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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↗

PubMed1974

Studies with radioactive endotoxin. II. Clearance of 3H-labelled endotoxin from the blood of calves.

The clearance of (3)H-labelled Pseudomonas endotoxin from the blood was studied 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 (3)H-endotoxin from the blood of nontolerant calves occurred more slowly than did clearance of (51)Cr-endotoxin and was not significantly (P<0.05) affected by the development of tolerance. The lungs and liver were the major organs involved in the clearance of (3)H-endotoxin from the blood of calves. Leukocytes and erythrocytes, but not platelets, were shown to participate in endotoxin clearance in calves. (3)H(2)O, the control substance used in calves, was not concentrated within any particular organ but rapidly equilibrated with total body water and was slowly excreted.

Animals↗

PubMed1982

In vitro effect of endotoxin from Shigella sonnei. phase I on human blood platelets and mononuclear leucocytes: comparison of "free endotoxin" with cell-extracted preparations.

The in vitro effect of a purified endotoxin preparation from culture fluids of Shigella sonnei, phase I (purified free endotoxin, PFE) and of three endotoxin preparations chemically extracted from the intact parent cells on human blood mononuclear leucocytes and platelets was investigated. PFE, like cell-extracted preparations, caused generation of strong procoagulant activity (tissue factor) by human mononuclear cells. PFE-stimulated cells, however, developed significantly greater activity than cells stimulated by the other endotoxins. they had about 4-fold more activity. Neither free nor cell-extracted preparations induced aggregation in human citrated or heparinized platelet-rich plasma (PRP) or unmasking of platelet factor 3 (PF3). These findings suggest that free endotoxin from Shigella sonnei, phase I resembles endotoxin extracted from cells by conventional procedures in their interaction with human platelets and mononuclear leucocytes. In view of the possible contribution of free endotoxin to endotoxemia in human and experimental gram-negative sepsis, our data that free endotoxin stimulates human mononuclear leucocytes to produce a potent trigger of blood coagulation (tissue factor) may be relevant to the understanding of the mechanism(s) responsible for the initiation of intravascular coagulation in severe human infections.

Blood Platelets↗

PubMed1976

Cholestatic effects of Escherichia coli endotoxin endotoxin on the isolated perfused rat liver.

The effects of Escherichia coli endotoxin on the function of the ex vivo perfused rat liver were examined in order to investigate the possible role of circulating endotoxin in the pathogenesis of cholestatic jaundice observed in humans with gram-negative bacterial infections. Endotoxin led to a dose-dependent impairment of bile flow and of sulfobromophthalein (BSP) excretion. The demonstration that indocyanine green excretion was also significantly decreased by endotoxin suggests that the impaired dye excretion was not due to an inhibition of BSP conjugation in the hepatocyte. Analysis of the kinetic data suggested that the effects of endotoxin were on the excretory mechanisms of the hepatocyte. These effects did not seem attributable to endotoxin-mediated changes in perfusate flow since a mechanical reduction in perfusate flow caused no decrease in the excretion of bile or BSP. The results of the present study provide supportive evidence for the hypothesis that circulating endotoxin can adversely affect hepatic function and may contribute to the production of intrahepatic cholestasis seen during bacterial infection. Hepatocyte injury by endotoxin, as judged by the leakage of enzymes from hepatocyte suspensions or from the perfused rat liver, could not be demonstrated.

Animals↗

PubMed1994

Polyclonal B cell activation, endotoxin tolerance, and limulus tests of endotoxin preparations of some periodontopathogens.

Potencies of polyclonal B-cell activation in C3H/HeN mice of Actinobacillus actinomycetemcomitans, Fusobacterium nucleatum, and Porphyromonas gingivalis endotoxins were 0.36, 0.13 and 0.04, taking Salmonella abortusequi as 1.0. F. nucleatum and P. gingivalis endotoxins showed positive reactions in C3H/HeJ mice. Most activities in C3H/HeN other than that of F. nucleatum were suppressed by polymyxin B. In C3H/HeJ mice, similar inhibitions were only 60% for P. gingivalis and hardly observed with F. nucleatum. The resistances to polymyxin B could be due to protein in the endotoxins. A promoting effect of T cells added to B cells was observed only in the activity of F. nucleatum endotoxin in C3H/HeJ mice; there was no influence in other groups. Test endotoxins had nearly the same ability to produce colony stimulating factor as did references and could not produce the factor in tolerant mice. The clinical significance of tolerance is discussed. Regression lines of endotoxin doses and limulus activities of test endotoxins and Salmonella were parallel, either in specific or non-specific tests. The lines of two test groups were also parallel; values obtained by two tests were very close. These data indicate that the test endotoxins did not contain (1-3)-beta-D-glucan and elicited qualitatively similar limulus reactions to that of the reference, despite their different chemical natures. In conclusion, these test preparations had an endotoxicity similar to that of the reference and contribute to produce periodontitis through polyclonal B cell activation.

Aggregatibacter actinomycetemcomitans↗

PubMed2001

Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease.

BACKGROUND: Chronic alcohol ingestion leads to endotoxemia which is believed to play an important role in the pathogenesis of alcoholic liver disease (ALD). The purpose of this study was to determine if chronic ethanol consumption, in addition to affecting plasma endotoxin and cytokines, also affects the endotoxin-neutralizing capacity (ENC), sCD14, and sICAM-1, in patients with ALD. A second aim was to identify correlations between these latter parameters, endotoxin, and cytokines, especially IL-10. METHODS: Hospitalized patients with various degrees of ALD (n = 59), and 20 healthy volunteers were studied. Plasma endotoxin and ENC were determined using our kinetic Limulus amebocyte lysate test. Cytokines, sCD14, and sICAM-1 were measured by enzyme-linked immunosorbent assay. RESULTS: Patients with ALD exhibited a mild endotoxemia (p < 0.01) and a marked decrease in ENC (p < 0.0002). TNF-alpha (p < 0.05), IL-6 (p < 0.0001), sICAM (p < 0.005), and sCD14 (p < 0.0005) were significantly elevated in all patients with ALD, and IL-10 (p < 0.05) in patients with cirrhotic ALD. With the exception of IL-10, the cytokines correlated with each other and with sICAM-1. No correlations occurred between endotoxin, ENC, and sCD14, and between these and the cytokines and sICAM-1. Elevated levels of endotoxin correlate with acute excessive alcohol ingestion. No gender differences were observed. CONCLUSIONS: Acute alcohol intoxication rather than severe ALD results in significant endotoxemia. The limited capacity of plasma to neutralize endotoxin in liver injury seems to be an important factor in ALD which may be responsible for the release of endotoxin-induced mediators, such as cytokines, as well as s-ICAM-1, that are relevant in the pathogenesis of ALD.

Alcoholic Intoxication↗

PubMed1965

MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS. II. PASSIVE TRANSFER OF IMMUNIY TO BACTERIAL ENDOTOXIN WITH FRACTIONS CONTAINING 19S ANTIBODIES.

Serum from rabbits rendered tolerant or immune to 100 MPD-3/kg of endotoxin when passively transferred to normal rabbits gave partial tolerance to the standard dose of endotoxin. The same serum was fractionated by DEAE chromatography into 4 major fractions. Immunoelectrophoretic analysis indicated that the 7S gamma(2)-and the 19S gamma(1)-immunoglobulins were separated into two distinct fractions. Of the four fractions tested, only fraction IV containing 19S gamma(1)-immunoglobulm conferred complete pyrogenic tolerance to 100 MPD-3/kg of endotoxin. Additional fractionation of DEAE fraction IV by exclusion chromatography on sephadex G-200 gave 3 fractions. Of these only the first, containing 19S gamma(1)-immunoglobulin conferred complete pyrogenic and lethal tolerance to normal rabbits. There was no correlation between the quantity of O-specific antibodies and the ability to transfer tolerance. It is concluded that endotoxin tolerance involves a classical immune mechanism which includes both 19S gamma(1)-immunoglobulin specific for toxophore groups common to many endotoxins and a normally functioning RES. To avoid confusion with immunologic tolerance, it is suggested that the term endotoxin immunity be substituted for endotoxin tolerance.

Animals↗

PubMed2005

Effects of postoperative enteral immune-enhancing diet on plasma endotoxin level, plasma endotoxin inactivation capacity and clinical outcome.

This study examined the postoperative plasma endotoxin level, plasma endotoxin inactivation capacity and clinical outcome after administration of an enteral diet supplemented with glutamine, arginine and omega-3-fatty acid in patients undergoing gastrointestinal operations on an prospective, randomized and double-blind design. 40 patients undergoing gastrointestinal operations were randomized into two groups, with each having 20 patients. One group received standard enteral nutrition and the other was fed the formulation supplemented with glutamine, arginine and omega-3-fatty acid. The two groups were isonitrogenous. The infusion was started from day 1 after surgery and continued for 7 days. Blood samples were collected on the morning of day 1 before operation and on the morning of 1, 4 and 7 day(s) after operation and analyzed for plasma endotoxin level and endotoxin inactivation capacity (EIC). Our study found no differences between the two groups on plasma endotoxin level. After surgery a rapid reduction in plasma endotoxin inactivation capacity was observed in both groups, a significant recovery of the plasma endotoxin inactivation capacity was observed on morning of day 4 after surgery in the study group (0.12 +/- 0.02 EU/mL and 0.078 +/- 0.022 EU/mL respectively, P < 0.01). Shortened hospital stay was observed in the experimental group (11.7 +/- 2.0 days in the control group and 10.6 +/- 1.2 days in the experimental group respectively, P = 0.03). It is concluded that perioperative parenteral nutrition supplemented with glutamine, arginine and omega-3-fatty acid ameliorated postoperative immunodepression but without direct effect on endotoxemia.

Adult↗

PubMed1985

Induction of tolerance in mice and rats to the effect of endotoxin to decrease the hepatic microsomal mixed-function oxidase system. Evidence for a possible macrophage-derived factor in the endotoxin effect.

Daily administration of low, non-lethal doses of bacterial endotoxin to mice and rats has been shown to induce tolerance to the effect of an acute challenge dose of endotoxin to decrease the hepatic microsomal drug metabolizing activity, the level of cytochrome P-450, and to increase heme oxygenase activity. The serum collected at various times after injection of endotoxin into control animals when injected into untreated animals markedly depressed aniline hydroxylase activity, ethylmorphine N-demethylase activity, and the level of cytochrome P-450. Tolerant animals were not affected by the post-endotoxin serum injection, suggesting the decreased activity caused by the serum in untreated animals was probably due to endotoxin contained in the serum. Injection of tolerant mice and rats with supernatant medium obtained from cultures of peritoneal macrophages incubated with 100 micrograms/ml of endotoxin caused a loss of hepatic microsomal drug-metabolizing activity, and a decrease in the level of cytochrome P-450. These results suggest that peritoneal macrophages release a factor in response to endotoxin that mediates the decreased hepatic mixed-function oxidase activity.

Animals↗

PubMed1994

Effect of a recombinant endotoxin-neutralizing protein on endotoxin shock in rabbits.

OBJECTIVES: Limulus anti-lipopolysaccharide factor, an 11.8-kilodalton peptide isolated from amebocytes of Limulus polyphemus inhibits the biologic activities of endotoxin in vitro, including gelation of Limulus amebocyte lysate. A recombinant version of Limulus anti-lipopolysaccharide factor, termed endotoxin neutralizing protein, has now been expressed in yeast. Endotoxin-neutralizing protein was evaluated for its potential prophylactic and therapeutic effects in rabbits challenged with Escherichia coli endotoxin. DESIGN: Controlled animal trial. SETTING: Animal research laboratory. SUBJECTS: A total of 112 New Zealand white rabbits were studied. INTERVENTIONS: Rabbits were challenged with an LD80 dose of E. coli endotoxin (100 micrograms/kg); control animals (n = 52) were treated with saline solution at the time of endotoxin challenge; experimental animals received endotoxin-neutralizing protein 2.5 mg/kg prechallenge (n = 20), 5.0 mg/kg prechallenge (n = 20), or 5.0 mg/kg 30 mins postchallenge (n = 20).

Animals↗

PubMed2000

Endotoxin inducible transcription is repressed in endotoxin tolerant cells.

Stimulation of the human promonocytic cell line, THP-1, with endotoxin results in a rapid and transient increase in interleukin 1beta expression. Endotoxin pretreatment of THP-1 cells results in tolerance, characterized by decreased levels of endotoxin-induced interleukin 1beta expression due to decreased transcription of the interleukin 1beta gene. We hypothesized that tolerant cells could not activate transcription factors necessary to express the interleukin 1beta gene. This hypothesis was tested in tolerant THP-1 cells by using stable and transiently transfected reporter genes containing the interleukin 1beta promoter. We found decreased endotoxin-induced transcription of all reporter genes tested; however, individual transcription factors, such as NFkappaB, retain normal, CD14-dependent, nuclear translocation and DNA binding. Tolerance is specific for endotoxin, because phorbol ester is still able to activate transcription of the endogenous interleukin 1beta gene and transfected reporter genes. A constitutively active reporter gene that is not inducible by endotoxin is unaffected. We further show that nuclear extracts of tolerant cells show transcription inhibitor activity that is specific for promoter sequences of the interleukin 1beta gene. These results support a mechanism of endotoxin tolerance that is independent of transcription factor DNA binding and appears to be associated with the inability of DNA-bound transcription factors to activate transcription, perhaps through the activity of a repressor.

Bacterial Proteins↗

PubMed1977

Anaphylactic reactions to endotoxin in guinea-pig tissues: relationship to endotoxin toxicity.

1 A lipopolysaccharide extract of Escherichia coli 026:B6 cells (026:B6(B) endotoxin) was shown to be toxic to normal adult guinea-pigs. 2 The agent had no action on isolated preparations of ileum and heart taken from normal adult guinea-pigs. 3 Ileal segments from animals actively immunized against 026:B6(B) endotoxin showed dose-dependent contractions when exposed to endotoxin. Desensitization phenomena were demonstrated. 4 Reactivity of 026:B6(B) endotoxin was transferred to isolated preparations of ileum and heart from normal animals by passive transfer of immune serum. 5 Tissue responses to 026:B6(B) were associated with release of ileal spasmogen into the bath medium. Mepyramine blocked the effects of this spasmogen at bath concentrations which caused little change in ileal responses to carbachol. 6 It is concluded that E. coli endotoxin can elicit anaphylactic reactions, and that this process may potentiate endotoxin toxicity in sensitized animals. However, endotoxin toxicity in guinea-pigs does not appear to depend on this kind of allergic process.

Anaphylaxis↗

PubMedDate not supplied

[Influence of physical loading on the content of intestinal microflora endotoxin in blood plasma and immunity indices to endotoxin].

The content of endotoxin of Gram-negative bacteria and humoral and granulocytic immunity indices to endotoxin in sportsmen and untrained persons before and after undergoing physical load were studied. The study revealed that prior to physical load the content of intestinal microflora endotoxin in the blood stream of volunteer students increased and the humoral immunity indices to endotoxin decreased. Judging by the content of cortisol in the blood, the state of stress increased after a physical load. In the groups with good adaptation a decreased endotoxin content in the blood stream was noted, especially 24 hours after load. On the contrary, in the groups with dysadaptation the content of endotoxin in blood plasma increased after a load and was accompanied by a decrease in antibody titers and in the reserve of leukocytes capable of binding endotoxin.

Antibodies, Bacterial↗