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PubMed1992

Role of the spleen in endotoxin-induced hepatic injury in chronic alcohol-fed rats.

The present experiments were designed to study the role of the spleen in endotoxin-induced hepatic injury in chronic alcohol-fed rats. Administration of 2 mg/kg body weight of endotoxin caused severe hepatic injury in chronic alcohol-fed rats as compared with controls. This injury was significantly less in those whose spleens had been resected 1 week prior to endotoxin administration. There were no differences in plasma endotoxin levels 16 h after intravenous injection of endotoxin between sham-operated control rats, and chronic alcohol-fed rats with and without splenectomy. The plasma tumor necrosis factor (TNF) level 1 h after intravenous injection of endotoxin was significantly higher in chronic alcohol-fed rats than in controls. However, TNF levels were significantly lower in those with splenectomy. Neutrophil infiltration was seen in the liver sinusoid of sham-operated chronic alcohol-fed rats as early as 1 h after injection of endotoxin, and was observed even 15 h later. These results suggest that endotoxin-induced liver injury is closely related to factors derived from the spleen and induced by plasma endotoxin, especially when Kupffer cell function is reduced by chronic alcohol feeding. In addition, TNF and neutrophils may play an important role in this type of liver injury.

Alanine Transaminase↗
PubMed1980

The endotoxin-liberating effect of antibiotics on meningococci in vitro.

Three strains of Neisseria meningitis (two endotoxin-liberating and one in vitro variant non-liberating) were studied during treatment with MIC and 100 times MIC values of benzylpenicillin and chloramphenicol in a chemically-defined, protein-free medium. Treatment with the highest dose of benzylpenicillin had the most rapid effect on meningococci, although the antibacterial effect was the same for the two penicillin concentrations after 20 h. Chloramphenicol treatment showed a much slower antibacterial effect. After 2 h of antibacterial treatment, an increase of filtrable endotoxin in the medium was found for the endotoxin-ligerating strains only when the highest penicillin dose was used. During the same period there was a rapid cell death. After 20 hours of treatment, however, the endotoxin-liberating strains treated with high and low concentrations of penicillin had a markedly reduced content of filtrable endotoxin, compared to the controls and to the cultures treated with chloramphenicol. Antibacterial treatment had no, or only minimal, effect on the total content of endotoxin in the cultures, compared to the untreated controls. The endotoxin non-liberating strain had about the same total content of endotoxin as the liberating strains, but did not liberate filtrable endotoxin into the medium unless filtered with a much higher pressure through a filter with smaller pore size.

Chloramphenicol↗
PubMed1994

The influence of endotoxin upon middle ear fibroblasts cultured in normal middle ear gas and atmospheric air.

Otitis media represents a continuum of inflammatory stages frequently in association with bacteria and/or endotoxin. Furthermore, the disease is often treated with insertion of ventilation tubes, which causes hyperoxia relative to the physiological state in the tympanic cavity. The present study was undertaken to quantitate the interaction between endotoxin and relative hyperoxia in cultures of rabbit middle ear fibroblasts incubated in normal middle ear gas and atmospheric air, respectively. Growth was monitored by determination of DNA, cell protein and cell division. The synthetic activity was estimated by collagen production. The antioxidant defense was determined by measuring the intra-and extracellular concentrations of superoxide dismutase (SOD). The results demonstrated that hyperoxia significantly impaired the growth of middle ear fibroblasts, which was compensated for by addition of endotoxin stimulating the growth. The collagen synthesis increased significantly in atmospheric air with a synergistic effect of endotoxin. Hyperoxia induced intracellular SOD formation, while endotoxin tended to reduce the synthesis. Finally, exposure to atmospheric air caused significantly larger amounts of reducing agents extracellularly in cultures without endotoxin compared to endotoxin incubated cultures. It is suggested that endotoxin possess both synergistic and antagonistic potential as regards the effects of relative hyperoxia, and that the interaction between endotoxin and hyperoxia may be an important factor in otitis media.

Animals↗
PubMedDate not supplied

Plasma endotoxin concentrations in clinically normal and potentially septic equine neonates.

Plasma endotoxin concentrations were measured at 1 to 2 and 5 to 6 days of age in clinically normal foals and in potentially septic neonatal foals admitted to North Carolina State University's Veterinary Teaching Hospital for a variety of conditions. In 1 to 2 and 5 to 6 day old normal foals, median plasma endotoxin concentrations were 2.17 (range, 1.61-2.54; n = 6) and 2.89 (range, 2.61-3.50; n = 7) endotoxin units/mL (EU/mL), respectively. Median plasma endotoxin concentration in potentially septic foals with negative blood cultures or gram positive isolates (n = 8) was 2.73 (range, 0.59-4.04) EU/mL. In hospitalized foals with gram negative isolates (n = 6), median plasma endotoxin concentration was 78.06 (range, 0.76-2,696.41) EU/mL, but individual endotoxin values were only increased in foals that were extremely sick and died within hours of sampling. Plasma endotoxin concentrations were significantly greater in foals with sepsis scores > or = 11 compared with foals with sepsis scores < or = 10. Increased plasma endotoxin concentrations appear to predict an unfavorable outcome in septic foals, but normal endotoxin concentrations do not appear to have any predictive value.

Animals↗
PubMed1998

Time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic drug-metabolizing enzyme activity in rats.

The time-dependent effects of Klebsiella pneumoniae endotoxin on hepatic cytochrome P450-dependent drug-metabolizing capacity (cytochrome P450 and b5 content, activity of aminopyrine N-demethylase, p-nitroanisole O-demethylase, aniline hydroxylase and benzphetamine N-demethylase) and on the pharmacokinetics of antipyrine have been determined in rats. Measurement of enzyme activity and antipyrine (after intravenous injection of 20 mg kg(-1)) were performed 2, 24 and 96 h after a single intraperitoneal injection of endotoxin (1 mg kg(-1)) and after repeated doses (once daily for 4 days). The contribution of tumour necrosis factor alpha (TNFalpha) to the endotoxin-induced changes was also examined in rats pretreated with granulocyte colony-stimulating factor (G-CSF). The systemic clearance of antipyrine and the activity of hepatic cytochrome P450-dependent drug-metabolizing enzymes were dramatically reduced 24 h after a single injection of endotoxin, but had returned to control levels by 96h. The magnitudes of these decreases in these measurements after repeated doses of endotoxin were similar to those seen 24h after the single dose. The systemic clearance of antipyrine correlated significantly with cytochrome P450 content and aminopyrine N-demethylase activity. In histopathological experiments, moderate hypertrophy of Kupffer cells was observed, with no evidence of severe liver-tissue damage. G-CSF pretreatment suppressed the increased plasma concentrations of TNFalpha produced 2 h after single endotoxin injection, but did not eliminate the endotoxin-induced decrease in the systemic clearance of antipyrine, suggesting that TNFalpha is not the sole component responsible for the reduction of cytochrome P450-mediated drug-metabolizing enzyme activity. These results provide evidence that a single intraperitoneal injection of 1.0 mgkg(-1)K. pneumoniae endotoxin in rats reduces hepatic P450 and b5 levels, and reduces the activity of various cytochrome P450-mediated drug-metabolizing enzymes without causing severe liver-tissue damage. This suggests that the effect of endotoxin on hepatic cytochrome P450-mediated drug-metabolizing isozymes is non-selective.

Animals↗
PubMed1986

Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin.

Multiple factors may modify the pharmacokinetics of aminoglycosides and increase their nephrotoxic potential. In this study, we investigated the influence of Escherichia coli endotoxin on the renal handling of several aminoglycosides and one cephalosporin. Drug levels in the renal parenchyma, as well as several parameters of renal function and histology, were compared in rats treated with endotoxin (0.25 mg/kg) and normal rats treated with either gentamicin (10 mg/kg), netilmicin (10 mg/kg), tobramycin (10 mg/kg), amikacin (50 mg/kg), or cephalothin (100 mg/kg). Blood pressure and pulse rate were recorded. Endotoxin was associated with a decrease in the half-life and in the apparent volume of distribution of gentamicin. The endotoxin-injected animals accumulated significantly (P less than 0.05) more aminoglycosides in their kidneys than the normal animals. The amount of cephalothin recovered in the renal parenchyma was identical in both groups. Slight decreases in the glomerular filtration rate and renal plasma flow were observed after endotoxin treatment. Blood pressure and cardiac frequency were minimally affected by endotoxin. No histological lesions were observed by light microscopy in animals receiving endotoxin. Thus, endotoxin modifies the renal handling of aminoglycosides in the absence of any major physiological disturbance or histological change. By increasing the total amount of drug within the kidneys, endotoxin might increase the nephrotoxic potential of aminoglycosides.

Amikacin↗
PubMed1973

Enhanced toxicity for mice of combinations of bacterial endotoxin with antitumor drugs.

The toxicity of Salmonella typhosa 0901W endotoxin to mice was potentiated by (per kilogram) 1 mg of colchicine, 20 mg of emetine, 100 mg of 6-mercaptopurine, 100 mg of 6-methylmercaptopurine riboside, 75 mg of methotrexate, 2 mg of sparsomycin, or 2.5 mg of vinblastine. No potentiation of endotoxin lethality was evident with simultaneously administered (per kilogram): 200 mg of cytosine arabinoside, 450 mg of dibromomannitol, 100 mg of 5-fluorouracil, 125 mg of 5-fluorouracil deoxyriboside, 8 mg of mitomycin C, 1 mg of nitrogen mustard, or 10 mg of tris(1-aziridinyl)-phosphine sulfide. With the exception of colchicine, all drugs prolonged the duration of sleep after the administration of 80 mg of hexobarbital per kg. Simultaneous injection of endotoxin with 100 mg of 6-mercaptopurine per kg, 75 mg of methotrexate per kg, or 1 mg of vincristine per kg resulted in significantly greater lethality than administration either prior to or after the drug. However when endotoxin was administered prior to 100 mg of 5-fluorouracil per kg, lethality was significantly increased. The route of administration of endotoxin and 5-fluorouracil, 6-mercaptopurine, methotrexate, or vincristine did not influence overall lethality. Pretreatment of mice with multiple doses of Escherichia coli endotoxin resulted in a significant reduction in the lethality of 6-mercaptopurine- or vincristine-endotoxin combinations, but had no influence on 5-fluorouracil- or methotrexate-endotoxin combinations. Endotoxin-pretreated mice were more susceptible to vincristine alone and more resistant to high doses of 5-fluorouracil. The lethality of 6-mercaptopurine was increased by simultaneous administration of gram-negative isolates from feces of human patients with neoplastic disease.

Animals↗
PubMed1973

Enhanced toxicity for mice of pactamycin with bacterial endotoxin.

Combinations of pactamycin and Salmonella typhosa 0901 endotoxin, administered simultaneously, killed more BALB/c mice than comparable doses of either agent alone The slopes of the dose-response curves for combinations of endotoxin and pactamycin were parallel to both that for endotoxin alone and the antitumor drug alone; therefore, no new mechanism of toxicity has been evoked by the combination. The synergistic toxicity of endotoxin and pactamycin was due to an in vivo interaction rather than a direct reaction between the two agents. Phenobarbital pretreatment protected the mice from toxicity of the antitumor agent alone but not from the lethal action of the combination. Pretreatment with endotoxin increased the resistance of the mice to both endotoxin alone and the combination. Third agents unable to protect mice from the synergistic toxicity of endotoxin and pactamycin were alpha[p-(fluoren-9-ylidenemethyl)-phenyl]-2-piperidine-ethanol, neomycin, phenylbutazone, polymyxin B, and tybamate. Prednisolone pretreatment alleviated the toxicity of the combination. For the restricted series of killed bacteria and bacterial products tested for capability to enhance the toxicity of pactamycin, only gram-negative bacterial cells were potent. These results indicated that pactamycin rendered the mice more susceptible to endotoxin and that endotoxin was the causal lethal agent.

Animals↗
PubMed2001

Effect of endotoxin on P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 in rats.

The effects of Klebsiella pneumoniae endotoxin on the biliary excretion and renal handling of rhodamine-123 were investigated in rats at different times after intraperitoneal injection (1 mg/kg of body weight). The typical substrates for P glycoprotein, i.e., cyclosporine, colchicine, and erythromycin, inhibited the biliary clearance of rhodamine-123, whereas a substrate for organic cation transporter, cimetidine, did not inhibit clearance, suggesting that rhodamine-123 is transported mainly by P glycoprotein. The biliary, renal, and tubular secretory clearances of rhodamine-123 and the glomerular filtration rate significantly decreased 6 h after injection of endotoxin but returned to control levels by 24 h. These results suggest that endotoxin-induced decreases in P-glycoprotein-mediated biliary excretion and renal handling of rhodamine-123 were probably due to impairment of P-glycoprotein-mediated transport ability. Pretreatment with pentoxifylline (50 mg/kg) significantly inhibited endotoxin-induced increases in tumor necrosis factor alpha (TNF-alpha) levels in plasma, which ameliorated the endotoxin-induced reduction of the biliary excretion of rhodamine-123. It is likely that endotoxin-induced impairment of the transport of rhodamine-123 is caused, in part, by overproduction of TNF-alpha. The effect of endotoxin on the expression of P-glycoprotein mRNA in liver and kidneys of rats was investigated by using a reverse transcriptase PCR. The expression of Mdr1a mRNA in both liver and kidney decreased 6 h after endotoxin injection and returned to control levels after 24 h, whereas the expression of Mdr1b mRNA in liver increased at both times and that in kidney decreased at 24 h. These findings suggest that K. pneumoniae endotoxin dramatically decreases P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 probably by decreasing the expression of Mdr1a, which is likely due to increased plasma TNF-alpha levels.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2004

Pharmacodynamic evaluation of the neutralization of endotoxin by PMX622 in mice.

Polymyxin B (PMB) binds to and neutralizes endotoxin, but its systemic clinical utility is limited by neuro- and nephrotoxicity. PMX622 is a covalent conjugate of PMB and Dextran-70 designed to retain the ability of PMB to neutralize endotoxin and to retain the favorable colloidal, pharmacokinetic, and metabolic properties of Dextran-70. PMX622 has demonstrated efficacy in a number of animal models and effectively neutralized endotoxin in phase I clinical trials. Here, we systematically evaluated the pharmacodynamic properties of PMX622 in a murine model of endotoxin-induced lethality in galactosamine-sensitized mice. PMX622 completely and dose dependently inhibited lethality in this model. A stoichiometric relationship was found between the endotoxin challenge dose and the dose of PMX622 needed for protection. PMX622 neutralized endotoxin from four different genera of gram-negative bacteria but not Neisseria meningitidis. PMX622 was significantly less toxic than PMB in the mouse, suggesting that PMX622 has a better margin of safety than PMB. The timing of PMX622 administration relative to endotoxin was crucial. PMX622 was active for several hours prior to the endotoxin challenge; however, PMX622 did not protect mice if administered >/=15 min after endotoxin challenge. This suggests that PMX622 would best be clinically used prophylactically rather than therapeutically. These studies will be crucial in designing and interpreting human clinical trials assessing PMX622 efficacy.

Animals↗
PubMed1986

Removal of endotoxin from water by microfiltration through a microporous polyethylene hollow-fiber membrane.

The microporous polyethylene hollow-fiber membrane has a unique microfibrile structure throughout its depth and has been found to possess the functions of filtration and adsorption of endotoxin in water. The membrane has a maximum pore diameter of approximately 0.04 micron, a diameter which is within the range of microfiltration. Approximately 10 and 20% of the endotoxin in tap water and subterranean water, respectively, was smaller than 0.025 micron. Endotoxin in these water sources was efficiently removed by the microporous polyethylene hollow-fiber membrane. Escherichia coli O113 culture broth contained 26.4% of endotoxin smaller than 0.025 micron which was also removed. Endotoxin was leaked into the filtrate only when endotoxin samples were successively passed through the membrane. These results indicate that endotoxin smaller than the pore size of the membrane was adsorbed and then leaked into the filtrate because of a reduction in binding sites. Dissociation of 3H-labeled endotoxin from the membrane was performed, resulting in the removal of endotoxin associated with the membrane by alcoholic alkali at 78% efficiency.

Animals↗
PubMed2005

Acute inflammatory response to endotoxin in mice and humans.

Endotoxin injection has been widely used to study the acute inflammatory response. In this study, we directly compared the inflammatory responses to endotoxin in mice and humans. Escherichia coli type O113 endotoxin was prepared under identical conditions, verified to be of equal biological potency, and used for both mice and humans. The dose of endotoxin needed to induce an interleukin-6 (IL-6) concentration in plasma of approximately 1,000 pg/ml 2 h after injection was 2 ng/kg of body weight in humans and 500 ng/kg in mice. Healthy adult volunteers were injected intravenously with endotoxin, and male C57BL/6 mice (n=4 to 12) were injected intraperitoneally with endotoxin. Physiological, hematological, and cytokine responses were determined. Endotoxin induced a rapid physiological response in humans (fever, tachycardia, and slight hypotension) but not in mice. Both mice and humans exhibited lymphopenia with a nadir at 4 h and recovery by 24 h. The levels of tumor necrosis factor (TNF) and IL-6 in plasma peaked at 2 h and returned to baseline levels by 4 to 6 h. IL-1 receptor antagonist RA and TNF soluble receptor I were upregulated in both mice and humans but were upregulated more strongly in humans. Mice produced greater levels of CXC chemokines, and both mice and humans exhibited peak production at 2 h. These studies demonstrate that although differences exist and a higher endotoxin challenge is necessary in mice, there are several similarities in the inflammatory response to endotoxin in mice and humans.

Adult↗
PubMed1998

Interleukin-1beta expression after inhibition of protein phosphatases in endotoxin-tolerant cells.

Endotoxin (lipopolysaccharide [LPS]) is a potent activator of a number of inflammatory genes in blood leukocytes, including interleukin-1 (IL-1). Blood leukocytes isolated from patients with septic shock fail to produce IL-1 in response to LPS, a phenomenon known as endotoxin tolerance. To study the regulation of IL-1 expression in endotoxin-tolerant cells, the protein phosphatase inhibitor okadaic acid was used to examine the effects of protein phosphorylation on IL-1beta gene expression. We found that endotoxin-tolerant cells produced normal levels of IL-1beta when protein phosphatases were inhibited. In the human pro-monocytic cell line THP-1, okadaic acid increased mRNA accumulation and synthesis of IL-1beta protein. Normal and endotoxin-tolerant THP-1 cells accumulated IL-1beta mRNA and protein with similar delayed kinetics. Okadaic acid stabilization of IL-1beta mRNA appears to be the primary mechanism through which endotoxin-tolerant cells accumulate IL-1beta mRNA and protein. Endotoxin-tolerant cells were unable to activate transcription in response to okadaic acid. However, the transcription factor NF-kappaB, which is known to be involved in IL-1beta expression, was translocated to the nucleus in both normal and endotoxin-tolerant cells after treatment with okadaic acid. These studies revealed that protein phosphorylation can affect gene expression on at least two distinct levels, transcription factor activation and mRNA stability. Endotoxin-tolerant cells have decreased transcription activation potential, while IL-1beta mRNA stability remains responsive to protein phosphorylation.

Cell Line↗
PubMed1976

Significant contribution of spleen cells in mediating the lethal effects of endotoxin in vivo.

Two closely related, histocompatible mouse strains that have marked differences in both in vitro and in vivo responses to endotoxin were used to evaluate the contribution of lymphoid cells to the lethal effect of endotoxin. C3H/HeJ mice are endotoxin resistant, whereas C3H/HeN mice are endotoxin sensitive. In vitro spleen cell mitogenic responses to endotoxin were similar in untreated mice and in mice that received sublethal irradiation (450 R) followed by reconstitution with autologous spleen cells. Reconstitution with spleen cells from the related strain produced chimeric animals with spleen cell mitogenic activity like that of the donor strain. When chimeric animals were subjected to a lethal challenge of endotoxin, their response was markedly altered by the transferred lymphoid cells. C3H/HeJ animals reconstituted with C3H/HeN cells became more endotoxin sensitive, whereas C3H/HeJ cells became more endotoxin resistant. These results indicate that spleen cells play a significant, detrimental role in endotoxin-induced lethality.

Animals↗
PubMed1979

Endotoxin toxicity in rats with 6-sulfanilamidoindazole arthritis.

Seven oral administrations of 6-sulfanilamidoindazole (6-SAI) to 10- to 12-month-old rats sensitized the animals to endotoxin, with dosages as small as 2.5 microgram causing death in 80% of animals. Endotoxin in a dosage of 3,000 microgram was not lethal for nonmedicated control animals. 6-SAI-treated 1-month-old rats were not as sensitive to endotoxin as aged animals. The sulfonamide-induced sensitivity to endotoxin could not be passively transferred and could not be explained by blockade of the reticuloendothelial system or impairment of endotoxin detoxification. 6-SAI administration was associated with both depletion of liver glycogen and lowering of blood glucose concentration without changes in blood lactic acid concentration. Disseminated intravascular coagulation is believed to be involved in the pathogenesis of shock and death as evidenced by: (i) concomitant decreases in plasma fibrinogen concentration and elevations in fibrin degradation products after endotoxin challenge; (ii) protection against lethal actions of endotoxin by pretreatment with heparin. Treatment of 6-SAI-medicated rats with glucocorticoids before endotoxin challenge protected the animals against lethal doses of endotoxin and prevented deposition of fibrin thrombi in the glomerular capillaries.

Aging↗
PubMed1983

Influence of endotoxin treatment on dexamethasone induction of hepatic phosphoenolpyruvate carboxykinase.

Decreased glucocorticoid binding has been observed at a time after endotoxin (3 to 6 h) when imparied liver enzyme induction is known to occur. This study was undertaken to characterize the early time course of hypoglycemia and decreased liver phosphoenolpyruvate carboxykinase (PEPCK) activity in intact and adrenalectomized mice given endotoxin. In addition, altered steroid induction of hepatic PEPCK was examined in adrenalectomized mice given dexamethasone at intervals before and after a median lethal dose of endotoxin. Intact mice demonstrated a dramatic hyperglycemia at 1 h after endotoxin treatment, a response absent in adrenalectomized mice. Plasma glucose levels were significantly reduced from control values at 3 and 6 h posttreatment, with the most pronounced endotoxin-induced hypoglycemia seen in adrenalectomized mice. Hepatic PEPCK activity in intact mice given endotoxin was decreased at 3 and 6 h after treatment, although no change from basal, noninduced levels was seen in poisoned adrenalectomized mice. The increased increment in hepatic PEPCK activity due to fasting of intact control mice was reproduced in adrenalectomized control mice by the administration of dexamethasone. Furthermore, the induction of hepatic PEPCK by dexamethasone was inhibited by 1 h after endotoxin treatment, with enzyme activity falling to basal, noninduced levels by 6 h posttreatment. At these same time intervals after endotoxin treatment, no evidence of histopathology in the liver or adrenal glands was seen. These results coincide with changes in steroid binding seen previously and indicate that endotoxin treatment produces significant alterations in glucocorticoid action at the subcellular or molecular level.

Adrenal Glands↗
PubMed1971

Enhanced toxicity for mice of combinations of antibiotics with Escherichia coli cells or Salmonella typhosa endotoxin.

Enhanced lethality for BALB/c mice has been observed after the administration of Salmonella typhosa endotoxin with either actinomycin D, cycloheximide, or nogalamycin. The dose of actinomycin D required to kill half of the mice (LD(50)) was 0.8 mg/kg in normal animals, 0.35 mg/kg in mice administered 0.08 mg of endotoxin per kg, and 0.28 mg/kg in mice administered 0.2 mg of endotoxin per kg. The LD(50) of endotoxin in normal mice was 12 mg/kg and in mice given 0.4 mg of actinomycin D per kg was 0.067 mg/kg. The LD(50) of actinomycin D in mice administered 1.8 x 10(8) live Escherichia coli cells per kg or 1.8 x 10(9) heat-killed E. coli cells per kg was reduced to 0.4 mg/kg. The LD(50) of cycloheximide was 181 mg/kg in normal animals and 28 mg/kg in mice administered 4 mg of endotoxin per kg. The LD(50) of endotoxin in mice given 120 mg of cycloheximide per kg was 0.02 mg/kg. Enhanced lethality due to various combinations of cycloheximide and endotoxin was abolished by pretreatment of mice with endotoxin. The LD(50) of nogalamycin was 21 mg/kg in normal mice and 13 mg/kg in mice receiving 1 mg of endotoxin per kg.

Animals↗
PubMed1991

Toxic shock syndrome toxin 1 enhances synthesis of endotoxin-induced tumor necrosis factor in mice.

Toxic shock syndrome toxin 1 (TSST-1) was tested for its ability to enhance the production of endotoxin-induced tumor necrosis factor (TNF) in C3H/HeN mice. The TNF level in serum was quantified by a sandwich enzyme-linked immunosorbent assay (ELISA). It was found that when mice were injected with 20 micrograms of TSST-1 12 h before exposure to 1 micrograms of endotoxin, the serum endotoxin-induced TNF was 20 times as high as that found in mice exposed to endotoxin alone. Although 20 micrograms of TSST-1 did induce a maximum level of near 1 ng of TNF per ml of serum 1.5 h after exposure, the TNF concentration was greatly diminished after 5 to 6 h and was no longer detectable after 12 h. Pretreatment of mice with 20 micrograms of TSST-1 or 1 micrograms of endotoxin did not influence TNF induction by TSST-1 12 h later. Also, pretreatment of mice with 1 micrograms of endotoxin did not enhance TNF induction by endotoxin 12 h later. Enhancement was achieved only when mice were exposed to TSST-1 more than 4 h and less than 24 h before injection of endotoxin. Despite the relatively high serum TNF levels (30 to 50 ng/ml), no mortality was observed in the mice treated with both TSST and endotoxin.

Animals↗