoscopy with the highest levels available during endoscopy. The timed endotoxin plasma levels did not change significantly by use of the conventional limulus amebocyte test. However, ENC was found to decrease significantly 5 min after the onset of endoscopy. Maximal values were reached at the end of colonoscopy which recovered completely 24 h later. These results, obtained in a population which did not receive any infusions, demonstrate that the half life of endotoxin in the circulation seems to be very short and therefore endotoxin cannot itself be detected. On the other hand, small amounts of endotoxin reaching the blood stream are able to reduce ENC which can be analyzed by a modified limulus--amebocyte--lysate test. With the use of ENC and plasma endotoxin determinations, we are able to show significant endotoxemia during a minimal invasive procedure such as colonoscopy.

Adult↗
PubMedDate not supplied

Differentiation between endotoxin and non-endotoxin pyrogens in human albumin solutions using an ex vivo whole blood culture assay.

Purified E.coli endotoxin, Gram negative bacteria and Gram positive bacteria induce IL-6 secretion by whole blood cultures (WBC's). Polymyxin B at concentrations greater than 2 U/ml completely inhibits IL-6 secretion caused by 10 EU/ml of endotoxin. Polymyxin B has no effect on IL-6 secretion by WBC's in the absence of endotoxin. The inhibition of endotoxin induced IL-6 secretion is Polymyxin B concentration dependent at concentrations less than 1 U/ml. IL-6 induction caused by E.coli is only partially inactivated by 8 U/ml Polymyxin B. Polymyxin B has no effect on IL-6 secretion caused by B.subtilis. Two pyrogenic batches of human serum albumin (HSA), as tested by the rabbit assay for pyrogens, were also investigated. Polymyxin B at 4 U/ml inhibits less than 40 % of IL-6 secretion caused by these pyrogenic HSA batches. All the endotoxin activity in HSA samples spiked with purified endotoxin is inhibited by Polymyxin B indicating that HSA does not protect endotoxin against Polymyxin B inhibition. These results indicate that the pyrogenicity of these HSA batches are caused by Polymyxin B inhibitable and non-inhibitable fractions. This study shows that pyrogenic substances other than endotoxin can contaminate batches of pharmaceutical products and that results obtained using the Limulus Amoebocyte Lysate (LAL) assay does not necessarily indicate the pyrogenic status of pharmaceutical products. The WBC assay for pyrogens, having a broader sensitivity range than the LAL assay, is a better indicator of the pyrogenic status of pharmaceutical products.

Animals↗
PubMed1961

Biological properties of parent endotoxins and lipoid fractions, with a kinetic study of acid-hydrolyzed endotoxin.

The biological potencies of a number of lipid fractions separated from endotoxins by acid hydrolysis, including the material known as lipid A, were determined in parallel with those of their parent endotoxins, employing bio-assays based on the following dose-related host responses: fever, resistance to infection, tumor damage, primary inflammation of skin, and lethality. Without exception, lipid fractions dispersed by detergents exerted less than 1 per cent of the biological activity of the potent endotoxins from which they were derived. A study was made of the rate at which biologic activities diminished in relation to the release of bound lipid during progressive hydrolysis of Salmonella enteritidis endotoxin with dilute acid. Each of the five assays for endotoxin revealed that biological activity had been reduced to negligible proportions prior to any significant liberation from the endotoxin of water-insoluble firmly bound lipid. The major pharmacological activity of endotoxins, therefore, is acid-labile and cannot be accounted for in isolated lipids. This conclusion is also supported by the finding that lipids with activity similar to that of lipid A could be obtained by non-hydrolytic methods without diminishing the potency of the parent endotoxins.

Antitoxins↗
PubMed2001

Prediction of clinical outcome after cardiac surgery: the role of cytokines, endotoxin, and anti-endotoxin core antibodies.

Coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) can lead to a systemic inflammatory response syndrome with organ failure and increased morbidity and mortality. The mechanisms of these findings are still under discussion. We investigated whether anti-endotoxin core antibodies, endotoxin, and proinflammatory cytokines influence the clinical course after cardiac surgery. Seventy-eight patients undergoing CABG using CPB were investigated. Anti-endotoxin core antibodies, endotoxin, interleukin (IL)-6, IL-8, IL-1beta, and TNF-alpha were measured 24 h preoperatively and up to 72 h postoperatively. Patients with a postoperative mechanical ventilation time below 24 h (n = 65; Group A) were compared to patients with prolonged respirator therapy (>24 h; n = 13; Group B). Preoperative antibody levels were significantly lower in Group B (P < 0.001). In this group, antibody levels remained decreased during the observation period (P < 0.001). Endotoxin significantly increased 30' postoperatively in both groups (P < 0.002). The increase in Group B was 3-fold higher (P< 0.001). IL-8 increased postoperatively in both groups, peaking 3 h after surgery (P < 0.001). In Group B, the IL-8 release was significantly higher than in Group A (P < 0.001). IL-6 significantly increased in both groups, reaching its maximum 24 h postoperatively (P < 0.001). No differences between groups were observed. No significant changes of IL-1beta and TNF-alpha were observed. We conclude that anti-endotoxin core antibodies may be predictive of adverse outcome after cardiac surgery. The imbalance between antibodies and endotoxin results in an exaggerated increase in endotoxin and IL-8 with an impact on clinical outcome.

Aged↗
PubMed1985

Comparison of several control standard endotoxins to the National Reference Standard Endotoxin--an HIMA collaborative study.

A collaborative study, initiated under the auspices of the Health Industry Manufacturers Association (HIMA), was designed to establish the relationship of Escherichia coli O55:B5 endotoxin (the control standard endotoxin of HIMA and the Food and Drug Administration's Office of Medical Devices) to the U.S. National Reference Standard Endotoxin and to two internationally used control standard endotoxins. By using two Limulus amoebocyte lysate test systems, it was established that the E. coli O55:B5 endotoxin lot originally used by HIMA and the Office of Medical Devices to establish Limulus amoebocyte lysate release test criteria for pyrogen testing of medical devices contains approximately 4.5 endotoxin units (EU) per ng. Thus, the 1.0-ng/kg endotoxin dose limit currently established for medical devices is approximately the same as the 5.0-EU/kg endotoxin limit (on an activity basis) established by several other Food and Drug Administration agencies for human and animal parenteral drugs and biological products.

Endotoxins↗
PubMed1966

Reaction of endotoxin and surfactants. I. Physical and biological properties of endotoxin treated with sodium deoxycholate.

Ribi, E. (Rocky Mountain Laboratory, Hamilton, Mont.), R. L. Anacker, R. Brown, W. T. Haskins, B. Malmgren, K. C. Milner, and J. A. Rudbach. Reaction of endotoxin and surfactants. I. Physical and biological properties of endotoxin treated with sodium desoxycholate. J. Bacteriol. 92:1493-1509. 1966.-Endotoxins from three species of gram-negative bacteria were shown to be dissociated by the bile salt sodium deoxycholate (NaD) into nontoxic subunits with molecular weights of about 20,000. When the bile salt was removed by dialysis, the subunits reaggregated in an orderly manner to form a relatively uniform population of biologically active endotoxin particles with average molecular weights of 500,000 to 1,000,000. If a small amount of human plasma was added to the dissociated endotoxin before removal of the NaD, reassociation apparently did not occur and the preparation remained nonpyrogenic. However, the plasma protein could subsequently be removed from the endotoxin subunits, and reaggregation to the toxic form would then occur. The studies on the physical nature of endotoxin performed with biophysical solution techniques were supplemented and confirmed by direct examination of the endotoxin polymers by electron microscopy. The results of these studies were consonant with the theory that the biologically active endotoxic elements are composed of micellar aggregates of linear lipopolysaccharide subunits.

Animals↗
PubMed2002

Inhibition of histone deacetylation enhances endotoxin-stimulated transcription but does not reverse endotoxin tolerance.

Covalent modification of histones and the subsequent remodeling of chromatin have emerged as important mechanisms in regulating gene expression. In particular, recent identification of the enzyme families responsible for the steady-state balance of histone acetylation has served to redefine our understanding of these modifications as fundamental biochemical processes regulating transcription. Current evidence suggests that histone acetylation correlates positively with gene activation, while histone deacetylation acts to repress transcription. In this study, we examined the role of histone modification in the inflammatory response to endotoxin. We focused on the endotoxin-stimulated expression of the interleukin-1beta promoter and tested the hypotheses that persistent histone deacetylation was responsible for the decreased expression of this promoter observed after prolonged exposure to endotoxin, a manifestation of a phenomenon known as endotoxin tolerance. We found that histone deacetylase inhibitors enhanced endotoxin-stimulated transcription; however, deacetylation inhibitors could neither block the development of tolerance nor restore endotoxin sensitivity in a tolerant cell. Deacetylase inhibitors could not restore LPS-mediated transcription in tolerant cells. These results show that histone acetylation/deacetylation regulates, at least in part, the endotoxin-induced expression of inflammatory genes and that repressed transcription observed in endotoxin tolerance is not caused by enhanced activity of histone deacetylases.

Blotting, Northern↗
PubMed1992

Both the polysaccharide and lipid A parts of endotoxins are needed for the inhibitory effects of endotoxins on cellular LDL uptake.

We previously reported that endotoxins inhibit low-density lipoprotein (LDL) uptake and degradation in Hep G2 cells. In the present study, we tried to elucidate which part(s) of the endotoxin molecules contribute(s) to the inhibitory effect of endotoxins on LDL uptake and degradation. The results show that the endotoxin isolated from Salmonella minnesota Re595 (Re mutant), which lacks polysaccharide, had no effect on the uptake and degradation of 125I-labelled LDL in Hep G2 cells. This mutant form also decreased the inhibitory effects of endotoxins which have complete polysaccharides on cellular LDL uptake and degradation. However, the polysaccharide part of endotoxins by itself had no effect on LDL catabolism by the cells. This suggests that both the polysaccharide and the lipid A parts of endotoxins are needed for the inhibitory effects of endotoxins on LDL uptake and degradation.

Endotoxins↗
PubMed1974

Studies with radioactive endotoxin. I. Clearance of 51Cr-labelled endotoxin from the blood of calves.

The clearance of (51)Cr-labelled Pseudomonas endotoxin from the blood was studied in calves in a nontolerant and in an endotoxin-tolerant state. Calves were rendered tolerant to the toxic effects of the endotoxin by four daily intravenous injections of endotoxin at the dose rate of 5 microg/kg body weight. Clearance of a small amount of (51)Cr-endotoxin from the blood of nontolerant calves was almost complete within three minutes of injection and was not significantly faster in tolerant calves. The lungs and liver were the major organs involved in clearance of endotoxin from the blood. The (51)Cr label was slowly excreted by the kidneys. Neither platelets nor leukocytes were demonstrated to participate in endotoxin clearance in calves. (51)CrCl(3) was injected into control calves. Relative to the distribution and loss of labelled endotoxin, the (51)CrCl(3) was cleared slowly from the blood, was distributed uniformly throughout the body and was excreted rapidly.

Animals↗