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PubMed1990

Endotoxin measurement: aerosol sampling and application of a new Limulus method.

A new Limulus test was designed specifically for measuring endotoxin in environmental aerosols. The new Limulus method has a detection limit for airborne endotoxin of 2.2 pg (NP-1 activity)/m3 and can precisely quantitate aerosols containing 14 or more pg/m3 from samples representing 6.5 m3 of air. Aerosols in the range 100 to 500 pg/m3 were measured with 95% confidence of +/- 32% and an aerosol of 10 pg/m3 with 95% confidence of +/- 50%. Qualitative information about airborne endotoxin was also obtained from the assay. A wide variety of filter media were found to inactivate lipopolysaccharide in solution. This implies that airborne endotoxin can be measured only relative to the conditions of a particular study and that comparison of endotoxin aerosol measurements made under different circumstances are invalid. The research and policy implications of this observation are discussed. The need for improved collection and extraction methods notwithstanding, it was proposed that a buffered, parallel-line Limulus assay method be adopted as the standard method for measuring environmental endotoxin. The kinetic-turbidimetric Limulus assay with resistant-parallel-line estimates (KLARE), rate response method, should be considered a prime candidate for the standard method because of its precision, sensitivity, resistance to interference by pH, internal validation of estimates, and ability to provide qualitative as well as quantitative information about airborne endotoxin.

Aerosols↗
PubMed1994

Workers' exposure to airborne bacteria and endotoxins at industrial wastewater treatment plants.

A study of sewage workers' exposure to airborne culturable bacteria and inhaled endotoxins was performed at nine waste-water treatment plants that treat mainly industrial effluents. Airborne endotoxins were collected on glass fiber filters and analyzed using a chromogenic limulus assay. Endotoxin concentrations measured in the immediate vicinity of the waste-water treatment process varied from 0.1 to 350 ng/m3. The eight-hour time weighted average concentrations of endotoxin to which workers were exposed exceeded the suggested exposure limit (30 ng/m3 endotoxin) at four of the plants. Air samples of culturable bacteria concentrations varied between 10 and 10(5) colony-forming units/m3. Of the particles carrying culturable bacteria, 88% had an aerodynamic diameter of less than 4.7 microns. The most common genera of airborne gram-negative bacteria were acinetobacter, citrobacter, enterobacter, klebsiella, and pseudomonas. High levels of exposure to bacteria and bacterial endotoxin usually were related to certain phases of the treatment process. The microbiological contamination of air was highest near the inlets where incoming wastewater entered the basins, in the sludge treatment area, and inside the biofilter tower. In these spaces it is necessary to control and reduce exposure to airborne bacteria and endotoxin at wastewater plants.

Air Microbiology↗
PubMed1997

Environmental endotoxin measurement: interference and sources of variation in the Limulus assay of house dust.

Studies suggest that endotoxin levels in offices and homes may be associated with sick building syndrome or increased asthma severity. However, reported endotoxin levels in these studies were highly inconsistent, suggesting incompatible measurements from various laboratories. Therefore, an investigation of Limulus assay for endotoxin in house dust was undertaken. Interference with the assay was common and could produce endotoxin estimates varying by a factor of > 100, depending on the dilution used. Analysis of dose-response curves allowed detection of two types of interference: dilution-dependent and dilution-independent. Dilution-dependent interference persisted when samples were reassayed, but valid estimates could be obtained by appropriate dilution and data analysis. Valid estimates could not be obtained from assay showing dilution-independent interference. However, dilution-independent interference was frequently overcome by repeating the assay. Estimates based on a single sample dilution produced reasonable results on average when a dilution factor of 900 was used. However, the results were less precise from a single dilution (median coefficient of variation [CV] 40%) than from the complete dose-response curve (median CV 23%) and ranged from 11 to 240% of the estimates based on complete dose-response data. A comparison of extraction methods found that sonication in a phosphate-triethylamine buffer produced greater endotoxin activity than extraction in buffer with addition of saponin or sodium dodecyl sulfate. Endotoxin activity was stable for 8 to 10 weeks in dust samples stored at 4 and -20 degrees C but was not stable in extracts. The lot of Limulus amebocyte lysate reagent and method of detecting a response in the kinetic Limulus assay had significant effects on endotoxin estimates.

Analysis of Variance↗
PubMed1997

Field evaluation of endotoxin air sampling assay methods.

This study tested the importance of filter media, extraction and assay protocol, and bioaerosol source on the determination of endotoxin under field conditions in swine and poultry confinement buildings. Multiple simultaneous air samples were collected using glass fiber (GF) and polycarbonate (PC) filters, and these were assayed using two methods in two separate laboratories: an endpoint chromogenic Limulus amebocyte lysate (LAL) assay (QCL) performed in water and a kinetic chromogenic LAL assay (KQCL) performed in buffer with resistant-parallel line estimation analysis (KLARE). In addition, two aqueous filter extraction methods were compared in the QCL assay: 120 min extraction at 22 degrees C with vigorous shaking and 30 min extraction at 68 degrees C with gentle rocking. These extraction methods yielded endotoxin activities that were not significantly different and were very highly correlated. Reproducibility of endotoxin determinations from duplicate air sampling filters was very high (Cronbach alpha all > 0.94). When analyzed by the QCL method GF filters yielded significantly higher endotoxin activity than PC filters. QCL and KLARE methods gave similar estimates for endotoxin activity from PC filters; however, GF filters analyzed by the QCL method yielded significantly higher endotoxin activity estimates, suggesting enhancement of the QCL assay or inhibition of the KLARE asay with GF filters. Correlation between QCL-GF and QCL-PC was high (r = 0.98) while that between KLARE-GF and KLARE-PC was moderate (r = 0.68). Analysis of variance demonstrated that assay methodology, filter-type, barn-type, and interactions between assay and filter-type and between assay and barn-type were important factors influencing endotoxin exposure assessment.

Air Pollution, Indoor↗
PubMed1956

A study of the effect of serum on the immunological reaction of a bacterial endotoxin.

Contact of a purified endotoxin from Shigella fiexneri Type Z with normal rabbit or human serum results in an alteration of its immunological reaction with antiserum, as determined by precipitation in gel. Analysis of fractions of normal serum obtained by zone electrophoresis in starch indicates that the component responsible for altering the immunological reaction of endotoxin is associated with beta globulin. Normal serum has no similar effect on the immunological reaction of a variety of other protein and polysaccharide antigens. Serum from rabbits made tolerant to the pyrogenic action of an endotoxin from Serratia marcescens (P-35) possesses the ability to alter the reaction of Shigella endotoxin with its specific antiserum, although the serum from tolerant rabbits does not significantly enhance the pyrogenicity of Shigella toxm. The component of normal rabbit serum responsible for the effect on the immunological reaction of Shigella endotoxin is not destroyed by heating at 56 degrees C. The possible relationship of the effect of normal serum on the immunological reaction of endotoxin and the augmentation of fever induced by endotoxins is discussed.

Animals↗
PubMed1961

Studies on the pathogenesis of staphylococcal infection. IV. The effect of bacterial endotoxin.

Intracutaneous and intravenous injection of pyrogenic, non-lethal doses of bacterial endotoxin were found to increase the infectivity of pathogenic but not non-pathogenic staphylococci in rabbit skin. The increased infectivity of the microorganism was characterized by accelerated multiplication at the site of inoculation and by the production of necrosis and hemorrhage locally. Histologically, the infection of skin in endotoxin-prepared animals was characterized by necrosis, masses of bacteria, but absence of leukocytic infiltration into the area of bacterial growth. The infectivity of staphylococci in skin of endotoxin-prepared rabbits could be controlled by antibody to the alpha hemolysin of the microorganism. The effect of endotoxin upon staphylococcal infection was demonstrable only within 4 hours after injection of the endotoxin. It could not be prevented with chlorpromazine or dibenamine and was closely related to the effect of endotoxin upon leukocytes. It was suggested that the effect of endotoxin upon leukocytes was probably responsible for its influence upon staphylococcal infection. The implications of these findings in the pathogenesis of staphylococcal infection are discussed.

Animals↗
PubMed1961

The effect of bacterial endotoxins on the water intake and body weight of mice.

Injection of endotoxin of Gram-negative bacilli into NCS mice caused an immediate reduction or interruption of water intake by these animals, with a resultant loss of body weight. Endotoxins prepared by three different techniques from four different cultures of Gram-negative bacilli yielded products having approximately the same activity in inhibiting water intake. The minimum effective dose was 0.1 microg. or less. With all toxin preparations tested, the duration of the effect was directly related to the dose injected. The heat-killed cells of Esch. coli proved approximately as effective as the endotoxins prepared from Gram-negative bacilli. In contrast, heat-killed cells of Mycobacterium tuberculosis (BCG) were much less active, and heat-killed cells of Staphylococcus aureus were essentially inactive. Mice previously treated with endotoxin exhibited a marked degree of tolerance to the inhibition of water intake caused in normal animals by a subsequent treatment with the same material. Tolerance could also be induced by vaccination with heat-killed Gram-negative bacilli. Tolerance overlapped from one bacterial species to another but was more pronounced toward the endotoxin prepared from the bacterial culture with which the animal was vaccinated. The duration of the inhibitory effect of endotoxin on water intake was much shorter with mice fed a complete diet than with mice fed a deficient diet (corn). It took approximately the same dose of endotoxin (0.1 microg.) to inhibit water intake, reduce the influx of polymorphonuclear leucocytes, and enhance staphylococcal infection.

Animals↗
PubMed1961

Endotoxin fever in granulocytopenic animals.

The febrile response to bacterial endotoxin was measured in rabbits made leukopenic with nitrogen mustard. A striking increase in susceptibility to the lethal effects of endotoxin occurred in severely leukopenic animals. Animals without circulating granulocytes, or with only basophils, developed no significant fever after endotoxin injection. Animals with circulating granulocytes other than basophils exhibited a biphasic febrile response to endotoxin; this response was significantly less in magnitude than that of control animals. Control animals, severely granulocytopenic animals, and animals with no circulating granulocytes other than basophils showed comparable febrile responses to serum pyrogen. These results suggest that granulocytes inactivate endotoxin in vivo and support the hypothesis that leukocyte pyrogen is a necessary intermediate in endotoxin fever. Basophils do not appear to participate in this process. These observations also contradict previous studies that were taken to indicate a normal febrile response to endotoxin in leukopenic animals and suggest that those results are related to the persistence of granulocytes.

Agranulocytosis↗
PubMed1991

Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents.

Interleukin 8 (IL-8), a potent activator of neutrophils, may be important in the early host response to serious Gram-negative infections. IL-8 was measured with other acute phase cytokines (tumor necrosis factor alpha [TNF-alpha], IL-6 and IL-1 beta) in 25 normal humans randomized to receive either intravenous endotoxin alone or endotoxin after oral administration of ibuprofen or pentoxifylline, agents that alter some of the inflammatory responses induced by endotoxin in vitro. TNF immunoreactivity was maximum at 1.5 h, and total TNF (area under the curve) was 4.2- and 4.5-fold greater in subjects given endotoxin/ibuprofen compared to subjects given endotoxin alone (p = 0.026) or endotoxin/pentoxifylline (p = 0.004), respectively. IL-6 levels were maximum at 2-3 h and did not differ among the three groups. No IL-1 beta was detected in any subject. IL-8 levels peaked at 2 h in subjects given either endotoxin alone or endotoxin/pentoxifylline, falling towards baseline by 5 h. Subjects given endotoxin/ibuprofen had a more sustained rise in IL-8 with peak levels 2.8- and 2.5-fold higher at 3 h compared to endotoxin alone (p = 0.048) or endotoxin/pentoxifylline (p = 0.023), respectively. Differences in total IL-8 release among groups approached statistical significance (ANOVA, p = 0.07). This trend reflected the increased release of IL-8 by the subjects receiving ibuprofen compared to pentoxifylline (1.9-fold higher; p = 0.024). This suggests that cyclooxygenase products may provide important negative feedback loops for cytokine production in vivo. Increases in circulating IL-8 are part of the acute inflammatory response of humans to endotoxin. Altered cytokine responses caused by antiinflammatory therapy may have important implications for both host defense and injury during septicemia.

Adult↗
PubMed1953

Studies of the effect bacterial endotoxins on rabbit leucocytes. II. Development of acquired resistance.

Bacterial endotoxin injected intravenously into rabbits inhibited the migration of leucocytes from the buffy coat of centrifuged blood (4). Repeated daily injections of endotoxin resulted in the rabbits becoming resistant to the fever-inducing action of the toxin, and migration of leucocytes from centrifuged blood was no longer inhibited by injection of the toxin. Leucocyte migration from the buffy coat of centrifuged blood after injection of toxin into the rabbits appeared gradually over the first few days of repeated injections, and disappeared during the 10 to 15 days after cessation of daily injections of toxin. The resistance to endotoxin, demonstrated by leucocyte migration and pyrogen tolerance, could not be passively transferred with serum from resistant animals, and was non-specific, in that resistance to one endotoxin conferred some resistance to toxin from an organism of a different species. No relationship could be demonstrated between precipitin titer and resistance. Thorotrast abolished resistance to the fever-inducing activity of endotoxin, but its effect on leucocyte resistance was not clear, since when injected alone it inhibited migration of leucocytes from the buffy coat of centrifuged blood. The suggestion is made that the failure of toxin to inhibit the migration of leucocytes from resistant rabbits is due either to the presence of leucocytes which have become adapted to the toxin by repeated exposure, or to rapid removal of the toxin by the reticulo-endothelial system. It is unlikely that leucocyte resistance participates in the development of tolerance to the fever-inducing action of endotoxin. However, in view of the participation of the leucocyte in the pathogenesis of the Shwartzman reaction, the presence of leucocytes resistant to endotoxin may be responsible in part for the development of resistance to the Shwartzman phenomenon.

Animals↗
PubMed1984

Comparative investigation of a quantitative chromogenic endotoxin assay and blood cultures.

In a prospective study, the clinical relevance of a quantitative chromogenic endotoxin assay in plasma (detection limit 10 ng/L, assay time 2.5 hours) versus blood cultures was evaluated in 51 critically ill patients with increased susceptibility for infectious complications. Of the 400 samples tested, the endotoxin assay and bacterial culture both were negative in 342 samples. In 21 samples from 15 patients, gram-negative aerobic microorganisms were cultured. Corresponding endotoxin assays were positive in 14 samples (mean 100 ng/L). Twenty-three samples grew gram-positive bacteria. The associated endotoxin assays all were negative. Twelve samples were found to be endotoxin-positive without a corresponding gram-negative bacterial culture. In 7 of these 12 positive endotoxin assays, a laboratory or clinical explanation for these positive tests could be provided. In view of the high sensitivity, specificity, and predictive values obtained, the authors conclude that the endotoxin assay used is a useful clinical adjunct for both the detection and exclusion of gram-negative septicemia.

Bacterial Infections↗
PubMed1996

Methylprednisolone inhibits endotoxin-induced depression of contractile function in human arteries in vitro.

We have studied the effect of methylprednisolone on endotoxin-induced depression of contractile function in human gastroepiploic arteries. Endotoxin diminished the contractile response to noradrenaline in both the presence and absence of endothelium. This attenuation began after 4 h and reached a maximum after 10 h of endotoxin exposure. The cGMP content of endotoxin-treated rings was approximately seven-fold higher than in control rings. These endotoxin-mediated responses were blocked by L-NAME and methylene blue. These data indicate that the main cause of vascular hyposensitivity to noradrenaline was massive generation of nitric oxide. Pretreatment with methyl-prednisolone at concentrations (2.0-20.0 micrograms ml-1) similar to those achieved in plasma after therapeutic administration dose-dependently inhibited these endotoxin-mediated responses. These data support the concept that pharmacological administration of methylprednisolone has the potential to prevent endotoxin-induced depression of the contractile response to noradrenaline seen in endotoxaemic shock.

Acetylcholine↗
PubMed1976

Hypertriglyceridemia produced by endotoxin: role of impaired triglyceride disposal mechanisms.

The role of Salmonella typhimurium endotoxin in producing hypertriglyceridemia was investigated in 70 male rhesus monkeys. Dose-response studies were performed with 0.3-9.0 mg of endotoxin/kg injected intravenously; free fatty acids and triglycerides were measured during the subsequent 8 hr. The effect of endotoxin on lipid disposal mechanisms was assessed by both intravenous lipid-loading tests and total plasma lipolytic activity after administration of heparin. The possible interference of endotoxin with lipid-clearing enzymes was also explored. Smaller doses of endotoxin (0.3 and 0.9 mg/kg) produced significant increments in free fatty acids within 2-5 hr of administration, with minimal trilgyceride increments. Larger doses of endotoxin (2.8-9.0 mg/kg) failed to produce significant elevations in free fatty acids but did result in significant triglyceride increases 2-6 hr after administration. Within 4 hr after administration of 7 mg of endotoxin/kg, both tests showed impaired disposal of lipids. However, once lipid-clearing enzymes were activated, endotoxin did not reduce lipolytic activity in vitro. These results support the contention that endotoxin significantly elevates serum triglyceride concentrations and leads to impaired lipid disposal mechanisms by interfering with the activation of lipid-clearing enzymes.

Animals↗
PubMed1984

Kinetics of endotoxin release during antibiotic therapy for experimental gram-negative bacterial sepsis.

For study of the kinetics of endotoxin release from bacterial cells during therapy for gram-negative bacterial sepsis, serial blood samples were obtained from rabbits with Escherichia coli sepsis that were treated with either antibiotic or placebo. The concentrations of viable bacteria, free endotoxin, and total endotoxin in each blood sample were quantitated. In animals treated with placebo the concentration of free endotoxin was proportional to the level of bacteremia. In contrast, in animals treated with antibiotic the plasma levels of free endotoxin increased 10- to 2,000-fold, in spite of decreasing levels of bacteremia. Free endotoxin that was present in the plasma following antibiotic treatment appeared to be derived in part from the breakdown of circulating bacteria and in part from the disintegration of bacteria in tissues other than the blood. The results of this study demonstrate that significant amounts of endotoxin are released from bacterial cells following administration of antibiotics in vivo.

Animals↗
PubMed1989

Cerebrospinal fluid endotoxin levels in children with H. influenzae meningitis before and after administration of intravenous ceftriaxone.

Total, cell-free, and cell-bound endotoxin and bacterial density were measured in cerebrospinal fluid (CSF) of 22 children with Hemophilus influenzae meningitis. Also the effect of ceftriaxone on CSF endotoxin levels was investigated in eight patients by reexamining their CSF 2-6 h after the initial dose. Initial CSF bacterial density correlated with initial CSF endotoxin levels (P less than .001). Ceftriaxone induced a marked increase of free endotoxin in CSF, from an initial (mean +/- SE) 0.75 +/- 0.21 to 1.29 +/- 0.23 log10 ng/ml (P less than .01). This increase correlated positively with the number of bacteria killed in the CSF (P less than .01). The increase in free endotoxin was associated with an increase in mean CSF lactate levels from 8.5 to 9.7 units/l (P less than .05) and mean lactate dehydrogenase levels from 102 to 180 mmol/l (P less than .02) and a decrease in mean CSF glucose from 1.17 to 0.46 mmol/l (P less than .05). Initial CSF total endotoxin concentrations correlated both with the Herson-Todd clinical severity score (P less than .001) and with the number of febrile hospital days (P less than .001). These findings suggest that highly bactericidal agents initially lead to release of free endotoxin from gram-negative organisms into CSF, with associated enhanced inflammatory response by the host.

Ceftriaxone↗
PubMed1990

Endotoxin increases the nephrotoxic potential of gentamicin and vancomycin plus gentamicin.

To assess the possible role of endotoxin as an amplification factor for experimental nephrotoxicity due to gentamicin plus vancomycin, rats were given continuous intravenous (iv) endotoxin or saline followed by twice-daily intraperitoneal (ip) saline, vancomycin (20 mg/kg ip), gentamicin (15 mg/kg subcutaneously), or both gentamicin and vancomycin. After 5 or 8 days of treatment, functional and histologic parameters of renal function were evaluated: cortical drug levels, tritiated thymidine incorporation into cellular DNA, creatinine clearance, and appearance by light and electron microscopy. In animals not given endotoxin, only rats that received gentamicin plus vancomycin developed measurable abnormalities. Endotoxin did not cause nephrotoxicity in vancomycin-treated rats. However, in endotoxin-infused rats treated with gentamicin or gentamicin plus vancomycin for 8 days, the increase in blood urea nitrogen, decrease in creatinine clearance, and rise in renal cortical DNA synthesis were more severe than those in non-endotoxin-infused rats (P less than .01). In these studies, endotoxin amplified the nephrotoxic potential of gentamicin alone and gentamicin plus vancomycin.

Animals↗
PubMed1998

Anti-endotoxin therapeutic options for the treatment of sepsis.

The identification of lipopolysaccharide binding protein (LBP) and CD14 as key molecules in the cellular response to endotoxin has been a major advance in unravelling the pathophysiological basis of Gram-negative sepsis. Much interest has focused on developing effective anti-endotoxin treatments to abrogate the inflammatory consequences of Gram-negative infection. The therapeutic options can be divided into those aimed at neutralizing or clearing circulating endotoxin, including anti-endotoxin antibodies and endotoxin neutralizing proteins, and those that antagonize the effects of endotoxin on human cells--for example, lipid A analogues. Initial experiences with anti-lipopolysaccharide antibodies have been disappointing but a new generation of anti-endotoxin agents is about to enter clinical trials. Whether these will prove sufficiently effective to reduce the morbidity and mortality of Gram-negative sepsis remains to be seen.

Endothelium↗
PubMed1993

Reproductive condition, glomerular adenosine diphosphatase activity, and platelet aggregation in the rat: effect of endotoxin.

In experiment A, the activity of the glomerular antithrombotic enzyme adenosine diphosphatase (ADPase) and the sensitivity of this enzyme for endotoxin (1.0 microgram/kg BW) in various reproductive conditions of female rats were studied through use of enzyme histochemical methods. In experiment B, the effect of this dose of endotoxin on the thrombotic tendency of the glomeruli in pregnant (Pr) and pseudopregnant (PSP) rats was studied by means of ex vivo alternate perfusion of the kidneys with human platelets and adenosine diphosphate (ADP). In experiment A, cyclic (C), ovariectomized (OVX), Pr, and PSP rats were infused with endotoxin or saline. Three days later (for Pr and PSP rats, Day 8), animals were killed. In intact rats (C, Pr, PSP), the activity of glomerular ADPase was the same; however, the activity decreased after OVX. Endotoxin decreased the activity of glomerular ADPase in Pr rats only. In endotoxin-treated Pr rats, spontaneously formed platelet microaggregates were present in a few glomeruli; in glomeruli of the other groups, microaggregates were not observed. Platelet microaggregates were also present in the venous microvasculature of endotoxin-treated Pr rats and, to a lesser extent, in that of other groups, while saline-treated OVX rats were negative in this respect. In experiment B, Pr and PSP rats were treated as in experiment A; ex vivo kidney perfusion was performed on Day 8. Immediately after perfusion, rats were killed. Only Pr endotoxin-treated rats exhibited significantly increased intraglomerular platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗