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PubMed2000

Endotoxin-induced mesenteric microvascular changes involve iNOS-derived nitric oxide: results from a study using iNOS knock out mice.

The administration of endotoxin alters intestinal blood flow, increases nitric oxide (NO) production, and induces gut barrier dysfunction. Thus, we investigated the hypothesis that microvascular reactivity and permeability of the mesenteric vascular bed are altered to a lesser degree in iNOS knock out (iNOS -/-) mice than their wild-type (iNOS +/+) litter mates after an endotoxin challenge. To test this hypothesis, we compared the microvascular response of iNOS knockout (iNOS -/-) mice after a topical or systemic endotoxin challenge against that of their wild-type litter mates (iNOS +/+). Intravital microscopy was used to measure arteriolar diameter and postcapillary venular permeability in the mouse ileum. Both parameters were determined by computer-assisted image analysis. Diameter was measured in A1, A2, and A3 arterioles (1, 2, 3 = rank of deployment). Changes in microvascular permeability were measured from changes in interstitial fluorescence caused by extravasation of fluorescein isothiocyanate (FITC)-dextran 150 (molecular weight = 150 kDa) and expressed as changes in integrated optical intensity (IOI). In the first series of experiments, endotoxin (100 microg/mL) was applied topically to the ileal segment. In the second series, endotoxin (10 mg/kg) was administered intraperitoneally (i.p.). Administration of topical or i.p.. endotoxin caused vasoconstriction and was associated with an early increase in permeability in both iNOS +/+ and -/- mice, although over time the responses of the iNOS -/- and iNOS +/+ mice diverged. Twenty minutes after topical endotoxin, the increase in permeability in iNOS -/- mice had reached a plateau whereas it continued to increase in the iNOS +/+ mice, such that at 80 min post-topical endotoxin, IOI was 27+/-7 in iNOS -/- vs. 39+/-5 in iNOS +/+ (P < 0.05). A similar permeability response was observed after i.p.. endotoxin, where the increase in post-capillary venular permeability was greater in the iNOS +/+ mice (P < 0.05). Both iNOS -/- and iNOS +/+ mice had a similar transient vasoconstrictive response after topical endotoxin challenge (reduction in A2 arteriolar diameters by -17+/-4% vs. -24+/-7%), with return to baseline values by 60-80 min post-endotoxin challenge. The iNOS +/+ but not the iNOS -/- mice manifested a secondary vasodilatory response that persisted throughout the experimental period. The arteriolar vasoreactive response of the iNOS -/- and iNOS +/+ mice to i.p.. endotoxin was similar to that of topical endotoxin, but of a lesser magnitude. In conclusion, the similarity in effects between topical and systemic endotoxin indicates that endotoxin causes microvascular dysfunction in the gut by directly on the microcirculation. In addition, our data suggest that NO production by iNOS is involved in the microvascular alterations associated with gut barrier dysfunction.

Administration, Topical↗
PubMed2003

Regulation of interactions of endotoxin with host cells.

Potent Toll-like receptor 4 (TLR4)-dependent cell activation by endotoxin requires lipopolysaccharide-binding protein (LBP) and CD14-dependent delivery of endotoxin to cells containing MD-2 and TLR4. We have used metabolically labeled [(14)C] meningococcal lipooligosaccharide (LOS), purified recombinant endotoxin-binding proteins, and cultured endothelial cells to better define protein:endotoxin intermediates key in cell activation in the absence of functional membrane (m) CD14. Protein:endotoxin complexes or aggregates (agg) were purified by gel sieving and characterized by immunocapture and bio-assays. Cell activation closely correlated with LBP, albumin and soluble (s) CD14-dependent conversion of endotoxin agg (M(r) > or = 20 x 10(6)) to monomeric (M(r) approximately 55 x 10(3)) endotoxin:sCD14 complexes. Ordered interaction of LBP (+ albumin) and sCD14 with LOSagg was required for the efficient formation of a bioactive endotoxin:sCD14 complex and potent cell activation. Increasing the ratio of LBP/sCD14 or addition of bactericidal/permeability-increasing protein (BPI) reduced accumulation of endotoxin:sCD14 complexes and instead yielded aggregates of endotoxin (M(r) approximately 1-20 x 10(6)) containing LBP or BPI that were taken up by cells in a CD14- and TLR4-independent manner without inducing pro-inflammatory responses. These findings strongly suggest that host machinery linked to TLR4-dependent cellular activation or TLR4-independent cellular clearance of endotoxin selectively recognizes different protein:endotoxin complexes. At the outset of infection, the low concentrations of LBP present and absence of extracellular BPI favor formation of pro-inflammatory endotoxin:CD14 complexes. The mobilization of LBP and BPI that is triggered by inflammation directs endotoxin for clearance and hence resolution of endotoxin-triggered inflammation.

Albumins↗
PubMed2005

Monomeric endotoxin:protein complexes are essential for TLR4-dependent cell activation.

Potent TLR4-dependent cell activation by Gram-negative bacterial endotoxin depends on sequential endotoxin?protein and protein?protein interactions with LBP, CD14, MD-2 and TLR4. LBP and CD14 combine, in an albumin-dependent fashion, to extract single endotoxin molecules from purified endotoxin aggregates (E(agg)) or the bacterial outer membrane and form monomeric endotoxin:CD14 complexes that are the preferred presentation of endotoxin for transfer to MD-2. Endotoxin in endotoxin:CD14is readily transferred to MD-2, again in an albumin-dependent manner, to form monomeric endotoxin:MD-2 complex. This monomeric endotoxin:protein complex (endotoxin:MD-2) activates TLR4 at picomolar concentrations, independently of albumin, and is, therefore, the apparent ligand in endotoxin-dependent TLR4 activation. Tetra-, penta-, and hexa-acylated forms of meningococcal endotoxin (LOS) react similarly with LBP, CD14, and MD-2 to form endotoxin:MD-2 complexes. However, tetra- and penta-acylated LOS:MD-2 complexes are less potent TLR4 agonists than hexa-acylated LOS:MD-2. This is mirrored in the reduced activity of tetra-, penta- versus hexa-acylated LOS aggregates (LOS(agg)) + LBP toward cells containing mCD14, MD-2, and TLR4. Therefore, changes in agonist potency of under-acylated meninigococcal LOS are determined by differences in properties of monomeric endotoxin:MD-2.

Cell Line↗
PubMed1999

Endotoxin disrupts the estradiol-induced luteinizing hormone surge: interference with estradiol signal reading, not surge release.

Three experiments were conducted to investigate whether the immune/inflammatory stimulus endotoxin disrupts the estradiol-induced LH surge of the ewe. Ovariectomized sheep were set up in an artificial follicular phase model in which luteolysis is simulated by progesterone withdrawal and the follicular phase estradiol rise is reproduced experimentally. In the first experiment, we tested the hypothesis that endotoxin interferes with the estradiol-induced LH surge. Ewes were either infused with endotoxin (300 ng/kg/h, i.v.) for 30 h beginning at onset of a 48-h estradiol stimulus or sham infused as a control. Endotoxin significantly delayed the time to the LH surge (P < 0.01), but did not alter surge amplitude, duration, or incidence. The second experiment tested the hypothesis that the delaying effects of endotoxin on the LH surge depend on when endotoxin is introduced relative to the onset of the estradiol signal. Previous work in the ewe has shown that a 14-h estradiol signal is adequate to generate GnRH and LH surges, which begin 6-8 h later. Thus, we again infused endotoxin for 30 h, but began it 14 h after the onset of the estradiol signal. In contrast to the first experiment, endotoxin given later had no effect on any parameter of the LH surge. In the third experiment, we tested the hypothesis that endotoxin acts during the first 14 h to disrupt the initial activating effects of estradiol. Estradiol was delivered for just 14 h, and endotoxin was infused only during this time. Under these conditions, endotoxin blocked the LH surge in five of eight ewes. In a similar follow-up study, endotoxin again blocked the LH surge in six of seven ewes. We conclude that endotoxin can disrupt the estradiol-induced LH surge by interfering with the early activating effects of the estradiol signal during the first 14 h (reading of the signal). In contrast, endotoxin does not disrupt later stages of signal processing (i.e. events during the interval between estradiol signal delivery and surge onset), nor does it prevent actual hormonal surge output. Thus, endotoxin appears to disrupt estrogen action per se rather than the release of GnRH or LH at the time of the surge.

Animals↗
PubMed2001

Predictors of airborne endotoxin in the home.

We identified home characteristics associated with the level of airborne endotoxin in 111 Boston-area homes enrolled in a cohort study of home exposures and childhood asthma, and we developed a predictive model to estimate airborne endotoxin. We measured endotoxin in family-room air and in dust from the baby's bed, family room, bedroom, and kitchen floor. Level of airborne endotoxin was weakly correlated (r < 0.3) with level of endotoxin in each of the four types of dust samples and was significantly correlated with endotoxin in family-room dust (p < 0.05). Endotoxin in family-room dust accounted for < 6% of the variability of airborne endotoxin. In a multivariate model, certain home characteristics were positively (p < 0.05) associated with airborne endotoxin. These included current presence of dog (difference in level, dog vs. no dog = 72%, partial R(2 )= 12.8%), past presence of dog (partial R(2) = 5.5%), and endotoxin level in family-room dust (partial R(2) = 5.3%). Use of a dehumidifier (partial R(2) = 6.4%) was negatively associated (p = 0.02; difference = -31%) with airborne endotoxin. Other home characteristics were identified as important determinants of increased airborne endotoxin in this model, but individual coefficients were not statistically significant (alpha = 0.05): total amount of fine dust collected in the home (partial R(2 )= 3.8%), concrete floor in family room (3.7%), water damage (3.6%), and use of cool-mist humidifier in past year (2.7%). This multivariate model explained 42% of the variability of airborne endotoxin levels, a substantial improvement over that with dust endotoxin alone. Airborne endotoxin in Boston-area homes appears to be determined by the presence of dogs, moisture sources, and increased amounts of settled dust.

Air Pollutants↗
PubMed2006

Home endotoxin exposure and wheeze in infants: correction for bias due to exposure measurement error.

Exposure to elevated levels of endotoxin in family-room dust was previously observed to be significantly associated with increased wheeze in the first year of life among a cohort of 404 children in the Boston, Massachusetts, metropolitan area. However, it is likely that family-room dust endotoxin was a surrogate for airborne endotoxin exposure. Therefore, a related substudy characterized the relationship between levels of airborne household endotoxin and the level of endotoxin present in house dust, in addition to identifying other significant predictors of airborne endotoxin in the home. We now reexamine the relationship between endotoxin exposure and wheeze under the assumption that the level of airborne endotoxin in the home is the exposure of interest and that the amount of endotoxin in household dust is a surrogate for this exposure. We applied a measurement error correction technique, using all available data to estimate the effect of endotoxin exposure in terms of airborne concentration and accounting for the measurement error induced by using house-dust endotoxin as a surrogate measure in the portion of the data in which airborne endotoxin could not be directly measured. After adjusting for confounding by lower respiratory infection status and race/ethnicity, endotoxin exposure was found to be significantly associated with a nearly 6-fold increase in prevalence of wheeze for a one interquartile range increase in airborne endotoxin (95% confidence interval, 1.2-26) among the 360 children in households with dust endotoxin levels between the 5th and 95th percentiles.

Air Pollution, Indoor↗
PubMed1977

Tissue factor generation by human mononuclear cells: effects of endotoxin and dissociation of tissue factor generation from mitogenic response.

The effects of the presence of endotoxin in a mononuclear cell culture system have been assessed. Endotoxin was shown to be mitogenic for human peripheral blood lymphocytes and capable of stimulating the generation of tissue factor. Concentrations of endotoxin, found to contaminate many commercial mitogens and antigens, activated mononuclear cells in a time-dependent manner. Generation of tissue factor was detected in cultures harvested from 2 to 72 hours following stimulation with endotoxin. Dose-response curves relating concentrations of endotoxin to mononuclear cell stimulation were determined; as little as 0.001 microng/ml. of E. coli endotoxin was capable of stimulating the generation of tissue factor in the cell cultures. The mitogenic effect of endotoxin was modest, however, and appeared to be unrelated to the ability of endotoxin to active tissue factor. Inhibition of DNA synthesis in the cell cultures by cytosine arabinoside or nonlethal irradiation failed to impair the generation of tissue factor. Endotoxin contamination of various reagents used in cell culture was evaluated with the Limulus assay, which detected as little as 1 X 10(-4) microng/ml. of endotoxin. Endotoxin was detected in preparations of phytohemagglutinin, purified protein derivative of the tubercle bacillus, mumps vaccine, tetanus toxoid, concanavalin A, and pokeweed mitogen. Because of the broad implications of contamination by endotoxin of various reagents, we assessed the specificity of the Limulus assay for the detection of endotoxin in the lectin, concanavalin A, and determined that the reaction was specific for endotoxin. Contamination by endotoxin of mononuclear cell culture systems should be considered as a possible factor in the production of various biological effects attributed to some commonly used mitogens and antigens.

Cytarabine↗
PubMed2005

Inflammatory and immunological responses to subchronic exposure to endotoxin-contaminated metalworking fluid aerosols in F344 rats.

Rats were exposed for 6 h per day in inhalation chambers to a 10 mg/m(3) concentration of metalworking fluid (MWF) contaminated with endotoxin at concentrations of 1813 (low dose) and 20,250 eu/m(3) (high dose) 5 days per week for 8 weeks. It was found that 94.7% of the MWF aerosol particles had diameters in the range of 0.42-4.6 microm, with geometric mean diameter of 1.56 microm. The body weight and pulmonary function parameters were measured every week during the 8 weeks of exposure, whereas bronchoalveolar lavage (BAL) fluid was prepared to measure the inflammatory markers and cytokines after the 8 weeks of exposure. There were no changes in body weight and respiratory function (tidal volume and respiratory frequency) during the 8 weeks of exposure to the MWF containing endotoxins, yet lung weight increased significantly (P < 0.05) in the rats exposed to the MWF both with and without endotoxins. The number of polymorphonuclear (PMN) cells in the BAL fluid increased significantly (P < 0.05) in the rats exposed to MWF with endotoxins, and the levels of cytokines such as IL-4, INF-gamma, IL-1beta, and TNF-alpha also were significantly increased (P < 0.05) compared to the control. The NOx production activity of the BAL cells increased significantly (P < 0.05) in the rats exposed to the MWF with and without endotoxins. Increases in lung weight, number of PMN cells, and levels of extracellular cytokines and NOx were all more significant in the rats exposed to the MWF with endotoxins rather than in those exposed to MWF without endotoxins. In spleen cell cultures, T-cell proliferation activity was decreased, yet cytokine levels (INF-gamma, IL-1beta, IL-4, and TNF-alpha) remained unchanged after repeated exposure to MWF with and without endotoxins. Although the levels of total IgG(1), IgG(2a), and IgE antibodies in the serum were not changed, the levels of endotoxin-specific antibodies, including IgG(2a) and IgE, were increased significantly (P < 0.05) in the rats exposed to endotoxins, but there was not a significant increase in endotoxin-specific IgG(1). When taken together, the results indicate that lung inflammatory responses can be induced without changing pulmonary function after repeated exposure to MWFs contaminated with endotoxins. In addition, endotoxin-specific IgG(2a) and IgE may be effective biomarkers for workers exposed to MWFs contaminated with endotoxins in the workplace.

Aerosols↗
PubMed2003

Seasonal variability of endotoxin in ambient fine particulate matter.

Endotoxin is a toxic, pro-inflammatory compound that has been detected in indoor air and dust in homes and occupational settings, and also in outdoor air. Data on the outdoor sampling of endotoxin are limited. Currently, little is known about the seasonal variation and influence of temperature on outdoor endotoxin levels. In the present study, we report endotoxin levels in fine fraction particulate matter with a 50% aerodynamic cutoff diameter of 2.5 microm (PM2.5) and describe the seasonal variation of endotoxin in Munich, Germany. In 1999-2000, PM2.5 was collected at forty outdoor monitoring sites across Munich. Approximately four samples were collected at each site for a total of 158 samples. Endotoxin concentrations in the PM2.5 samples were determined using the kinetic chromogenic Limulus Amebocyte Lysate (LAL) assay. The geometric mean endotoxin concentration was 1.07 EU mg PM2.5(-1) (95% C.I.: 0.915-1.251) or 0.015 EU m(-3) of sampled air (95% C.I.: 0.013-0.018). Munich endotoxin levels were significantly related to ambient temperature (p < 0.0001) and percent relative humidity (p < 0.0001). Sampling periods with higher average temperatures yielded higher levels of endotoxin in PM2.5 (r = 0.641), whereas decreases in percent relative humidity were associated with increased endotoxin levels in PM2.5 (r = -0.388). Endotoxin levels were significantly higher during the warmer seasons of spring [means ratio (MR): 2.5-2.7] and summer (MR: 2.1-3.0) than during winter. Although temperature and relative humidity do not explain all of the variability in endotoxin levels, their effects were significant in our data set. Temperature effects and seasonal variation of endotoxin should be considered in future studies of outdoor endotoxin.

Air Pollutants↗
PubMed2004

Enhanced pulmonary inflammatory response to inhaled endotoxin in pregnant rats.

Evidence suggests that pregnant animals are more sensitive than nonpregnant animals to the systemic administration of endotoxin. Studies were undertaken to assess whether an enhanced sensitivity of the pulmonary system to aerosolized endotoxin might exist during pregnancy. Pregnant Sprague-Dawley female rats (17 d of gestation) or age-matched virgin female rats were exposed to air or endotoxin (lipopolysaccharide) by inhalation for 3 h. At 18 h following exposure to endotoxin, lactate dehydrogenase activity levels in bronchoalveolar lavage (BAL) fluid samples from pregnant rats were 1.5-fold greater than those from endotoxin-exposed virgin rats. BAL polymorphonuclear leukocyte (PMN) numbers were also approximately twofold greater in pregnant rats than in virgins following the inhalation of endotoxin. The increases in BAL PMNs in pregnant rats following endotoxin exposure were observed just following exposure to endotoxin as well as at 18 h following exposure. These results indicate that an increased pulmonary inflammatory response to inhaled endotoxin occurs during pregnancy in rats. Additional findings suggest that these pregnancy-linked pulmonary responses to endotoxin cannot be explained by the following potential mechanisms: changes in the inhaled dose of endotoxin, or alterations in the responsiveness of alveolar macrophages to endotoxin. To our knowledge this is the first study that has evaluated pulmonary responses to inhaled endotoxin during pregnancy. Our finding that pregnancy is associated with an increased lung inflammatory response to aerosolized endotoxin raises the possibility that there may be a generalized enhancement of pulmonary responses to inhaled toxic agents during pregnancy.

Aerosols↗
PubMed2005

Surface sampling for endotoxin assessment using electrostatic wiping cloths.

OBJECTIVES: Much of the cost of exposure assessment for studies of residential cohorts is in scheduling and travel time for field staff. One way to reduce costs is to simplify methods such that subjects can sample their own residence. Analysis of settled dust is being widely used for assessment of exposures to allergens, lead and pesticides and can also be used for endotoxins. While vacuum sampling is the most common surface sampling method, wipe sampling has the advantage that it can be readily performed by the resident when convenient and samples can then be mailed to researchers. Thus, we evaluated the feasibility of wipe sampling for endotoxin environmental assessment using electrostatic wipes with or without the use of disposable examination gloves. METHODS: Multiple lots of six types of commercial wipes and eight types of gloves were extracted and analyzed for endotoxin content using the kinetic chromogenic Limulus amebocyte lysate assay. Wipes were compared across brands, between lots, within lots, between pairs depending on proximity to cardboard packaging, and in wipe tests with or without gloves. Collected dust samples of known concentration were also tested in spiking assays for endotoxin recovery. RESULTS: The most striking finding was the high variability of endotoxin contamination of both wipes and gloves across brands and between various lots. The content of endotoxin in unused gloves ranged from <1.5 to 5810 endotoxin units (EU). The range for unused wipes was 3.6-87.8 EU. Surfaces of equal loading and area were sampled using three types of cloths that had low initial endotoxin contamination. The cloths were very good at collecting dust and endotoxin could be assayed from aqueous extracts of the wipes. Samples collected using cloths with bare washed hands yielded higher endotoxin loading per mass of collected dust versus samples collected wearing endotoxin-free gloves. This demonstrated additional endotoxin loading from the subject's hand. CONCLUSION: This study shows that wipe sampling while wearing medical gloves can be an effective method for collecting and assessing endotoxin on surfaces, so long as each lot of wipes and gloves have been tested and determined to be low in endotoxin.

Air Pollutants↗
PubMed1999

Vascular permeability increase and plasma volume loss induced by endotoxin was attenuated by hypertonic saline with or without dextran.

Endotoxin given intravenously is known to cause plasma leakage and subsequent loss of circulating plasma volume. Hypertonic saline resuscitation has been successfully applied in hemorrhagic and traumatic shock, but its application for the treatment or prevention of septic or endotoxin shock is less well studied. Our aim was to investigate the effects of endotoxin on plasma leakage in hamsters when administered in two different ways: applied locally to the hamster cheek pouch microcirculation or systemically by i.v. injection. The cheek pouch was studied by intravital microscopy using FITC-labeled dextran as a tracer of plasma leakage. Escherichia coli lipopolysaccharide (LPS) was continuously added into the superfusion buffer of the cheek pouch preparation during 120 min in two control groups (each n = 6) and two further groups (each n = 6) treated with either hypertonic saline (HS) or hypertonic saline and dextran (HSD). Treatment was given as an i.v. injection 0.35 mL NaCl 7.5%/100 g b.w. during 4 min starting 15 min prior to the start of endotoxin application. Endotoxin caused a reversible increase in the number of postcapillary venular leaks with a maximal response at 70 min after start of endotoxin application. The maximal responses were reduced to 36% in the HS-treated and to 37% in the HSD-treated group in comparison to what was seen in the control groups. In the second part of the study endotoxin was given i.v. 0.3 mg/kg to anesthetized hamsters (n = 41) and arterial blood samples were collected at 0, 60, 120, and 180 min after endotoxin injection for measurement of hematocrit and plasma FITC-dextran concentration. Hamsters were divided into seven groups: untreated control group (n = 6); HSC control group given only an i.v. injection of hypertonic saline (n = 6); LPS group given endotoxin 0.3 mg/kg during 1 min (n = 9); HSp group given hypertonic saline (NaCl 7.5%) 10 min prior to i.v. endotoxin (n = 6); HSa group given hypertonic saline 10 min after i.v. endotoxin (n = 6); HSD group given hypertonic saline with dextran 40, 10 min prior to i.v. endotoxin (n = 6); HSD control group given only i.v. hypertonic saline + dextran and no endotoxin (n = 2). Injection of endotoxin caused a significant increase in hematocrit, which was counteracted by hypertonic saline treatment, with or without dextran, probably due to reduced extravasation of plasma in postcapillary venules.

Animals↗
PubMed1982

In vitro and in vivo association and subcellular distribution of toxic and experimentally modified endotoxin.

Cell association and organ distribution of toxic and experimentally modified endotoxin were compared in whole animals and hepatoma tissue culture (HTC) cells. For both toxic and poly-l-alpha-ornithine mixed endotoxin in vivo, most of the endotoxin becomes associated with the reticuloendothelial system (RES) rich organs. Organ distribution does not change from 1 to 5 h. Significantly less detoxified endotoxin becomes associated with RES-rich organs. Association and nuclear transfer of toxic endotoxin in HTC cells are gradual and time-dependent processes. Plasma treatment increased association of endotoxin with HTC cells. Poly-l-alpha-ornithine (4 micrograms/mL) also significantly increases HTC cell association of endotoxin, and nuclear transfer of endotoxin was similar in principle to the toxic material. Association of detoxified endotoxin with HTC cells is significantly higher than toxic endotoxin and increases with time. In contrast with toxic and poly-l-alpha-ornithine mixed endotoxin, nuclear association of alkaline-treated detoxified endotoxin did not increase significantly during 5 h incubation. Cumulatively, these observations indicate that while tissue culture cells could provide a more controllable experimental system by which to study the fate and pathogenic mechanism of endotoxin at the cellular and subcellular level, HTC cells under the conditions employed herein do not yield binding data which compare favorably with in vivo results. Caution must be exercised when extrapolating in vitro data to the actual in vivo action of endotoxin.

Animals↗
PubMed2004

Ambient endotoxin concentrations in PM10 from Southern California.

Concentrations of endotoxin in urban air pollution have not previously been extensively characterized. We measured 24-hr levels of PM10 (particulate matter < 10 microm in aerodynamic diameter) and the associated endotoxin component once every 6 weeks for 1 year in 13 communities in Southern California. All the samples collected had detectable PM10 and endotoxin levels. The geometric mean PM10 was 34.6 microg/m3 [geometric SD (GSD), 2.1; range, 3.0-135]. By volume, the endotoxin geometric mean was 0.44 endotoxin units (EU)/m3 (GSD, 3.1; range, 0.03-5.44). Per unit material collected, the geometric mean of endotoxin collected was 13.6 EU/mg (GSD, 3.2; range, 0.7-96.8). No correlation was found between endotoxin concentrations and other ambient pollutants concurrently measured [ozone, nitrogen dioxide, total acids, or PM2.5 (particulate matter < 2.5 micro m in aerodynamic diameter]. PM10 and endotoxin concentrations were significantly correlated, most strongly in summer. Samples collected in more rural and agricultural areas had lower PM10 and mid-range endotoxin levels. The high desert and mountain communities had lower PM10 levels but endotoxin levels comparable with or higher than the rural agricultural sites. By volume, endotoxin levels were highest at sites downwind of Los Angeles, California, which were also the locations of highest PM10. Endotoxin concentrations measured in this study were all < 5.5 EU/m3, which is lower than recognized thresholds for acute adverse health effects for occupational exposures but in the same range as indoor household concentrations. This study provides the first extensive characterization of endotoxin concentration across a large metropolitan area in relation to PM10 and other pollutant monitoring, and supports the need for studies of the role of endotoxin in childhood asthma in urban settings.

Air Pollutants↗
PubMed2004

[Study of the effect of the low dosage endotoxin damage on the expression of the organic cation transporter (OCT1) mRNA in hepatocytes].

OBJECTIVE: To elucidate the effect of the low dosage endotoxin damage on the expression of the organic cation transporter 1 (OCT1) mRNA in hepatocytes and make an approach to the probable effect of dexamethasone on the expression of the OCT1 mRNA after endotoxin damage. METHODS: (1) The endotoxin damage model was established in rats; (2) The change of the expression of OCT1 mRNA in hepatocytes after endotoxin damage was observed by in situ hybridization method; (3) The change of the ultra structure of hepatocytes after endotoxin damage was observed with the electron microscope; (4) Dexamethasone was injected intraperitoneally before endotoxin damage in order to determine the influence of dexamethasone on the expression of OCT1 mRNA after endotoxin treatment. RESULTS: The expression of OCT1 mRNA decreased until 16 hours (0.5745+/-0.012, P<0.01) after endotoxin treatment and then increased after this time point, which was still lower than the normal control; The expression of OCT1 mRNA in rat hepatocytes increased at each time point after endotoxin damage with dexamethasone treatment. It was highest at 16 hours (0.6327+/-0.007, P<0.01) after endotoxin damage, but it was still lower than that of the normal control. CONCLUSION: Endotoxin could repress the expression of OCT1 mRNA even before the low dosage endotoxin inducing serious damage to the structure of hepatocytes; Dexamethasone could not induce the expression of OCT1 mRNA in normal hepatocytes, but could lighten the repression of endotoxin on the expression of OCT1 mRNA. And then the expression of OCT1 mRNA could increase at some extent after endotoxin damage with dexamethasone treatment.

Animals↗
PubMed1998

[Bacterial endotoxins and their effects].

The lipopolysaccharide endotoxin macromolecules are cell wall's components of the Gram negative bacteria. The endotoxins are produced by Gram negative bacteria of intestinal flora. If the endotoxins are translocated from the intestinal tract to the circulation or injected into bloodstream, they elicit (depending from the quantity of endotoxin), slight or serious effects (e.g. endotoxin shock). In the effects of endotoxin certain cell populations (e.g. thrombocytes, macrophages, leukocytes, etc.), certain organs and organ-systems (e.g. liver, spleen, bone marrow, endocrine and lymphoreticular systems etc.) are involved. Effects of endotoxin are produced by mediators (e.g. endotoxin binding proteins, cytokines, prostaglandins, prostacyclins, NO etc.). The endotoxin sensitivity of vertebrate organisms is dependent from the phylogenetical status of the species. Most sensitive species is the human. Generally accepted that endotoxin has an important role in the pathogenesis of septic shock. In other pathological processes (e.g. intestinal syndrome of radiation disease, Gram negative infections, various shock forms etc.) are supposed or proved the role of endotoxins. Lead acetate induced endotoxin hypersensitivity or LAL methods are good tools for demonstration of the role of endotoxin in the pathogenesis of various processes. For this reason, the experimental endotoxin shock is used a model of septic and other shocks.

Endotoxins↗
PubMed2006

Non-enterobacterial endotoxins stimulate human coronary artery but not venous endothelial cell activation via Toll-like receptor 2.

OBJECTIVE: To determine whether non-enterobacterial endotoxins, which are likely to constitute the majority of the circulating endotoxin pool, may stimulate coronary artery endothelial cell activation. METHODS AND RESULTS: Interleukin-8 secretion, monocyte adhesion, and E-selectin expression were measured in human umbilical vein endothelial cells (HUVECs) and coronary artery endothelial cells (HCAECs) challenged in vitro with highly purified endotoxins of common host colonisers Escherichia coli, Porphyromonas gingivalis, Pseudomonas aeruginosa, and Bacteroides fragilis. HCAECs but not HUVECs expressed Toll-like receptor (TLR)-2 and were responsive to non-enterobacterial endotoxins. Transfection of TLR-deficient HEK-293 cells with TLR2 or TLR4/MD2 revealed that while E. coli endotoxin utilised solely TLR4 to signal, the endotoxins, deglycosylated endotoxins (lipid-A), and whole heat-killed bacteria of the other species stimulated TLR2-but not TLR4-dependent cell-signalling. Blockade of TLR2 with neutralizing antibody prevented HCAEC activation by non-enterobacterial endotoxins. Comparison of each endotoxin with E. coli endotoxin in limulus amoebocyte lysate assay revealed that the non-enterobacterial endotoxins are greatly underestimated by this assay, which has been used in all previous studies to estimate plasma endotoxin concentrations. CONCLUSION: Circulating non-enterobacterial endotoxins may be an underestimated contributor to endothelial activation and atherosclerosis in individuals at risk of increased plasma endotoxin burden.

Analysis of Variance↗
PubMed1999

Effect of chronic coadministration of endotoxin and ethanol on rat liver pathology and proinflammatory and anti-inflammatory cytokines.

To better understand how gut-derived endotoxins influence alcohol-induced liver injury and the expression of inflammatory cytokines a new animal model was developed. After 2 weeks on a modified ethanol-containing liquid diet, some rats also were infused with endotoxin via osmotic minipumps for 4 additional weeks. Ethanol diet alone increased plasma endotoxin threefold to 9.3 pg/mL. Endotoxin infusion increased the levels to 388 and 513 pg/mL in controls and ethanol-fed animals, respectively. Panlobular macrovesicular and microvesicular steatosis and inflammatory foci were observed in livers from both ethanol- and ethanol-endotoxin-treated animals, but there was no significant potentiation by endotoxin. Only minor changes, mainly polymorphonuclear infiltration, were seen in animals treated with endotoxin alone although the messenger RNA (mRNA) expression of both proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin 1beta (IL-1beta) and anti-inflammatory cytokines IL-4 and IL-10 were markedly increased, as shown by competitive polymerase chain reaction (PCR) analysis using cyclophilin as standard. The effect of endotoxin infusion on cytokine mRNA expression in ethanol-fed animals was not significantly different. Expression of transforming growth factor beta1 (TGF-beta1) mRNA was increased twofold by ethanol, eightfold by endotoxin, but only threefold by ethanol-endotoxin treatment. The mRNA expression of lipopolysaccharide binding protein (LBP) and CD14 endotoxin receptor was not significantly increased by chronic endotoxin treatment, contrasting with the marked elevation observed after acute endotoxin challenge. These results suggest that the tolerance observed despite sustained hepatic expression of proinflammatory cytokines is counteracted by the anti-inflammatory cytokines and by down-regulation of CD14 and LBP. Furthermore, a similar adaptation may occur in alcoholics with continuous endotoxemia.

Acute-Phase Proteins↗