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At least 19 recordsLinked to original sources

PubMed1995

Temporal sequence of pulmonary cytokine gene expression in response to endotoxin in C3H/HeN endotoxin-sensitive and C3H/HeJ endotoxin-resistant mice.

Although previous studies suggested that tumor necrosis factor alpha (TNF-alpha) was a critical cytokine responsible for the inflammation observed after exposure to endotoxin, other mediators may also play an important role in the regulation of systemic inflammatory responses independent of TNF-alpha. The present study compared the temporal sequence of endotoxin-induced TNF-alpha, interleukin-1 alpha (IL-1 alpha), and interleukin-10 (IL-10) gene expression and cellular localization of cytokine proteins in pulmonary tissue of two strains of mice that have a genetically based differential sensitivity to endotoxin. Lung tissue and plasma were harvested from endotoxin-sensitive C3H/HeN and endotoxin-resistant C3H/HeJ mice at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h, and 24 h after intraperitoneal (i.p.) injection of 5 mg/kg endotoxin (Escherichia coli-derived lipopolysaccharide, serotype 0111:B4). There were significant elevations in both TNF-alpha gene and IL-1 alpha expression immediately (15 min) after endotoxin injection in C3H/HeN mice. Although levels of TNF-alpha mRNA in the two mouse strains were similar at 1-2 h, the IL-1 alpha gene expression in pulmonary tissue isolated from endotoxin-resistant mice was not comparable to the levels detected in C3H/HeN endotoxin-sensitive mice at the same times. The most dramatic difference in endotoxin-induced cytokine gene expression between the two strains of mice was in IL-10 mRNA levels in pulmonary tissue isolated from endotoxin-sensitive mice, compared to the lack of detectable increase in IL-10 gene expression in C3H/HeJ endotoxin-resistant mice above baseline at any time point examined. Quantitation of neutrophil infiltration into pulmonary tissue using immunochemical detection of GR-1, a myeloid differentiation-specific antibody, demonstrated that there was a significantly decreased inflammatory infiltrate in pulmonary tissue isolated from C3H/HeJ mice following endotoxin administration, which correlated with decreased levels of proinflammatory cytokine immunoreactive protein within pulmonary cells. Pulmonary cytokine synthesis and immunoreactive protein production did not directly correlate with either the magnitude or the temporal sequence of increases in plasma cytokine levels, suggesting that systemic levels of cytokines may not accurately reflect the cytokine response within the local tissue milieu. The present observations demonstrate that the differential synthesis and production of immunosuppressive cytokines as well as proinflammatory cytokines may be important variables in the determination of the extent of infiltration of inflammatory cells into the local pulmonary site in response to endotoxin and may significantly contribute to the determination of sensitivity or resistance to endotoxin in this murine model.

Animals↗

PubMed2000

Synthetic endotoxin-binding peptides block endotoxin-triggered TNF-alpha production by macrophages in vitro and in vivo and prevent endotoxin-mediated toxic shock.

Lipid A, the conserved portion of endotoxin, is the major mediator of septic shock; therefore, endotoxin-neutralizing molecules could have important clinical applications. Here we show that peptides derived from Limulus anti-LPS factor (LALF), bactericidal/permeability increasing protein (BPI) and endotoxin-binding protein, bind to lipid A and block the recombinant LALF/lipid A interaction in vitro. Because their neutralizing capacity in vitro as well as in vivo has been limited, we created hybrid peptides comprising two endotoxin-binding domains. The hybrid molecule LL-10-H-14, containing endotoxin-binding domains from LALF and endotoxin-binding protein, turned out to be the most active peptide within the series of peptides tested here to inhibit the CD14/lipid A interaction and is able in vitro to block the endotoxin-induced TNF-alpha release of murine macrophages up to 90%. Furthermore, LL-10-H-14 not only reduced peak serum levels of TNF-alpha of mice when preinjected but also reduced TNF-alpha levels when given 15 min after the endotoxin challenge. As compared with other peptides, only LL-10-H-14 is able to strongly decrease endotoxin-stimulated TNF-alpha release by human macrophage cell lines as well as by PBMC. Furthermore, the hybrid peptide is protective against endotoxin-provoked lethal shock. As such, LL-10-H-14 could have prophylactic and/or therapeutic properties in humans for the management of septic shock.

Amino Acid Sequence↗

PubMed1986

Comparative induction of hepatic zinc-thionein and increase in tissue calcium by bacterial endotoxin in endotoxin-sensitive (C3H/HeN) and endotoxin-resistant (C3H/HeJ) mice.

Induction of zinc-thionein (Zn-Th) by endotoxin was studied in mice using an endotoxin-sensitive C3H/HeN strain and an endotoxin-resistant C3H/HeJ strain to find a relation between the sensitivity of these strains to endotoxin and the inducibility of hepatic Zn-Th by the endotoxin. Both strains of female mice were injected with endotoxin at two doses and the increase in hepatic Zn-Th levels was examined after 24 h. At the lower dose (0.25 mg/kg body weight), C3H/HeJ mice induced Zn-Th at a markedly lower level than C3H/HeN mice. However, both strains exhibited a comparable amount of Zn-Th when a higher dose (10 mg/kg body weight) of endotoxin was used. A parallel increase in hepatic calcium concentration was observed with the induction of hepatic Zn-Th in both strains. The injection of a spleen supernatant fraction from C3H/HeJ mice into C3H/HeN mice did not reduce the Zn-Th induction by endotoxin in C3H/HeN mice.

Animals↗

PubMed1986

Stability of endotoxin detected in human plasma against endotoxin-inactivating factor (EIF): quantitative analysis of EIF using chromogenic endotoxin assay.

Using a quantitative blood endotoxin assay utilizing chromogenic substrate coupled with perchloric acid pretreatment (PCA-LCT), we showed the presence of endotoxin-inactivating factor (EIF) in human plasma in vitro. EIF activity inactivated added endotoxin to about 10(-4) of the initial level within 20 min, followed by a stable phase where the residual endotoxin became resistant to EIF and was not further inactivated. The residual endotoxin may represent the endotoxin in patient plasma which is also EIF resistant. We postulate that endotoxin, upon entering the blood, is rapidly inactivated by chemical modification of its active site, lipid A, through EIF. Subsequently, inactivated endotoxin, mainly consisting of polysaccharide, is gradually removed from circulation by endocytosis in the reticuloendothelial system.

Chromogenic Compounds↗

PubMed1974

Studies with radioactive endotoxin. III. Localization of 3H-labelled endotoxin in the formed elements of the blood and detection of endotoxin in calf blood with the Limulus amebocyte lysate.

(3)H-labelled Pseudomonas endotoxin was incubated in vitro with blood from nontolerant and endotoxin tolerant calves. Formed elements were separated from serial samples of the incubated mixtures. The labelled endotoxin became associated with neutrophils, monocytes, lymphocytes, platelets and erythrocytes. Association of (3)H-endotoxin with formed elements of the blood occurred during the first five minutes of incubation and did not significantly change over the course of a three hour incubation period. Tolerance did not result in increased uptake of (3)H-endotoxin by formed elements of the blood. Tolerance of calves to endotoxin is apparently not due to increased uptake of endotoxin by formed elements of the blood. The Limulus amebocyte lysate assay was unreliable for the detection of endotoxin which was present in calf blood in vitro and requires further modification.

Animals↗

PubMed1978

Endotoxin receptor site. II. Specificity of endotoxin receptor of platelets and sensitivity to endotoxin in vivo.

The biological specificity of the endotoxin receptor on platelet membranes was examined. The binding indices of platelets in experimental endotoxemia which was induced by intravenous administration of endotoxin (Lipopolysaccharide of E. coli, Difco) to rabbits were found to be 30% of the control at 60 min after the injection. The result suggests that the endotoxin receptor of platelets was already occupied. The binding indices of human platelets were measured after pretreatment with pharmacologically active substances which were assumed to effect platelet activity. The binding of LPS to platelets showed competitive inhibition at pharmacologically effective doses, but other substances merely inhibited platelet activity. One interpretation is that there is a common receptor on platelet cell membranes for lipopolysaccharide of E. coli and endotoxin. The sensitivity to endotoxin in vivo and binding indices of platelets were examined in rabbits and guinea pigs since their response to endotoxin is almost opposite with regard to sensitivity. The binding indices of platelets from rabbits and guinea pigs showed a positive correlation with the endotoxin sensitivity. Those findings indicate that platelets play a key role in vivo in the clinical course of endotoxemia.

Age Factors↗

PubMed1963

EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM. VI. THE ROLE OF TRYPTOPHAN PYRROLASE IN RESPONSE OF MICE TO ENDOTOXIN.

Cortisone is known to protect mice against the lethal effects of endotoxin. It also elevates liver tryptophan pyrrolase (TP) activity, an enzyme that converts tryptophan into an intermediate which, in turn, is transformed in a series of reactions into nicotinamide, a component of the pyridine nucleotides. In the present report, results of experiments attempting to link the prophylactic action of cortisone in endointoxication to metabolism of tryptophan are described. It was shown first that both nicotinamide and diphosphopyridine nucleotide (DPN), compounds along the pathway initiated by TP, are each as effective as cortisone in protecting mice against lethality of different amounts of endotoxin. L-Tryptophan, which alone results in an increase in liver TP, fails to protect against endotoxin when it is given either 4 hours before or concurrently with the toxin while it potentiates the toxin when administered 4 hours later. Cortisone, nicotinamide, and DPN all fail to protect mice against lethality when given 4 hours after endotoxin but they do not potentiate it as does tryptophan. Additional evidence linking tryptophan metabolism to endotoxin poisoning was derived from assays for TP. Activity of the enzyme in livers of mice 17 hours after injecting an LD(50) of endotoxin is less than one-half the control value. It remains below normal for 48 hours. In adrenalectomized mice, TP activity is about the same as in mice 17 hours after endotoxin. Animals protected against lethality of endotoxin by cortisone have normal levels of TP but if the cortisone is given 4 hours after the toxin, TP activity is the same as in mice given endotoxin alone. Tryptophan is unable to maintain a normal level of TP when it is given concurrently with endotoxin. TP activity is not depressed when mice made tolerant to endotoxin are given an injection of endotoxin at the LD(50) level for normal animals. Normal activity of the enzyme was always observed in livers of mice protected against endotoxin but not in those where protection failed. The total amount of oxidized pyridine nucleotides (PN(+)) in livers of mice 17 hours after an LD(60) of endotoxin is about two-thirds the normal level. Animals injected with either cortisone or nicotinamide at the same time as endotoxin maintain the PN(+) level in liver. Mice exposed to 5 degrees C during the postinjection period can be protected with cortisone or nicotinamide against lethality of endotoxin but not with DPN. Changes in TP activity do not parallel those found in mice kept at 25 degrees C. The toxic manifestations of endotoxin appear to be different, therefore, in animals stressed by cold.

Adrenalectomy↗

PubMed1990

Biological responses of sheep treated with endotoxin-contaminated superoxide dismutase and endotoxin preparations.

The purpose of this study was to evaluate the biological response of sheep to different doses of endotoxin and endotoxin-contaminated enzyme preparations. The enzyme used in this experiment was superoxide dismutase (SOD), as it is currently being used in many different experiments and because several preparations were found to be heavily contaminated with endotoxin. A group of ewes were injected intravenously with a variety of different treatments. Peripheral blood was used to determine the total number of leukocytes, a differential cell count to find out the numbers of polymorphonucleocytes (PMN) and monocytes (M), and to measure the concentration of 15-ketodihydro-PGF2 alpha. In addition, rectal temperature was recorded. Treatments included saline (control), Pharmacia-Chiron's Cu/Zn-SOD (r-hSOD, 8 mg/kg), Sigma's bovine SOD (bSOD, 8 mg/kg), Grünenthal's bSOD (8 mg/kg), various doses of Salmonella typhimurium endotoxin (1000, 200, 100, 50, 20, 10, 5, and 1 ng/kg), and a mixture of endotoxin (200 ng/kg) plus r-hSOD (8 mg/kg). Results indicate that sheep react to endotoxin-contaminated SOD preparations with an endotoxemia which is similar to that seen in animals receiving endotoxin alone. This endotoxemia includes, among other things, a rise in rectal temperature, a peak in the PGF2 alpha metabolite, and an increased PMN/M ratio. Endotoxin administered at doses of 50 to 200 ng/kg also caused the expected signs of endotoxemia. At 1000 ng/kg endotoxin actually led to a decreased rectal temperature. This may be due to a type of endotoxemic shock, resulting in a decrease in peripheral blood circulation. Low doses of endotoxin (10, 5, and 1 ng/kg) caused a leukocytosis via increases in PMN; no greater changes in rectal temperature or the PGF2 alpha metabolite were noted. The combination of r-hSOD with 200 ng/kg of endotoxin caused an endotoxemia similar to that caused by 200 ng/kg of endotoxin alone. In conclusion, if an endotoxin-contaminated SOD-preparation was used to study the efficacy of SOD, there would be a serious risk of interaction by the endotoxins. In such a case it would be impossible to distinguish the effects of the endotoxin from those of the preparation itself. It is therefore important that researchers are alert to the problem of endotoxin contamination.

Animals↗

PubMed1969

The role of endotoxin during typhoid fever and tularemia in man. IV. The integrity of the endotoxin tolerance mechanisms during infection.

Volunteers infected with Salmonella typhosa develop a remarkable hyperreactivity to the pyrogenic and subjective toxic activities of homologous (S. typhos) and heterologous (Pseudomonas) endotoxins. The present studies quantitate this augmented reactivity and demonstrate by three differing approaches that significant tolerance to these endotoxins can be readily induced within the framework of the hyperreactive state. Thus, (a) tolerance induced before illness by repeated daily intravenous injections of the endotoxins remained demonstrable during overt illness, (b) daily intravenous injections of the endotoxins begun during overt illness evoked progressively increasing tolerance, and (c) continuous intravenous infusions of S. typhosa endotoxin during illness rapidly induced a pyrogenic refractory state. Despite unequivocal activation of the endotoxin tolerance mechanisms by any of the above methods, the febrile and toxic course of typhoid fever proceeded unabated. Similarly, in other volunteers with Pasteurella tularensis infection, continuous intravenous infusions of S. typhosa endotoxin evoked initial hyperreactive febrile and subjective toxic responses followed by rapid appearance of a pyrogenic refractory state without modification of the underlying clinical illness. These observations suggest that circulating endotoxin plays no major role in pathogenesis of the sustained fever and toxemia during typhoid fever and tularemia in man. The mechanisms responsible for the systemic hyperreactivity to endotoxin during typhoid fever and tularemia were further investigated. Low grade endotoxemia, nonspecific effects of tissue injury, impaired ability of the reticuloendothelial system to clear circulating endotoxin, and production of cytophilic antibodies capable of sensitizing leukocytes to endotoxin did not appear responsible. Inflammatory reactions to intradermal S. typhosa endotoxin increased significantly during typhoid fever. However, since no such dermal hyperreactivity developed to Pseudomonas endotoxin during typhoid fever nor to S. typhosa endotoxin during tularemia, the systemic hyperreactivity to bacterial endotoxins during typhoid fever and tularemia could not presently be ascribed to enhanced levels of acquired hypersensitivity.

Adult↗

PubMed1990

Endotoxin-induced procoagulant activity, eicosanoid synthesis, and tumor necrosis factor production by rat peritoneal macrophages: effect of endotoxin tolerance and glucan.

Macrophages release pro-inflammatory substances that may augment intravascular coagulopathy associated with endotoxemia. In the present study, the effect of Salmonella enteritidis endotoxin on expression of procoagulant activity (PCA), eicosanoid metabolism, and production of tumor necrosis factor (TNF) by rat peritoneal macrophages was determined. Endotoxin induced significant dose-dependent increases in the concentrations of immunoreactive (i) thromboxane B2 (TxB2), 6-ketoprostaglandin F1 alpha (i6-keto-PGF1 alpha), and TNF in culture media. Calcium ionophore (A23187; 0.5 microM) induced an approximate two-fold greater increase (P less than 0.05) in iTxB2 and i6-keto-PGF1 alpha than that stimulated by the maximal endotoxin dose. Endotoxin (0.5, 5, and 50 micrograms/ml) induced similar increases in PCA in macrophage lysates which paralleled the production of iTxB2 and i6-keto-PGF1 alpha. In contrast to its marked effect on eicosanoid metabolism, A23187 elicited little increase in PCA. After the responses of peritoneal macrophages from normal animals were characterized, we hypothesized that procedures which alter the in vivo response of rats to endotoxin would similarly alter the in vitro responses of their peritoneal macrophages. In subsequent studies, the effect of altered endotoxin sensitivity on expression of PCA, eicosanoid synthesis, and TNF activity were assessed. Endotoxin tolerance, induced by repeated injection of sublethal doses of endotoxin in vivo, rendered rat peritoneal macrophages refractory to in vitro endotoxin-induced production of iTxB2, i6-keto-PGF1 alpha, PCA, and TNF activity. In contrast, pretreatment of rats with the macrophage stimulant glucan, which enhances endotoxin lethality, augmented the in vitro production of iTxB2, PCA, and TNF by endotoxin-stimulated peritoneal macrophages. These studies demonstrate that endotoxin-induced macrophage arachidonic acid metabolism is associated with expression of PCA and secretion of TNF. Additionally, macrophage synthesis of these pathogenic mediators is reduced under conditions associated with endotoxin resistance (endotoxin tolerance) and is augmented during endotoxin hypersensitivity (glucan stimulation).

6-Ketoprostaglandin F1 alpha↗

PubMed1991

Increased endotoxin sensitivity following T-2 toxin treatment is associated with increased absorption of endotoxin.

Oral exposure to T-2 Toxin (T-2) in experimental animals results in a syndrome similar to that observed in endotoxemia. Endotoxins are lipopolysaccharide, outer-membrane components of gram-negative bacteria which induce acute, inflammatory responses. In the present study, several aspects of endotoxin pathophysiology were investigated in mice following simultaneous exposure to T-2 and endotoxin, including mortality, hypothermia, tumor necrosis factor-alpha (TNF-alpha) and corticosterone production, and thymic weight. The disposition of endotoxin was also assessed, Acute, simultaneous exposure to T-2 (4 mg/kg, po) and endotoxin (3 micrograms/mouse, ip) resulted in increased mortality, hypothermia, TNF-alpha production, and thymic atrophy compared to treatment with either T-2 of endotoxin alone. Pretreatment of mice with endotoxin, a regime that renders the animals resistant to the effects of endotoxin, reduced many endotoxin effects in animals treated simultaneously with T-2 and endotoxin. Upon further investigation, it was observed that T-2 increased the absorption rate of endotoxin: as the peak height of serum endotoxin increased, the time-to-peak decreased, and the area under the curve was unchanged in animals treated simultaneously with T-2 and endotoxin. It was concluded that increased endotoxin absorption accounted for the increases in mortality, hypothermia, and TNF-alpha associated with T-2 exposure.

Animals↗

PubMed2000

Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release.

OBJECTIVE: To study the release of free endotoxin from Escherichia coli exposed to varying concentrations of the penicillin-binding protein (PBP) 3-specific beta-lactam antibiotic cefuroxime, the aminoglycoside tobramycin, and a combination of the two, and to test the relationship between bacterial killing rate and endotoxin release. METHODS: A clinical isolate of Escherichia coli in logarithmic phase was exposed to 0.1, 2, 10, and 50 x minimum inhibitory concentration (MIC) of cefuroxime, tobramycin, and a combination of the two. Samples for viable counts and endotoxin analysis were drawn immediately before and after the addition of the antibiotics and at 1, 2, 4, 6, and 24 h. All experiments were performed in triplicate. For the analysis of endotoxin, a chromogenic limulus amoebocyte lysate assay was used. RESULTS: Endotoxin liberation was found to be proportional to the number of killed bacteria for each antibiotic regimen at each concentration level justifying the endotoxin-liberating potential to be expressed as release of endotoxin per killed bacterium, an expression that was independent of the inoculum size. At all concentration levels there was a statistically significant difference between the treatments, with the highest release of endotoxin per killed bacterium for cefuroxime, lower for tobramycin and the lowest for the combination of the two drugs (P < 0.001). With increasing doses, there was a significant reduction (P < 0.001) in the propensity to release endotoxin. When the bacterial killing rate was correlated to the propensity to release endotoxin in bacteria exposed to tobramycin or the combination of tobramycin and cefuroxime, a significant negative correlation was found (P < 0.01). This reduction in endotoxin release was not caused by an unspecific endotoxin binding of tobramycin. CONCLUSIONS: Addition of tobramycin reduced the cefuroxime-induced endotoxin release per killed bacterium to a level which was even lower than that of tobramycin alone in spite of an increased killing rate. Increasing concentrations of tobramycin led to reduction in endotoxin release, which may be of benefit when dosing aminoglycosides once daily.

Anti-Bacterial Agents↗

PubMed1966

Mechanisms of endotoxin tolerance. IV. Specificity of the pyrogenic refractory state during continuous intravenous infusions of endotoxin.

The mechanisms underlying the pyrogenic refractory state which develops rapidly during a continuous intravenous infusion of bacterial endotoxin have been further explored. The findings demonstrate that: (a) rabbits rendered refractory to a continuous intravenous infusion of E. coli endotoxin at a standard rate (18 x 10(-4) microg/min) become highly refractory to a single intravenous test bolus of endotoxin, but remain fully responsive to preformed endogenous pyrogen and to substances known to release endogenous pyrogen, i.e. influenza virus, old tuberculin in specifically sensitized rabbits, and staphylococcal enterotoxin; (b) administration of fresh whole blood from normal donors containing an average of 1.6 - 10(8) granulocytes fails to restore febrile responsiveness to the continuing E. coli endotoxin infusion; (c) refractory phase plasma and liver homogenates exhibit no enhanced capacity to inactivate E. coli endotoxin pyrogenicity; (d) splenectomized animals readily develop the pyrogenic refractory state during E. coli endotoxin infusions and exhibit diminished, rather than the increased inflammatory responses to intradermal endotoxin seen in sham-operated controls; (e) continuous intravenous infusions of gelatin-stabilized, heat-killed pneumococci produce sustained fevers; and (f) continuous intravenous infusions of old tuberculin into specifically sensitized animals rapidly elicit a pyrogenic refractory state. The present observations, considered together with those of other investigators, support the hypothesis that pyrogenic unresponsiveness to endotoxin involves two distinct immunologic mechanisms. In terms of this hypothesis, the rapid reduction in febrile responsiveness to endotoxin is mediated by desensitization at the cellular level. With small doses of endotoxin, such as those employed in the present studies, this desensitization is primarily specific; with larger doses, nonspecific mechanisms are superimposed. So long as the subsequent doses of endotoxin are closely spaced or continuously infused, optimal conditions are provided for cellular desensitization and pyrogenic unresponsiveness to a given quantity of endotoxin can be induced rapidly and maintained without the requirement for antibody. However, as the interval between endotoxin challenge is lengthened, cellular desensitization wanes and tolerance becomes increasingly dependent upon those antibodies directed against the common toxophore groupings responsible for endotoxin pyrogenicity which assist the reticuloendothelial system in the clearance and destruction of this molecule.

Animals↗

PubMed1985

Endotoxin-tolerant rats are still protected from oxygen toxicity by low-dose endotoxin treatment.

To determine if we could reduce endotoxin's potential for toxicity, we produced "endotoxin-tolerant" rats by administering progressively increasing daily doses of endotoxin (10 ng, 100 ng, 1 microgram, 10 micrograms/kg). This dosage regimen produced a high degree of tolerance to the toxic actions of endotoxin: whereas only 3/17 (18%) of control rats survived a normally lethal dose of endotoxin (25 mg/kg), survival for the endotoxin-tolerant rats was 16/16. When endotoxin-tolerant rats received a standard protective dose of 500 micrograms/kg endotoxin just before transfer to 96-98% O2, 19/20 survived the 72-h exposure period vs. 20-30% survival for controls. Thus whereas the endotoxin-tolerant state blocked the tested lethal and toxic effects of endotoxin, it did not nullify the O2 protective action of endotoxin. In addition, endotoxin's stimulatory effects on the lung antioxidant enzymes in the 96-98% O2-exposed rats was also not blocked by the endotoxin-tolerant state. Thus the therapeutic ratio (TR) of endotoxin as an experimental pharmacological treatment against O2-induced lung damage has been markedly enhanced (TR = ratio of dose producing beneficial effects to dose producing toxic effects).

Acid Phosphatase↗

PubMed1995

Potency of endotoxin from bicarbonate dialysate compared with endotoxins from Escherichia coli and Shigella flexneri.

Endotoxin is a potent activator of the complement system and other host immunoregulators, including the cytokines, tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. In this study, the potency of an endotoxin from bicarbonate dialysate was compared with endotoxins from two enteric microorganisms, Shigella flexneri and Escherichia coli. Endotoxin concentrations were standardized for the three endotoxins by use of the Limulus amebocyte lysate turbidimetric assay. Endotoxin potency was assessed by the comparative plasma concentrations of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6 after an in vitro whole-blood challenge by each type of endotoxin. Blood collected from 10 hemodialysis patients was spiked with 0.1, 1, and 10 ng/mL of E. coli and Shigella endotoxin and with 1 and 10 ng/mL of bicarbonate dialysate endotoxin. After incubation, plasma was separated and frozen at -70 degrees C until assayed for cytokine concentrations. Dialysate endotoxin was found to be 10 to 100 times less potent than E. coli and Shigella endotoxins. It was concluded that there are significant differences in the potency of endotoxins from different strains of bacteria and that these differences should be noted when designing or evaluating studies on the clinical effects of endotoxins in hemodialysis settings.

Bicarbonates↗

PubMed1986

Endotoxin tolerance diminishes endotoxin-induced alterations in carbohydrate kinetics.

This study was designed to determine if attenuated mortality to a challenge dose of endotoxin was accompanied by or separated from alterations in glucose metabolism in endotoxin-tolerant rats. The in vivo effects of endotoxin were studied in catheterized endotoxin-tolerant rats and nontolerant control animals. Tolerance was induced by iv injections of 100 micrograms endotoxin/100 g BW (tolerance dose) for either 2 or 4 consecutive days; control rats received daily saline injections. On the day after the final tolerance dose, glucose kinetics were assessed by the constant infusion of [6-3H]-glucose prior to and after a challenge dose of endotoxin (1,000 micrograms/100 g) in tolerant and nontolerant rats. Following the challenge dose, 2-day tolerant animals exhibited an improved survival at 72 hr (LD 14 vs LD 92), a significantly smaller reduction in mean arterial blood pressure (20 vs 34%), and smaller increases in plasma glucose (9.4 +/- 0.6 vs 11.4 +/- 0.6 mM) and lactate (3.2 +/- 0.3 vs 8.5 +/- 1.4 mM) concentrations, compared to those in nontolerant control rats. However, increases in the rates of glucose appearance (Ra) and metabolic clearance (MCR) were not diminished. In 4-day tolerant rats, lethality to endotoxin was abolished, and no alterations in blood pressure or glucose kinetics were seen during the 4-hr period after endotoxin. However, the basal glucose Ra and MCR determined prior to endotoxin challenge were elevated in these rats compared to controls. Hyperglucagonemia was evident following the endotoxin challenge in control and 2-day tolerant rats, but not in 4-day tolerant animals. The hypothermia seen in nontolerant rats 4 hr after endotoxin was not present in either group of tolerant animals. The results show that after 2 days, tolerant animals have improved survival rates when challenged with endotoxin but still demonstrate acute changes in glucose kinetics. A complete protection against a normally lethal dose of endotoxin exists after 4 days. At this stage, rats showed no transient hemodynamic or metabolic alterations following endotoxin challenge.

Animals↗

PubMed1964

MECHANISMS OF ENDOTOXIN TOLERANCE. II. RELATIONSHIP BETWEEN ENDOTOXIN TOLERANCE AND RETICULOENDOTHELIAL SYSTEM PHAGOCYTIC ACTIVITY IN MAN.

Healthy male volunteers were rendered tolerant to the pyrogenic and toxic activities of bacterial endotoxin by daily intravenous injections. Five subjects were given 0.5 microg Salmonella typhosa endotoxin for 7 days; four subjects were given Pseudomonas endotoxin, increasing over a period of 30 days from 25 to 250 microg. Reticuloendothelial system (RES) phagocytic activity was assessed by serial measurements of the clearance of I(131)-labeled aggregated human serum albumin. In no subject was an increase in RES phagocytic activity detectable. Such negative findings could not be attributed to decreased RES blood flow.-Additional studies on the pyrogenic responses of man to various schedules of endotoxin administration revealed: (a) Hyperreactivity of some subjects to a second injection of endotoxin administered 24 hours after the initial dose; (b) prevention of such hyperreactivity by plasma from donors tolerant to a heterologous endotoxin, but not from normal donors; (c) reduced reactivity to a second injection of endotoxin given 7 days after the initial dose; (d) reversal of induced tolerance by administration of half the dose of endotoxin followed 2 hours later by the second half; (e) reversal of induced tolerance 24 hours after administration of a heterologous endotoxin; (f) enhanced dermal reactivity to endotoxin induced inflammation during tolerance. The observations are consistent with the hypothesis that tolerance to the pyrogenic activity of endotoxin in man is not based upon generalized enhancement of RES phagocytic activity or exhaustion of host reactivity but rather involves the participation of specific antibody which assists the RES in the clearance and inactivation of the endotoxin molecule.

Antigen-Antibody Reactions↗

PubMed1995

[Usefulness of endotoxin-specific limulus test for the measurement of endotoxin in cerebrospinal fluid in diagnosis of bacterial meningitis].

Using a new endotoxin-specific chromogneic limulus assay (Endoscopy test), endotoxin concentrations were measured in 93 specimens of cerebrospinal fluid (CSF) from 66 pediatric patients. Eighteen patients were diagnosed as having menigitios. Of these, 6 cases (group A) with gram-negative meningitis proven by culture had high CSF endotoxin concentrations of 115.3, (82-133) (median, range) pg/ml. Ten cases (group B) with gram-positive or aseptic meningitis had endotoxin concentrations of 2.15 (0.1-3.6) pg ml. Other 2 cases with bacterial meningitis (group C), in whom no pathogen was detected, had CSF endotoxin concentrations of more than 100 pg/ml. Four cases with encephalitis (group D) and 45 cases with non-meningitis or non- encephalitis (group E), had CSF endotoxin concentrations of less than 5 pg/ml. Despite a negative culture after antibiotic treatment in group A patients, endotoxin was cleared slowly from the CSF. A clearing of endotoxin from CSF was followed by alleviation of fever with a more gradual decline in CRP values. In 2 cases of group C, the negative bacterial culture appeared to be attributable to the previous treatment with antibiotics. However, these patients had high CSF endotoxin levels, indicating gram negative bacterial meningitis. In 17 CSF specimens from 5 patients of group A, in whom Haemophilus influenzae was detected on admission, an additional a latex agglutination test for the detection of H. influenzae polysaccharide antigen was performed. Only 3 specimens from 3 patients with CSF endotoxin concentrations of more than 80 pg/ml had a positive agglutination test. These results suggest that quantitation of endotoxin concentrations is useful for the diagnosis of gram-negative meningitis. And also, the clearance of endotoxin from CSF during treatment appears to be useful in determining the timing of when antibiotic should be stopped.

Adolescent↗