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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↗
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↗
PubMed1977

Biological activities of tritiated endotoxins: correlation of the Limulus lysate assay with rabbit pyrogen and complement-activation assays for endotoxin.

Tritiated endotoxins were prepared by three different methods. The biological activities of the tritiated endotoxins were determined by the Limulus amebocyte lysate assay, a rabbit pyrogen assay, and a complement-activation assay and were compared to native, unlabeled endotoxin. All three tritiated endotoxin preparations manifested adequate biological activity in each of the three assay systems, and all three assays ranked the biological activity of the different endotoxin preparations in the same order. Endotoxin tritiated by the Wilzbach procedure retained most of its biological activity and also had the highest specific radioactivity. The good correlation between the Limulus lysate, rabbit pyrogen, and complement-activation assays suggests that the same active site of the endotoxin molecule is identified by the three different assays.

Animals↗
PubMed1986

Elimination of endotoxin from the blood by extracorporeal activated charcoal hemoperfusion in experimental canine endotoxin shock.

Circulating endotoxin is an important factor in the pathogenesis and clinical symptoms of endotoxin shock. The effect of extracorporeal activated charcoal hemoperfusion was investigated in experimental endotoxin shock of dogs produced by i.v. injection of Escherichia coli 089 endotoxin (1 mg/kg body weight). The endotoxin was labeled with 99mTc. The aorta and vein cava caudalis of anesthetized dogs were cannulated through the arteria and vein femorales. The cannulae were contacted to the hemoperfusion charcoal cartridge. The efficiency of hemoperfusion was tested from the blood samples, and the endotoxin content of blood was measured biologically (in lead acetate-treated rats) and isotopically (99mTc radioactivity) at 15, 30, 60, 90, and 120 min after injection. It was demonstrated that extracorporeal activated charcoal hemoperfusion can eliminate the majority of circulating endotoxin from the blood within 30 min.

Animals↗
PubMed1985

Role of subcutaneous tissue endotoxin in the production of prostanoid-induced lung injury: comparison with intravenous endotoxin response.

Local injection of endotoxin into soft tissues of the flank results in hypoxia and pulmonary hypertension. Our purpose was to determine whether this was caused by tissue prostanoid production or production by the lung as is seen with endotoxemia. Twenty-six sheep were prepared with lung and flank tissue lymph fistulae. Thirteen sheep were given 2 micrograms/kg Escherichia coli endotoxin into the flank soft tissue, six of which were pretreated with ibuprofen, 12.5 mg/kg. Thirteen sheep were given intravenous endotoxin, 2 micrograms/kg, with six pretreated with ibuprofen. An early hypertensive phase was noted with both insults characterized by pulmonary hypertension, hypoxia, and increased lung lymph flow (QL). With subcutaneous tissue endotoxin, there was a significant increase in tissue lymph TxB2 and 6-keto-PGF1 alpha when compared to lung lymph and increased values in venous plasma compared to arterial plasma, indicating tissue to be the source. With intravenous endotoxin, lung lymph and aortic plasma levels were significantly higher than tissue lymph and venous plasma, respectively. The hypoxia, hypertension and increased prostanoids were prevented using ibuprofen. An increased lung permeability phase was noted with intravenous endotoxin but not with tissue endotoxin. As expected, this phase was not inhibited with ibuprofen and, therefore, not prostanoid-induced.

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Plasma endotoxin concentration after an intraperitoneal injection of endotoxin in fed and fasted suckling rats.

In the adult host response to endotoxin (lipopolysaccharide (LPS)) is dose-related. An intraperitoneal injection is commonly used for LPS administration in small animals. However, plasma endotoxin concentration following an intraperitoneal bolus injection of LPS is not well known. This study was performed to evaluate plasma endotoxin concentration following a bolus intraperitoneal injection of LPS in both fed and 24 h fasted 10 day old rats. Plasma endotoxin concentration increased in a dose-dependent manner after LPS injection (.03 or .1 mg/kg Salmonella enteritidis LPS) in both fed and fasted rats. Plasma endotoxin concentrations were higher (p < .05) in fed than fasted rats. A high dose of LPS (.1 mg/kg) induced 95 and 40% mortality in fed and fasted rats, respectively. A low dose of LPS (.03 mg/kg) induced 26.7% mortality in fed rats but no mortality in fasted rats. The hematocrit was significantly lower in fed than fasted rats. Plasma endotoxin inactivation was similar in fed and fasted rats. Host response appears to be related to plasma endotoxin concentration.

Animals↗
PubMed1996

Potentiation of lethal endotoxin shock by streptococcal pyrogenic exotoxin in rabbits: possible relevance of hyperreactivity of macrophages to endotoxin.

Streptococcal pyrogenic exotoxin (SPE) potentiates lethal shock induced by endotoxin. We have previously reported that macrophages derived from SPE-treated rabbits showed hyperreactivity to endotoxin, and that the effect of SPE on macrophages was mediated by a lymphokine(s). Here we show that culture supernatants of SPE-stimulated lymphocytes, when administered into rabbits three hours before or together with endotoxin, potentiate a variety of endotoxin-induced pathophysiological changes and even lethal shock. These results suggest that SPE-induced lymphokine(s) mediates the potentiating effect of SPE on the lethal endotoxin shock through enhancing endotoxin reactivity of macrophages which play the central role in mediating endotoxin toxicity.

Animals↗
PubMed2003

Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock.

INTRODUCTION: Antibiotics used for treatment of severe bacterial infections have been shown to exert effects on the inflammatory response in addition to their antibacterial effects. The aim of the present study was to investigate whether the biological effects of endotoxin in a porcine model could be neutralized by tobramycin, and whether tobramycin or ceftazidime was able to modulate the inflammatory response. METHOD: Thirteen piglets were subjected to endotoxin infusion at an initial rate of 4 microgram/kg per hour, which was reduced to 1 microgram/kg per hour after 30 min. Before endotoxin infusion, the animals received saline (n = 4), ceftazidime (n = 5), or tobramycin (n = 4) at clinically relevant doses. Physiological parameters were measured and blood samples were taken hourly for 6 hours for analysis of tumour necrosis factor-alpha, IL-6 and endotoxin concentrations. RESULTS: All of the animals exhibited physiological signs of severe sepsis without major differences between the groups. Plasma endotoxin concentration was stable after 1 hour. There were no differences in endotoxin concentration or initial tumour necrosis factor-alpha and IL-6 concentrations between the groups. At 6 hours the IL-6 concentration was significantly lower in the ceftazidime group than in the saline group (P < 0.05), and in both the ceftazidime and the tobramycin groups there were significantly greater reductions from peak values (P < 0.05). CONCLUSION: There was no neutralization of the biological effects of endotoxin in this porcine model. However, our data indicate a possible anti-inflammatory effect exerted by both ceftazidime and tobramycin, which manifested as a significantly greater reduction in IL-6 in comparison with the untreated group.

Animals↗