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PubMed2004

Solubility of endotoxins from Escherichia coli and Pseudomonas aeruginosa.

BACKGROUND: The Limulus amebocyte lysate (LAL) assay may underestimate endotoxins because only soluble endotoxins are determined. The solubility of endotoxins was, therefore, studied in two species of Gram-negative bacteria. METHODS: Cultures were grown in serum broth, cells were harvested by centrifugation and washed in physiological saline. Bacterial suspensions were either filtered through PTFE filters and air dried at room temperature, dried in polypropylene tubes at room temperature in a desiccator, or freeze dried. Samples were extracted with aqueous Tween 20. The soluble and insoluble fractions were dried, methanolysed, and hydroxy-fatty acid methyl esters were determined by gas chromatography (GC) as markers of endotoxins. RESULTS: The solubility of the endotoxins from Escherichia coli and Pseudomonas aeruginosa ranged from 9% to 83%. Species and drying conditions had substantial influence on the solubility. CONCLUSIONS: Endotoxin exposure may be underestimated in environmental samples by the LAL test because a substantial fraction can be non-soluble and is not detected.

Bacterial Toxins↗
PubMed1983

Endotoxins in cotton: washing effects and size distribution.

Endotoxin contamination was measured in washed and unwashed cottons from three distinct growing areas, California, Mississippi, and Texas. The data show differences in endotoxin contamination based upon the geographic source of the cotton. It is also shown that washing bulk cotton before the carding process results in lower endotoxin in the cotton dust. Washing conditions can affect the endotoxin levels, and all size fractions of the airborne dust contain quantifiable endotoxin contamination. Endotoxin analyses provide a simple and reliable method for monitoring the cleanliness of cotton or airborne cotton dusts.

Air Microbiology↗
PubMed1982

Endotoxin, prostaglandins and renal fibrin deposition in obstructive jaundice.

The delayed clearance of endotoxins in obstructive jaundice may cause renal impairment by inducing renal vasoconstriction and glomerular fibrin deposition as a consequence of intravascular coagulation. As endotoxins activate arachidonic acid metabolism we have examined the effects of selective inhibitors on mortality, plasma TXB2 and 6-oxo-PGF1 alpha production and renal fibrin deposition in rats with obstructive jaundice following endotoxin administration. Jaundiced rats had a high mortality following endotoxin--58 per cent at 4 h and 83 per cent at 24 h. Pretreatment with indomethacin 3 mg/kg i.p., dazoxiben 3 mg i.p. or prostacyclin 300 ng/kg i.v. produced significant improvements in survival. Endotoxaemia was associated with significant elevations of plasma TXB2 and early inhibition of plasma 6-oxo-PGF1 alpha generation. Renal fibrin deposition, assessed using indirect immunofluorescence and a 125I-labelled fibrinogen uptake ratio, occurred in jaundiced kidneys following endotoxin and could be prevented using indomethacin, dazoxiben and prostacylin. These results suggest that endotoxin-induced TXA2 production can cause renal fibrin deposition in obstructive jaundice, thus contributing in the pathogenesis of the renal impairment.

6-Ketoprostaglandin F1 alpha↗
PubMedDate not supplied

Role of the liver in endotoxin-induced hyperinsulinemia and hyperglucagonemia in rats.

The intravenous administration of bacterial endotoxin to fasted rats elicited basal portal and systemic venous hyperinsulinemia and hyperglucagonemia. Enhanced pancreatic secretion of insulin and glucagon was implied by the elevated portal venous hormonal levels. Elevated insulin and glucagon levels were present at 4 hr after a 33 micrograms/100 gm intravenous endotoxin dose despite no fluctuation of the plasma glucose concentration. The role of the liver in the pancreatic hormonal response to endotoxin was investigated by infusing lipopolysaccharide slowly into the portal vein or systemic inferior vena cava. At doses of 33 and 100 micrograms per 100 gm, endotoxin administered via the systemic route stimulated significantly greater insulin and glucagon responses than did portal administration. Furthermore, rats with acute liver injury induced by partial (67%) hepatectomy, which depressed Kupffer cell phagocytosis, did respond to the 33 micrograms per 100 gm intraportal endotoxin dose with significantly greater hyperinsulinemia and hyperglucagonemia. These data suggest that hepatic Kupffer cells normally function to remove lipopolysaccharide from the portal venous blood and that at least at low pharmacological doses the pancreatic hormonal response to endotoxin is mediated by an unknown systemic mechanism.

Animals↗
PubMedDate not supplied

Endotoxin levels measured by a chromogenic assay in portal, hepatic and peripheral venous blood in patients with cirrhosis.

Endotoxin concentrations were measured in the portal, hepatic and peripheral venous blood of two groups of patients with cirrhosis using a limulus-based chromogenic assay. The high sensitivity of chromogenic detection allowed measurement of endotoxin as low as 10 to 15 pg per ml, an order of magnitude greater than previously possible by gelation studies. Group 1 consisted of 56 patients with cirrhosis undergoing angiographic evaluation. In this group, there was wide variability in hepatic venous concentration [73 +/- 110 pg per ml (mean +/- S.D.)] and peripheral venous concentration [31 +/- 58 pg per ml]. However, paired t test showed peripheral venous concentration was significantly (p less than 0.001) lower than hepatic venous concentration. Neither hepatic or peripheral venous endotoxin levels correlated significantly with a variety of clinical, biochemical or radiological parameters. Group 2 consisted of 21 patients with cirrhosis undergoing shunt surgery. Endotoxin levels again showed a wide range, with portal venous concentration (142 +/- 167 pg per ml) and simultaneous peripheral venous concentration (82 +/- 150 pg per ml). Paired t test in this group showed a significant (p less than 0.001) portal to peripheral venous gradient. This study showed the feasibility of measuring endotoxin in plasma to low concentrations by a chromogenic assay technique. It supports the concept of relatively high levels of endotoxin in the portal circulation. In the presence of liver disease, systemic endotoxemia occurs, which is augmented by stressful situations.

Chromogenic Compounds↗
PubMed1989

Bile acids inhibit endotoxin-induced release of tumor necrosis factor by monocytes: an in vitro study.

Endotoxins play an important role in the pathogenesis of complications of surgery in obstructive jaundice. Preoperative treatment with orally administered deoxycholic acid prevented endotoxin-related complications, such as renal malfunction. Other bile acids, however, were less effective, and the mechanism of action is not known. Endotoxin toxicity is considered to be largely mediated by tumor necrosis factor/cachectin, a cytokine release by mononucler phagocytes. Therefore, we studied the influence of different bile acids on endotoxin-induced tumor necrosis factor production by monocytes in vitro. Bile acids inhibit tumor necrosis factor production through a direct inhibitory effect on the monocytes. Deoxycholic acid was the most effective, chenodeoxycholic acid was less effective and ursodeoxycholic acid was ineffective in the concentrations used. Bile acids did not inactivate endotoxin as measured in a chromogenic Limulus amebocyte lysate assay. The therapeutic effect of bile acids in obstructive jaundice can be explained by an inhibition of endotoxin-induced tumor necrosis factor release by mononuclear phagocytes.

Bile Acids and Salts↗
PubMed1990

Endotoxin and the hyperdynamic circulation of portal vein-ligated rats.

Humoral factors may be responsible for the hyperdynamic circulation seen in portal hypertension. Endotoxin, a peripheral arteriolar vasodilator, has been proposed to mediate this hemodynamic picture. We examined the pathogenic role of endotoxin in portal vein-ligated rats, a prehepatic portal hypertensive model with a well-developed hyperdynamic circulation. To this end, we (a) administered oral neomycin, a poorly absorbable antibiotic, at doses of 50 and 100 mg/day for 7 days and found no evident splanchnic hemodynamic effects of a 2-log-fold reduction of cecal aerobic bacterial flora as assessed by the radioactive microsphere technique in portal vein-ligated rats studied in the postanesthesia awake state; (b) assayed endotoxin in arterial samples using a quantitative limulus assay and found no evidence of endotoxinemia in PVL rats; (c) induced a state of endotoxin tolerance by repeated daily intraperitoneal injections of low-dose endotoxin and found no amelioration of the hyperdynamic state in portal vein-ligated rats. Our results do not support the hypothesis that endotoxin plays a major pathogenic role in the hyperdynamic circulation of this experimental model.

Ammonia↗
PubMed1996

Release of soluble intercellular adhesion molecule 1 into bile and serum in murine endotoxin shock.

Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecules Mac-1 (CD11b/CD18) on neutrophils and its counterreceptor on endothelial cells and hepatocytes, intercellular adhesion molecule 1 (ICAM-1). To investigate a potential release of a soluble form of ICAM-1 (sICAM-1), animals received 100 micrograms/kg Salmonella abortus equi endotoxin alone or in combination with 700 mg/kg galactosamine. In endotoxin-sensitive mice (C3Heb/FeJ), injection of endotoxin did not cause liver injury but induced a time-dependent increase of sICAM-1 in serum (300%) and in bile (615%) without affecting bile flow. In galactosamine/endotoxin-treated animals, which developed liver injury, the increase in both compartments was only 97% and 104%, respectively. In either case, the increase in sICAM-1 concentrations paralleled the enhanced ICAM-1 expression in the liver. The endotoxin-resistant strain (C3H/HeJ) did not show elevated sICAM-1 levels in serum or bile after endotoxin administration. In contrast, the intravenous injection of murine tumor necrosis factor alpha (TNF-alpha), interleukin-1 alpha (IL-1 alpha) or IL-1 beta (13-23 micrograms/kg) into endotoxin-resistant mice induced a 225% to 364% increase in serum sICAM-1 and a 370% elevation of the biliary efflux of sICAM-1, again independent of changes in bile flow. These data indicate that cytokines are major inducers of sICAM-1 formation during endotoxemia in vivo. The described experimental model can be used to investigate the role of sICAM-1 in the pathophysiology of inflammatory liver disease.

Analysis of Variance↗
PubMed1985

Effect of oxygen and endotoxin on lactate dehydrogenase release, 5-hydroxytryptamine uptake, and antioxidant enzyme activities in endothelial cells.

We compared the effects of 95% O2 (hyperoxia) alone, endotoxin (20 ng/ml) alone, and 95% O2 plus endotoxin on the release of lactate dehydrogenase (LDH), uptake of 5-hydroxytryptamine (5-HT), and antioxidant enzyme activities in porcine pulmonary arterial and aortic endothelial cells in monolayer culture. Hyperoxia increased LDH release and decreased 5-HT in both endothelial cell types. Hyperoxia also caused a decrease in catalase (CAT) activity and an increase in total superoxide dismutase (SOD) and glutathione reductase (GSH-Red) activities in both cell types. Endotoxin alone had no effect on LDH release, 5-HT uptake, or antioxidant enzyme activities. However, endotoxin prevented the hyperoxic increase in LDH release and the hyperoxic decrease in 5-HT uptake. Endotoxin plus 95% O2 had no consistent effect on the antioxidant enzyme profile in pulmonary artery or aortic endothelial cells. These results indicate that (1) hyperoxia injures both pulmonary artery and aortic endothelial cells in culture and causes changes in the antioxidant enzyme profile that are similar in the two cell types; (2) hyperoxia-induced decreases in CAT activity and increases in SOD activity may be responsible for increased sensitivity of endothelial cells to O2 toxicity; and (3) endotoxin protects against hyperoxic injury to endothelial cells in vitro, but increases in antioxidant enzyme activities are not the mechanism for this protection.

Animals↗
PubMed1995

Endotoxin infusion in anesthetized sheep is associated with intrapulmonary sequestration of leukocytes that immunohistochemically express tumor necrosis factor-alpha.

Plasma levels of tumor necrosis factor-alpha (TNF-alpha) peak between 2 and 4 h during a 12-h continuous infusion of endotoxin in awake sheep. We hypothesized that a source of this TNF-alpha is the pool of leukocytes that accumulate in the pulmonary circulation. To test this hypothesis, we physiologically monitored six anesthetized sheep during baseline and 4-h endotoxin infusion periods (10 ng/kg x min). We obtained open-lung biopsies at baseline and at 20 min and 2 and 4 h during the endotoxin infusion period for immunohistochemical localization of TNF-alpha. The plasma concentration of TNF-alpha increased from an average baseline concentration of 0.06 +/- 0.03 ng/ml (mean +/- SD) to a peak of 1.40 +/- 0.28 ng/ml at 2 h of the endotoxin infusion. We observed increased cytoplasmic TNF-alpha immunoreactivity in situ among neutrophils and intravascular mononuclear phagocytes during the endotoxin infusion compared with baseline. Also, the number of immunopositive leukocytes increased in the pulmonary circulation during the continuous infusion of endotoxin. We conclude that TNF-alpha-producing leukocytes accumulate in the pulmonary circulation during endotoxemia. These cells probably contribute to both the rise in the circulating levels of TNF-alpha and the development of acute lung injury.

Anesthesia↗
PubMed1977

Diverse effects of triamicinolone on the ocular response to circulating endotoxin.

The ocular response to circulating bacterial endotoxin (E coli 055:B5, 100 microgram/kg) can be either significantly reduced or made more servere by pretreatment with the synthetic glucocorticoid triamcinolone. A single injection (25 mg/kg) 3 hr prior to endotoxin sharply curtails the response. Daily injections for 3 days preceding endotoxin produces an enhanced response. With this regimen, an enhanced alteration in ocular vascular permeability is produced 4 hr following endotoxin if 5 mg of triamcinolone is injected daily; if larger quantities of steroid are employed (25 mg), there is a slight reduction in ocular vascular permeability, but an enhanced intravascular fibrin accumulation in ocular blood vessels as well as in capillaries of renal glomeruli (generalised Shwartzman reaction). Once the enhancement of the ocular response to endotoxin has been established by prior treatment with steroids, additional triamcinolone given 2--3 hr before endotoxin is no longer effective in protecting against ocular or renal changes. These divergent effects of steroid could be produced by either subcutaneous or intra-orbital injection, and the response was equal in both eyes following intra-orbital injection, suggesting that steroids probably do not exert their effects locally in this situation. Although different mechanisms of action of corticosteroids may be responsible for these diverse effects, it is suggested that a loss of responsiveness to steroids may be important in their ability to enhance the effects of endotoxinemia.

Animals↗
PubMed1987

Sinusoidal circulatory disturbance by microthrombosis as a cause of endotoxin-induced hepatic injury.

The present study was undertaken in rats to examine the significance of sinusoidal circulatory disturbance by microthrombosis in the pathogenesis of hepatic damage and dysfunction due to endotoxin. Administration of endotoxin induced fibrin deposits and infiltration of polymorphonuclear leukocytes in the sinusoids, focal random coagulative hepatocellular necrosis and elevation of serum transaminase activities. When heparin was given simultaneously with endotoxin, the formation of fibrin thrombus in the sinusoids was prevented, and the endotoxin-induced morphological and functional changes in the liver were markedly inhibited. Infusion of thrombin into the portal vein induced a large amount of fibrin thrombi in the sinusoids, focal random necrotic foci resembling the lesions produced by endotoxin and elevation of levels of serum transaminases. These experimental data suggest that disturbance of hepatic microcirculation by sinusoidal thrombosis is the necessary and sufficient condition for the development of endotoxin-induced hepatic injury.

Alanine Transaminase↗
PubMed1997

The release and detection of endotoxin from liposomes.

Incorporation of lipopolysaccharide (LPS) into liposomes dramatically reduces its ability to coagulate Limulus amebocyte lysate (LAL). The coagulation of LAL is commonly used to signal the presence of endotoxin in vitro. This study demonstrates a simple method to release masked endotoxin from liposomal dispersions using moderate amounts of detergent to form mixed micelles containing lipid, detergent, and LPS. Several parameters were found to affect the degree of liposome solubilization and/or the sensitivity of the LAL assay. These included detergent type and concentration, temperature for solubilization, lipid composition, liposome morphology, and time for test incubation. The nonionic detergent polyoxyethylene 10 lauryl ether (C12E10) proved to be unique in its ability to solubilize liposomes and minimally interfere with endotoxin detection. The LAL endotoxin detection limit for samples dispersed in C12E10 varied with the phospholipid component; the sensitivity decreased in the order DSPC > DPPC = EPC >> DMPC. Cholesterol lowered the solubility limit of the liposomes, but did not appear to affect the LAL assay sensitivity once the liposomes were completely solubilized. The presence of negatively charged phospholipids, DSPG and Pops, also lowered the solubility limit. Pops, but not DSPG, at 10 mol% further decreased the LAL endotoxin detection limit. This detergent-solubilization method should be useful in liposomal LPS immunological studies or in other situations where accurate determination of endotoxin concentration is important.

Animals↗
PubMed1996

Neonatal endotoxin exposure alters the development of social behavior and the hypothalamic-pituitary-adrenal axis in selectively bred mice.

Developmental differences in the biobehavioral consequences of immune activation in early life were investigated in two lines of mice selectively bred for high and low levels of inter-male aggressive behavior. At age 5 or 6 days, male mice were administered saline or 0.05 mg/kg gram-negative bacterial endotoxin (Escherichia coli, LPS, ip). There was a transient endotoxin-induced reduction in the growth rate of the neonates in the high-aggressive line. At age 45-50 days, the animals' behaviors were assessed in a dyadic task. Hypothalami and sera were harvested 20 min later. Rates of socially reactive behaviors to conspecific contact (i.e., kick, startle) were increased in the endotoxin-treated groups from both lines. For the high-aggressive line only, endotoxin treatment increased behavioral immobility, decreased attack frequency, and decreased levels of hypothalamic corticotrophin-releasing factor (CRF). The effects of endotoxin exposure in early life on socially reactive behaviors in later life were associated with endotoxin-induced individual differences in CRF levels in the high-aggressive line but not the low-aggressive line. The findings demonstrate long-term social developmental consequences of immune activation during the neonatal period.

Aggression↗
PubMed1983

Endorphins in endotoxin-induced hyperglycemia in mice.

This study assessed the role of endogenous opiate systems in the hyperglycemic response to endotoxin challenge in mice. Blockade of opiate receptors by administration of the opiate antagonists naloxone (1.0 mg/kg) or naltrexone (1.0 or 5.0 mg/kg) significantly lessened to degree of hyperglycemia cause by endotoxin challenge (80 micrograms). Methyl naltrexone, a peripherally acting opiate antagonist, had no demonstrable effect on endotoxin-induced hyperglycemia. Finally, induction of tolerance to morphine prevented the hyperglycemic response to endotoxin challenge. These results suggest a causative role for central nervous system endorphinergic mechanisms in the hyperglycemic response to endotoxin administration. They support the view that centrally acting opiate antagonist, by blocking the brain opiate receptors, can influence metabolic adaptation to endotoxin shock.

Animals↗
PubMed1980

Endotoxin-induced tumor necrosis factor.

The serum of BCG-infected mice treated with endotoxin contains a substance (tumor necrosis factor, TNF) which mimics the tumor-necrotizing action of endotoxin itself. TNF is not residual endotoxin, but a factor released from host cells, probably macrophages. TNF induced in the same way in rats and rabbits also causes necrosis of transplanted murine tumors. Unlike endotoxin, TNF is toxic in vitro for neoplastic murine and human cell lines but not for mouse embryo culture. TNF has striking effects on immunologic reactions in vitro, some like those of endotoxin and others unlike those of endotoxin. TNF is a glycoprotein; its molecular weight is less than 70,000. Highly purified preparations do not contain lysosomal or nonlysosomal serum enzymes, interferon or prostaglandin E1.

Animals↗
PubMed1992

Heart sarcolemmal Ca2+ transport in endotoxin shock: II. Mechanism of impairment in ATP-dependent Ca2+ transport.

The role of the phosphorylation and dephosphorylation of sarcolemma and that of the alteration of membrane lipids in the endotoxin-induced impairment of the ATP-dependent Ca2+ transport in canine cardiac sarcolemma were investigated. The results indicate that the ATP-dependent Ca2+ transport in canine cardiac sarcolemma was decreased by 30-35% 4 h after endotoxin administration. Phosphorylation of sarcolemma by the catalytic subunit of the cAMP-dependent protein kinase or calmodulin stimulated ATP-dependent Ca2+ transport in both groups, however, the phosphorylation-stimulated activities remained significantly lower in endotoxic animals. Dephosphorylation of sarcolemma decreased ATP-dependent Ca2+ transport in both groups, yet, the time required to reach maximal dephosphorylation was reduced from 120 to 90 min 4 h post-endotoxin. Analysis of sarcolemmal membranes reveals that phosphatidylcholine and phosphatidylethanolamine contents were decreased while their respective lysophosphatide levels were increased significantly after endotoxin injection. Digestion of control heart sarcolemma with phospholipase A2 inhibited Ca2+ transport and the inhibition was reversible by phosphatidylcholine. The inhibition caused by the in vivo administration of endotoxin was completely reversible by the addition of phosphatidylcholine. Based on these data, it is concluded that endotoxin administration impairs ATP-dependent Ca2+ transport in canine cardiac sarcolemma and that the impairment may be due to i) a defective phosphorylation of sarcolemma; ii) a reduced number of Ca2+ pumps; iii) an accelerated dephosphorylation of sarcolemma; and iv) an alteration in membrane phospholipid profile in response to phospholipase A activation.

Animals↗
PubMed1989

Exacerbation of toxic effects by endotoxin contamination of recombinant human tumor necrosis factor.

The toxic effects of endotoxin-free human recombinant tumor necrosis factor (rH-TNF), shown to contain less than 50 pg endotoxin/mg rH-TNF, were investigated and compared with those of rH-TNF and endotoxin coadministered at 4-400 ng endotoxin/mg rH-TNF in female Sprague-Dawley rats. The mean lethal dose of 5.9 mg/kg rH-TNF found for the endotoxin-free rH-TNF was far higher than that attributed to rH-TNF by other investigators. Coadministration with endotoxin derived from E. Coli. Salmonella abortus equi, or Serratia marcescens reduced the apparent mean lethal dose of rH-TNF in correspondence to the endotoxin concentration, with a value of 0.7 mg/kg rH-TNF observed at 1600 ng, 757 ng, and 5260 ng endotoxin/mg rH-TNF, respectively. Coadministration also resulted in more severe histopathologic and physicochemical effects than rH-TNF alone. Histopathologic abnormalities observed only in coadministration included interlobular edema and hemorrhage of the pancreas and, most remarkably, splenomegaly, which was not observed with rH-TNF alone even at lethal doses. The results indicate that particular care in determining endotoxin contamination is essential in any consideration of TNF toxicity.

Animals↗