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PubMed2006

Endotoxin in inner-city homes: associations with wheeze and eczema in early childhood.

BACKGROUND: An inverse association between domestic exposure to endotoxin and atopy in childhood has been observed. The relevance of this aspect of the hygiene hypothesis to US inner-city communities that have disproportionately high asthma prevalence has not been determined. OBJECTIVES: To measure endotoxin in the dust from inner-city homes, evaluate associations between endotoxin and housing/lifestyle characteristics, and determine whether endotoxin exposure predicted wheeze, allergic rhinitis, and eczema over the first 3 years of life. METHODS: As part of an ongoing prospective birth cohort study, children of Dominican and African-American mothers living in New York City underwent repeated questionnaire measures. Dust samples collected from bedroom floors at age 12 or 36 months were assayed for endotoxin. RESULTS: Among the samples collected from 301 participants' homes, the geometric mean endotoxin concentration (95% CI) was 75.9 EU/mg (66-87), and load was 3892 EU/m2 (3351-4522). Lower endotoxin concentrations were associated with wet mop cleaning and certain neighborhoods. Endotoxin concentration correlated weakly with cockroach (Bla g 2: r = 0.22, P < .001) and mouse (mouse urinary protein: r = 0.28; P < .001) allergens in the dust. Children in homes with higher endotoxin concentration were less likely to have eczema at age 1 year (odds ratio, 0.70 [0.53-0.93]) and more likely to wheeze at age 2 years (odds ratio, 1.34 [1.01-1.78]). These associations were stronger among children with a maternal history of asthma. CONCLUSION: Endotoxin levels in this inner-city community are similar to those in nonfarm homes elsewhere. In this community, domestic endotoxin exposure was inversely associated with eczema at age 1 year, but positively associated with wheeze at age 2 years. CLINICAL IMPLICATIONS: Endotoxin exposure in the inner-city community may be related to wheeze in the early life; however, given the inverse association seen with eczema, the long-term development of allergic disease is still in question.

Allergens↗
PubMed2005

Endotoxin releases a substance from the aorta that dilates an isolated arteriole by up-regulating INOS.

BACKGROUND: Loss of vascular tone in resistance arterioles has been implicated as the cause of hypotension in septic shock. It is believed that the overproduction of nitric oxide (NO) by the inducible isoform of nitric oxide synthase (iNOS) results in the vasodilatation seen in septic shock. However, we have shown that endotoxin has no effect on vascular tone of an isolated resistance vessel unless the endotoxin flows over a segment of aorta or vena cava upstream in the superfusion line. The aim of this study was to determine if the subsequent vasodilation was due to the release of a direct vasodilator or production of NO in the arteriole and if its source was iNOS by using its selective inhibitor, aminoguanidine. MATERIALS AND METHODS: First-order rat cremaster arterioles (n = 36) were isolated and cannulated onto micropipettes, superfused with physiological buffer at 34 degrees C, pressurized to 70 mm Hg, and allowed to gain spontaneous tone over 90 min. A segment of abdominal aorta was then placed in series with the arteriole so that the superfusate passed over the aorta and then into the tissue bath containing the isolated arteriole. The vessels were allowed to equilibrate over 60 min. During this interval, the arteriole was exposed to l-NAME (100 mum), aminoguanidine (100 mum), or buffer. The aorta and arteriole were then superfused with endotoxin (Salmonella enteritidis 2.5 mug/ml). Internal diameters of cannulated arterioles were measured and recorded with videomicroscopy and videocalipers at a resolution of +/-1 mum every 15 min for 1 h. Six groups were created with n = 6 for each group: Group 1, endotoxin; Group 2, control; Group 3, l-NAME and endotoxin; Group 4, l-NAME; Group 5, aminoguanidine and endotoxin; and Group 6, aminoguanidine. RESULTS: After the 60-min equilibration period, there was no significant difference in resting tone among the six groups. At t = 120, the percentage of tone in the control group was 42.7 +/- 0.4% (mean +/- SEM) and this was not changed by treatment with aminoguanidine (42.2 +/- 0.7%). However, exposure to l-NAME alone resulted in vasoconstriction with a gain in tone to 49.5 +/- 1.6% (P > 0.05). Endotoxin alone caused arteriolar tone to fall to 33.5 +/- 1.2% (P < 0.05). Arterioles treated with aminoguanidine did not lose tone (42.6 +/- 1.7%) when exposed to endotoxin and arterioles treated with l-NAME retained their elevated tone (46.0 +/- 2.2%) after treatment with endotoxin. CONCLUSIONS: This study demonstrates that the aorta exposed to endotoxin releases a substance that vasodilates resistance arterioles through the up-regulation of iNOS. Aminoguanidine prevented the fall in tone following exposure to endotoxin, while use of the nonselective NOS inhibitor, l-NAME, not only blocked the fall due to endotoxin but increased basal tone by blocking the constitutively active eNOS.

Animals↗
PubMed2003

Relationship between endotoxin and prostaglandin (PGE2 and PGFM) concentrations and ovarian function in dairy cows with puerperal endometritis.

Blood concentrations of progesterone, 13,14-dihydro-15-keto-prostaglandin F2alpha (PGFM) and endotoxin, and uterine fluid concentrations of prostaglandin E(2) (PGE(2)), PGFM and endotoxin were evaluated in 14 dairy cows with puerperal endometritis (mild (n=6) and heavy (n=8)). Endotoxin was measured using a quantitative kinetic assay. Cows with heavy endometritis had significantly higher concentrations of plasma PGFM (P<0.01) and uterine fluid PGE(2) and endotoxin (P<0.05) than cows with mild endometritis. Concentrations of PGFM in plasma and uterine fluid, of PGFM and PGE(2), and PGE(2) and endotoxin in uterine fluid were positively and significantly (P<0.05) correlated. The presence of endotoxin in plasma was detected in one out of six mild and in eight out of eight heavy endometritis cows. Peak plasma endotoxin concentrations (0.08-9.14 endotoxin units/ml (EU/ml) were observed between 1 and 12 days postpartum (pp) and thereafter amounts generally remained below 0.1 EU/ml (last day of detection: Day 27 pp). Abnormal ovarian function was observed in six cows (four with prolonged anoestrus and two with long luteal phase after the first postpartum ovulation). Plasma endotoxin concentrations were detected in the anoestric cows. The results suggest that: (i) concentrations of uterine fluid endotoxin and PGE(2) and of plasma PGFM are related to the degree of endometritis; (ii) absorption of endotoxin from the uterus to the bloodstream occurs, mainly in heavy endometritis cows; and (iii) there is a relationship between uterine infection, endotoxin production and resumption of pp ovarian activity.

Animals↗
PubMed2000

Hypovolemia in rats increases mortality rates following endotoxin administration.

The aim of the present study was to examine whether acute or chronic hypovolemia increase the mortality rates of rats following endotoxin injection. Another aim of this study was to examine whether this increase in sensitivity can be explained by increased leakage of endotoxin from the digestive tract to the blood stream. Chronic hypovolemia was caused by water deprivation for 8 days. Acute hypovolemia was caused by injection of sucrose (300mg/100g) or by hemorrhage of a volume of up to 2.1 ml/100g. The hypovolemia was examined by measuring the plasma volume using Evans Blue (EB). Endotoxin at various doses was injected to the hypovolemic rats and the lethality of the various treatments was examined. Acute and chronic hypovolemia caused a significant increase inthe mortality rates of rats injected IP with a dose of 1-1.5 mg/100g endotoxin. Endotoxin administration (6mg/100g) by drinking to hypovolemic rats did not cause death at all. In contradistinction, injection of galactoseamine to rats that underwent similar treatments caused 100% mortality. Endotoxin tolerance reduced the mortality rates following galactoseamine injection to the control level of administration of endotoxin without hypovolemia (p < 0.001). Injection of the antibiotic polymixin B following the galactoseamine injection also decreased mortality rates to 40% (p < 0.05). Examination of plasma endotoxin concentration exhibited a significant increase following administration of endotoxin by drinking to hypovolemic rats (p < 0.001) compared to rats that received the same amount of endotoxin but without hypovolemia. These results indicate that one possible explanation for the increased mortality rate of the hypovolemic rats after endotoxin injection is due to leakage of endotoxin from the digestive tract.

Animals↗
PubMed2004

Endotoxin in storage medium of human corneal grafts and clinical course after penetrating normal-risk keratoplasty.

PURPOSE: It is well known that endotoxins in storage medium may stimulate cytokine production and expression of adhesion molecules as well as endothelial damage in human corneal grafts. It has been supposed that endotoxin exposure of corneal grafts may, therefore, cause immune reactions and lead to reduced endothelial cell count after penetrating keratoplasty. It was the purpose of this prospective study to evaluate if this hypothesis is true. METHODS: A consecutive series of 274 samples of sterile organ culture storage medium from 274 human corneal grafts was collected between August 1998 and February 1999 and tested for endotoxin using Limulus amebocyte-lysate assay (LAL) after 7 days of organ culture. Threshold endotoxin level was set at 1.0 U/ml. A total of 161 grafts were transplanted and 113 were discarded. Within the 161 corneas transplanted, 62 were grafted to normal-risk patients and 99 to high-risk patients. Only normal-risk keratoplasty patients were included in the study and followed for at least 10 months. Immune reactions, graft failures, and postoperative endothelial cell counts were recorded. RESULTS: The mean endotoxin level in organ culture medium of all transplanted grafts was 1.07+/-2.96. Mean endotoxin level in organ culture medium of discarded grafts was 1.68+/-5.76, with 71 samples being below and 42 above the threshold of 1.0 U/ml called endotoxin-negative and endotoxin-positive, respectively. In all 36 culture medium samples from the 62 grafts transplanted to the group of normal-risk keratoplasty patients were endotoxin-negative and 26 endotoxin-positive. An influence of endotoxin levels on incidence of immune reactions, graft failure, and postoperative endothelial cell counts could not be revealed in patients with normal-risk keratoplasty. CONCLUSION: Low endotoxin levels in storage medium neither seem to promote immune reactions nor to contribute to postoperative chronic endothelial cell loss in normal-risk keratoplasty patients.

Adolescent↗
PubMed1999

Characterization of endotoxin and cationic liposome interaction.

The objective of this study was to characterize the interaction of endotoxin with cationic liposomes used in nonviral gene delivery. Endotoxin-cationic liposome interaction was characterized using fluorescent anisotropy, and the Limulus amebocyte lysate (LAL) assay. Cellular toxicity of endotoxin-cationic liposome complex was examined using a dimethylthiazol diphenyltetrazolium bromide (MTT) assay. The effect of endotoxin on the lipid-DNA complex and subsequent transfection into COS-1 cells was also examined. A competitive interaction occurred between fluoroscein isothiocyanate (FITC)-labeled endotoxin and plasmid DNA for binding dioleoyl glycero trimethylammonium propane:dioleoyl glycero phosphoethanolamine (DOTAP:DOPE) liposomes using fluorescent anisotropy techniques. The LAL assay demonstrated no change in endotoxin activity upon interaction with liposomes. No loss of COS cell viability was detected via the MTT assay during a 5-hr exposure to endotoxin. Transient transfection studies indicate that increasing levels of endotoxin lowered activity more than 90% at 50,000 endotoxin units (EU)/ml. Endotoxin and cationic liposomes interact mainly by an electrostatic attraction. Endotoxin contamination can potentially impact transfection efficiency via competition with plasmid DNA for cationic liposome binding by increasing transfection variability at 50 EU/ml, a concentration of endotoxin contamination that can occur with small-scale plasmid preparations used for in vitro cell transfections, but would not be expected with typical GLP or GMP preparations used in clinical studies.

Animals↗
PubMed2005

Effects of perfluorohexan vapor on gas exchange, respiratory mechanics, and lung histology in pigs with lung injury after endotoxin infusion.

BACKGROUND: Inhaled perfluorohexan vapor has been shown to improve gas exchange and pulmonary mechanics in oleic acid- and ventilator-induced lung injury. However, in the clinical setting, lung injury frequently occurs in the context of systemic inflammation and consecutive lung injury, which may be induced experimentally by intravenous administration of endotoxin. The authors studied whether vaporized perfluorohexan is efficacious during endotoxin-induced lung injury in domestic pigs. METHODS: Twenty-two pigs (29 [23, 31] kg body weight [first, third interquartile]; tracheostomy) were anesthetized and mechanically ventilated. In the endotoxin (n = 8) and perfluorohexan groups (n = 7), we administered endotoxin of Escherichia coli 111:B4, 1 mg.kg . h for 1 h and 10 microg.kg.h for 5 h in consecutive order. In the perfluorohexan group, inhalation of the test drug was started 2 h 30 min after the start of the intravenous endotoxin and terminated after 30 min. In a control group (n=7), animals were instrumented and observed over time without further intervention. Oxygenation function was assessed from oxygen partial pressures (Po2, blood gases) and calculated shunt fraction. Respiratory compliance was calculated from airway pressure and tidal volume. Measurements were performed before and every hour during endotoxin infusion. RESULTS: After 6 h of endotoxin, gas exchange and pulmonary compliance were deteriorated in the endotoxin group (Pao2: 184 [114, 289] vs. 638 [615, 658] mmHg, pulmonary shunt fraction: 30 [23, 38] vs. 4 [3, 6]%, respiratory compliance: 12 [11, 14] vs. 22 [19, 23] ml/mbar; P < 0.05, endotoxin vs. control). Inhalation of vaporized perfluorohexan did not improve Pao 2 (107 [60, 221] mmHg), pulmonary shunt fraction (32 [26, 58]%), or respiratory compliance (14 [10, 17] ml/mbar) when compared with intravenous endotoxin (not significant, perfluorohexan vs. endotoxin). CONCLUSIONS: Inhalation of vaporized perfluorohexan does not improve pulmonary gas exchange or respiratory compliance in endotoxin-induced porcine lung injury.

Administration, Inhalation↗
PubMed1995

Pretreatment of normal humans with monophosphoryl lipid A induces tolerance to endotoxin: a prospective, double-blind, randomized, controlled trial.

OBJECTIVES: Endotoxin is one of the principal mediators of Gram-negative septic shock. Pretreatment with monophosphoryl lipid A, a hydrolyzed derivative of endotoxin from Salmonella minnesota R595, induces endotoxin tolerance and nonspecific resistance to infection in experimental animals. The present clinical trial was undertaken to test the response to monophosphoryl lipid A in humans and the ability of monophosphoryl lipid A to attenuate the response of normal human volunteers to U.S. Reference Ec-5 endotoxin. DESIGN: Prospective, double-blind, randomized, controlled trial. SETTING: Clinical research center. PATIENTS: Forty-four healthy volunteers. INTERVENTIONS: In part 1 of the study, 29 volunteers were randomized in varying ratios to receive vehicle control or monophosphoryl lipid A intravenously in a double-blind dose escalation trial. In part 2 of the study, 12 volunteers were randomized to receive either monophosphoryl lipid A (20 micrograms/kg) or vehicle control and, 24 hrs later, all 12 volunteers were challenged with U.S. Reference Ec-5 endotoxin (20 units/kg intravenous, bolus injection). Systemic response to endotoxin challenge was evaluated and compared between the monophosphoryl lipid A and vehicle control-pretreated subjects. MEASUREMENTS AND MAIN RESULTS: In part 1 of the study, subjective effects and increases in cytokine levels were not observed until a dose of 10 micrograms/kg of monophosphoryl lipid A was administered. Six volunteers receiving a maximum dose of 20 micrograms/kg experienced mild-to-moderate symptoms that did not require therapy. Moderate increases in temperature, heart rate, and tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 release were observed. IL-1 alpha and IL-1 beta were not detected but a significant increase in IL-1 receptor antagonist was observed. In part 2 of the study, monophosphoryl lipid A pretreatment reduced the number of volunteers who experienced one or more subjective complaints after endotoxin administration (3/6 vs. 6/6; p = .09). The febrile response and tachycardic response to endotoxin were significantly reduced by pretreatment with monophosphoryl lipid A. Monophosphoryl lipid A-pretreated volunteers demonstrated significantly reduced concentrations of TNF-alpha after endotoxin challenge, as compared with subjects treated with vehicle control (84 +/- 76 vs. 244 +/- 128 pg/mL; p < .05). IL-6 concentrations (100 +/- 91 vs. 268 +/- 171 pg/ml; p < .05) and IL-8 concentrations (136 +/- 86 vs. 632 +/- 323 pg/mL; p < .05) elicited by endotoxin challenge were also significantly reduced by monophosphoryl lipid A pretreatment. CONCLUSIONS: Data indicate that monophosphoryl lipid A, in a dose 10,000 times that of endotoxin, used in experimental pyrogenicity trials, is well tolerated in human volunteers. Pretreatment of normal human volunteers with monophosphoryl lipid A attenuated the systemic response to bacterial endotoxin. These data support further clinical testing of monophosphoryl lipid A for the prevention or amelioration of the severe sequelae of sepsis.

Adolescent↗
PubMed1995

Ketamine attenuates endotoxin-induced leukocyte adherence in rat mesenteric venules.

OBJECTIVES: To determine the influence of ketamine on endotoxin-induced leukocyte adherence and venular microhemodynamics. DESIGN: Randomized, controlled trial. SETTING: Experimental laboratory. SUBJECTS: Thirty male Wistar rats. INTERVENTIONS: The rats were pretreated with ketamine (10 mg/kg iv) or 0.9% saline, and both groups were given endotoxin (Escherichia coli lipopolysaccharide; 5 mg/kg iv). The control group received two doses of 0.9% saline. MEASUREMENTS AND MAIN RESULTS: The rates of leukocyte adherence and changes in microhemodynamics were monitored in rat mesenteric venules, using in vivo video microscopy. The number of adherent leukocytes was determined on-line in 10-min intervals from 60 mins before until 2 hrs after endotoxin administration. Venular diameters, red blood cell velocity, volumetric blood flow, and the venular wall shear rate were monitored before and at 10, 30, and 60 mins after endotoxin exposure. A 6.3-fold increase in the number of adherent leukocytes was observed 10 mins after administration of endotoxin when compared with control animals (5.87 +/- 0.69 vs. 0.93 +/- 0.21 adherent cells/100 microns; p < .001). This increase remained unchanged for 120 mins. In ketamine-pretreated rats, a 2.6-fold increase in leukocyte adherence occurred during the first 20 mins after endotoxin exposure (2.40 +/- 0.46 vs. 0.93 +/- 0.21 adherent cells/100 microns; p < .01). However, no difference in the number of adherent leukocytes between ketamine-pretreated and control animals was found after this 20-min period. In animals of the control group, no increase in leukocyte adherence occurred during the entire observation time. Diameters of mesenteric venules did not change after endotoxin exposure in any of the groups. Red blood cell velocity and venular blood flow in the endotoxin-treated groups decreased 10 mins after the injection of endotoxin when compared with controls, but these values did not show any difference when they were compared between ketamine and saline-pretreated animals. Similarly, venular wall shear rate in the endotoxin-treated groups decreased 10 and 30 mins after injection of endotoxin. However, no significant difference occurred between ketamine and saline-pretreated animals. CONCLUSIONS: Pretreatment with ketamine attenuates endotoxin-induced leukocyte adherence by a shear rate-independent mechanism, suggesting reduced expression of adhesion molecules. These results indicate that ketamine exerts an anti-inflammatory effect, which might be beneficial in septic patients.

Animals↗
PubMed1996

Augmentation of endotoxin-induced pulmonary responses by mononuclear cell phagocytosis in the reticuloendothelial system.

OBJECTIVE: To test the hypothesis that the effects of intravenous injection of latex particles would demonstrate the contribution of phagocytosis by mononuclear phagocytes to the development of Escherichia coli-induced acute lung injury in neutropenic guinea pigs. DESIGN: Prospective, controlled, experimental study. Intravenously injected the latex particles into 41 guinea pigs to investigate the contribution of the phagocytosis in acute lung injury. SUBJECTS: Forty-one guinea pigs. INTERVENTIONS: Forty-one guinea pigs were divided into five experimental groups: a saline group (n=9); an endotoxin group (n=10) receiving 2 mg/kg of intravenous E. coli endotoxin; a latex group (n=7) receiving 2 x 10(9)/kg of intravenous polystyrene latex (mean diameter 3.19 micrometers); an endotoxin + latex group (n=8); and an E. coli group (n=7) receiving 2 x 10(9) live E. coli/kg. MEASUREMENTS AND MAIN RESULTS: The lung wet/dry ratio was increased in the live E. coli-treated guinea pigs (6.71 +/- 0.16 [SEM], p < .01) as compared with the saline control (5.40 +/- 0.16, whereas the ratio was not increased in the endotoxin (5.52 +/- 0.14) or latex (5.58 +/- 0.20) groups. However, the lung wet/dry ratio was greater in the endotoxin + latex group (6.11 +/- 0.16, p < .05) than in the saline control. The 125I albumin lung tissue/plasma ratio was greater in the E. coli (2.00 +/- 0.29, p < .01) and endotoxin + latex (0.84 +/- 0.12, p < .05) groups than in the saline group (0.18 +/- 0.07), whereas no increases were observed in the endotoxin group (0.22 +/- 0.10) and the latex (0.34 +/- 0.13) group. More than 40% of the injected radiolabeled latex was observed to have accumulated in the reticuloendothelial system (liver and spleen), in both the saline control (40.1 +/- 2.3%, n=4) and endotoxin (57.3 +/- 6.8%, n=5) groups, with 2.6 +/- 1.5% and 3.1 +/- 1.7% in the lungs for the saline control and the endotoxin groups, respectively. The percent deposition of radiolabeled latex in the liver was greater in the endotoxin group (51.7 +/- 3.8%, p < .05) than in the saline group (37.6 +/- 5.9%). CONCLUSIONS: These findings suggest that, in neutropenic guinea pigs: a) the combination of endotoxin and latex particles induces acute lung injury; and b) the phagocytic properties of mononuclear phagocytes in the reticuloendothelial system augment endotoxin-induced pulmonary responses and may play a role in the development of live E. coli-induced acute lung injury.

Animals↗
PubMed2003

Metropolitan endotoxin exposure, allergy and asthma.

PURPOSE OF REVIEW: To review the role of metropolitan endotoxin exposure in asthma and allergy, emphasizing recently published articles (i.e. April 2002-June 2003). RECENT FINDINGS: In infants and toddlers in metropolitan communities, higher endotoxin levels in house dust are associated with less atopy and increased wheezing in infancy, but this increased risk may normalize by age 4 years. Increased endotoxin levels and exposure in metropolitan households with dogs and sometimes cats is intriguing in light of recent studies suggesting that animal exposure early in life is associated with less allergen sensitization and asthma. Dust endotoxin also appears to serve as a marker for other similar innate immune-stimulatory microbial components called pathogen-associated molecular patterns. Pathogen-associated molecular patterns, such as bacterial DNA, may augment and steer endotoxin-initiated immune responses in an immune-regulatory direction. These findings support the premise that the differences in health outcomes from endotoxin exposure are due to important moderating variables, such as age of exposure, timing of exposure relative to disease development, dose and frequency of exposure, co-exposures, and genetic predispositions in response to endotoxin. SUMMARY: We will discuss (1) endotoxin's ability to exacerbate established atopic disease and asthma; (2) factors influencing endotoxin levels in metropolitan homes; (3) relationships between endotoxin, pet exposure, and atopic disease; (4) endotoxin's paradoxical potential to both abrogate as well as exacerbate asthma; and (5) endotoxin's role as a marker for other similar pathogen-associated molecular patterns.

Animals↗
PubMed1996

Endotoxin induced expression of tumour necrosis factor, tissue factor and plasminogen activator inhibitor activity by peritoneal macrophages.

Peritoneal fluid was collected aseptically from 30 healthy adult horses and 115 horses with acute gastrointestinal disease and supernatant was separated from cells by centrifugation followed by freezing until assayed for endotoxin and tumour necrosis factor activity. Peritoneal macrophages obtained from healthy horses were incubated in vitro for 3, 6, 12 or 24 h in the absence (media control) or presence of Escherichia coli 055:B5 endotoxin (final concentrations of 1, 10, 100 or 1000 ng/ml). Macrophages obtained from horses with acute gastrointestinal disease were incubated for 12 h in the absence (media control) or presence of 100 ng endotoxin/ml. At the conclusion of the incubation, macrophage supernatants were collected and frozen at -70 degrees C until analysed for tumour necrosis factor activity. Macrophage membranes were lysed and frozen at -70 degrees C until assayed for tissue factor and plasminogen activator inhibitor type 2 activity. Compared to cells incubated with media, incubation of macrophages, obtained from healthy horses, with endotoxin significantly increased tumour necrosis factor, tissue factor and plasminogen activator inhibitor type 2 activity. These increases were dependent on the endotoxin concentration and the duration of incubation. Compared to cells incubated with media alone, incubation of macrophages, obtained from horses with acute gastrointestinal disease with endotoxin, significantly increased tumour necrosis factor and tissue factor activity. Endotoxin induced tumour necrosis factor activity in vitro was significantly less for macrophages from horses with acute gastrointestinal disease, as compared to that produced by similarly treated cells obtained from healthy horses. For those horses with acute gastrointestinal disease, macrophages obtained from horses with either endotoxin or tumour necrosis factor activity in the peritoneal fluid supernatant had significantly less endotoxin induced tumour necrosis factor in vitro, as compared to similarly treated cells obtained from horses without endotoxin or tumour necrosis factor activity in the peritoneal fluid supernatant. The results of this study indicate that exposure of equine peritoneal macrophages to endotoxin results in a significant increase in tumour necrosis factor, tissue factor and plasminogen activator inhibitor type 2 activity. After in vitro exposure to endotoxin, there is significant down-regulation of inflammatory mediator production by peritoneal macrophages obtained from endotoxaemic horses. These results suggest that these macrophages may exhibit early endotoxin tolerance.

Acute Disease↗
PubMed1996

Influence of antibiotic and E5 monoclonal immunoglobulin M interactions on endotoxin release from Escherichia coli and Pseudomonas aeruginosa.

Recent controversy surrounding the activity of monoclonal antibodies against endotoxin highlights the necessity of identifying all factors associated with increased mortality, one of which is endotoxin concentrations. Antibiotics may induce different patterns of endotoxin release. We compared the release of free endotoxin (in endotoxin units per milliliter) over 6 h and changes in numbers of CFU of exponentially growing Escherichia coli and Pseudomonas aeruginosa (10(6) to 10(7) CFU/ml) cultured in chemically defined endotoxin-free broth combined with pooled human serum and/or 10 micrograms of E5 immunoglobulin M monoclonal antibody per ml. MICs and MBCs were tested in each medium at the same inoculum. The inoculum was exposed to antibiotics at a single fixed multiple of the MIC for each medium (range, two to eight times the MIC). E5 antibody had no effect on MICs, MBCs, bactericidal activity, or endotoxin release. In the presence of 50% serum, amikacin, ceftazidime, imipenem, and ofloxacin each killed equivalent amounts of E. coli over 6 h; however, ceftazidime induced the highest release of endotoxin. Amikacin and ofloxacin produced the most favorable ratio of endotoxin release to amount of bacterial killing. In the presence of 50% serum, ceftazidime and imipenem reduced the P. aeruginosa inoculum to the greatest extent over 6 h. Although its bactericidal activity was diminished, ofloxacin caused the lowest release of free endotoxin. Imipenem and ofloxacin showed similar low ratios of endotoxin release to bacterial killing. In summary, antibiotic class, presence of serum, and type of organism influenced bactericidal activity and endotoxin release.

Anti-Bacterial Agents↗
PubMed1992

In vitro inactivation of bacterial endotoxin by human lipoproteins and apolipoproteins.

A chromogenic Limulus amebocyte lysate assay was used to measure the recovery of 1 endotoxin unit of endotoxin per ml. Purified human high-density lipoprotein, low-density lipoprotein, and apolipoprotein A1 (apo A1) at a maximum concentration of 1 g of protein per liter reduced the recovery to less than 40% of baseline in a both dose- and time-dependent manner and in the absence of other serum components. Furthermore, the lapine fever response to a dose of 1 ml of 5-ng/ml endotoxin per kg was reduced by greater than 0.5 degrees C (P less than 0.005) when the solution was preincubated in vitro with 0.5 g of apo A1 per liter. By the Limulus test, a maximum concentration of 0.01 g of apolipoprotein B (apo B) per liter (which contained deoxycholate, a known endotoxin-disaggregating agent) reduced recovery to 0% in a dose- but not time-dependent manner. In heat-inactivated (56 degrees C, 1 h) normal human serum, high-density lipoprotein cholesterol (P less than 0.005) and apo A1 (P less than 0.05) correlated inversely with endotoxin recovery, but, paradoxically, apo B correlated directly with endotoxin recovery (P less than 0.05), while low-density lipoprotein cholesterol showed no significant correlation. INTRALIPID alone had no effect on endotoxin recovery. Addition of a maximum of 10 g of INTRALIPID per liter to 0.0042 g of apo B per liter increased endotoxin recovery from approximately 30 to 80% (P less than 0.001), but addition of INTRALIPID to 0.25 g of apo A1 per liter decreased recovery from approximately 30 to 20% (P less than 0.001). We conclude that (i) lipoproteins are endotoxin inactivators; (ii) this ability of lipoproteins may be modulated by their lipid component (lipid-endotoxin interaction); (iii) apo A1 is capable of directly inactivating endotoxin (protein-endotoxin interaction).

Animals↗
PubMed1965

Chemical composition and biological properties of the endotoxin of Brucella abortus.

Baker, Phillip J. (University of Wisconsin, Madison), and J. B. Wilson. Chemical composition and biological properties of the endotoxin of Brucella abortus. J. Bacteriol. 90:895-902. 1965.-The ability of endotoxin to induce hypoferremia in mice was used to measure the specific activity of various endotoxin preparations of Escherichia coli and Brucella abortus and to determine the endotoxin content of several strains of B. abortus differing in virulence for guinea pigs. The endotoxin preparations from E. coli possessed greater biological activity than those from B. abortus. The same types of B. abortus endotoxin preparations, whether obtained from strains of high or low virulence, had about the same activity. Although differences in endotoxin content were noted among several strains of B. abortus of different virulence, there appeared to be no correlation between endotoxin content and virulence. Chemical analyses of B. abortus and E. coli endotoxins, based upon nitrogen, phosphorus, fatty acid ester, fatty acid amide, total fatty acids, hexose, and hexosamine content, revealed differences in chemical composition; however, these differences could not be correlated with differences in biological activity. The same types of endotoxin preparations, whether obtained from strains of B. abortus of high or low virulence, were similar in chemical composition and in biological activity. A correlation between the ability of endotoxin to induce hypoferremia and its lethal effects in mice is suggested. In general, endotoxin preparations of high hypoferremic activity had low mouse ld(50) values.

Animals↗
PubMed1998

The opiate sufentanil alters the inflammatory, endocrine, and metabolic responses to endotoxin in dogs.

Sufentanil is a synthetic mu-opioid receptor agonist frequently used in anesthesia and critically ill patients. To evaluate the effects of sufentanil on the inflammatory, neuroendocrine, and metabolic responses to endotoxin, we studied six dogs during saline infusion (control), during sufentanil infusion (1.5 microg . kg-1 . h-1), after endotoxin injection (1.0 microg/kg iv), and during combined endotoxin and sufentanil administration. The rate of appearance of glucose was determined by infusion of [6,6-2H2]glucose. Sufentanil depressed the endotoxin-induced increase in body temperature (36.9 +/- 0.3 vs. 40.6 +/- 0.5 degrees C, P < 0.05). Sufentanil depressed the tumor necrosis factor (TNF) response to endotoxin by approximately 60% (P < 0.01) but increased the interleukin-6 (IL-6) response by approximately 70% (P < 0.01). Sufentanil per se induced a transient neuroendocrine activation. Sufentanil also increased plasma concentrations of insulin and catecholamines after endotoxin (P < 0.05 vs. endotoxin alone) and increased plasma glucose levels by approximately 36% (from 6.1 +/- 0.1 to 8.3 +/- 0.6 mmol/l, P < 0.05 vs. endotoxin alone). Endotoxin stimulated glucose production transiently by 95% (24.2 +/- 3.2 vs. control 12.4 +/- 1.0 micromol . kg-1 . min-1, P < 0.05). Paradoxically, sufentanil inhibited this endotoxin-induced stimulation of glucose production (P < 0.05 vs. endotoxin alone). In conclusion, sufentanil modulates the response to intravenous endotoxin by dissociating the TNF and IL-6 response, increasing insulin and catecholamine levels, and depressing the increase in glucose production. Therefore, opiates alter inflammatory, endocrine, and metabolic regulation in endotoxemia.

Animals↗
PubMed1995

Mechanisms of endotoxin-induced dilatation of cerebral arterioles.

Lipopolysaccharide (LPS; endotoxin) produces dilatation of cerebral arterioles in vivo which may be due, in part, to expression of inducible nitric oxide (NO) synthase. We tested the hypothesis that aminoguanidine, an inhibitor of inducible NO synthase, would reduce endotoxin-induced dilatation of cerebral arterioles. Because mechanisms other than expression of inducible NO synthase may contribute to endotoxin-induced dilatation of cerebral arterioles, we also tested the hypothesis that calcitonin gene-related peptide (CGRP) contributes to vascular responses to endotoxin. Cerebral arteriolar diameter was measured using a closed cranial window in anesthetized rabbits under control conditions [77 +/- 3 (SE) microns] and during topical application of endotoxin (100 micrograms/ml). After 4 h, diameter of cerebral arterioles increased by 41 +/- 5%. Coapplication of aminoguanidine (0.3 mM) with endotoxin reduced vasodilatation at all time points (30 min to 4 h). Relative to control values, endotoxin treatment increased guanosine 3',5'-cyclic monophosphate (cGMP) concentration in cerebrospinal fluid (CSF) by approximately 20 fold at 4 h. Aminoguanidine attenuated the endotoxin-induced increased in CSF cGMP concentration. Aminoguanidine (0.3 mM) did not alter acetylcholine-mediated dilatation of cerebral arterioles. Coapplication of CGRP-(8-37) (0.5 microM), a specific blocker of CGRP receptors, with endotoxin significantly reduced vasodilatation in response to endotoxin at 2, 3, and 4 h. Thus 1) aminoguanidine inhibits endotoxin- but not acetylcholine-mediated dilatation of cerebral arterioles, and 2) activation of CGRP receptors mediates a portion of endotoxin-induced dilation of cerebral arterioles.

Acetylcholine↗
PubMed1994

Endotoxin responsiveness and grain dust-induced inflammation in the lower respiratory tract.

To identify the role of endotoxin responsiveness in grain dust-induced airway disease, we used two models of extotoxin hyporesponsiveness to perform inhalation exposure studies in mice. In the first model, we investigated whether genetic resistance to endotoxin would alter the inflammatory response to inhaled grain dust by comparing the inflammatory response in the lower respiratory tract of endotoxin-sensitive and -resistant male mice after inhalation of pyrogen-free saline, corn dust extract (CDE), sterile CDE (SCDE), or lipopolysaccharide (LPS). Endotoxin-sensitive and -resistant mice were exposed for 4 h to nebulized solutions of LPS, SCDE, or CDE. Another group of endotoxin-sensitive and -resistant mice was sham exposed for 4 h to nebulized sterile saline. Dose-response relationships for endotoxin were explored for LPS, SCDE, and CDE. Bronchoalveolar lavage (BAL) 5 h after the start of exposure demonstrated a higher concentration of total cells, neutrophils (PMNs), and tumor necrosis factor-alpha (TNF-alpha) in BAL fluid after inhalation of CDE, SCDE, or LPS in endotoxin-sensitive than in endotoxin-resistant mice. Whereas endotoxin-sensitive mice demonstrated a dose-response relationship between the endotoxin concentration in each of the solutions and the concentration of cells, PMNs, and TNF-alpha in BAL fluid, concentrations of TNF-alpha were significantly higher only in BAL fluid of endotoxin-resistant mice exposed to higher concentrations of SCDE or CDE. In the second model, we investigated whether acquired endotoxin tolerance would alter the inflammatory response to SCDE.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗