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PubMed1994

Granulocyte colony-stimulating factor exacerbates acute lung injury induced by intratracheal endotoxin in guinea pigs.

The effects of recombinant human granulocyte colony-stimulating factor (rG-CSF) on the lung injury induced by intratracheal endotoxin were studied using guinea pigs. Animals were divided into four groups: (1) saline control, (2) endotoxin alone, (3) cyclophosphamide (CPA)+endotoxin, and (4) CPA+rG-CSF+endotoxin. CPA was injected intraperitoneally to suppress hematopoietic function 7 d before the study. rG-CSF at a dose of 100 micrograms/kg was administered subcutaneously twice a day for 5 consecutive d beginning 2 d after the CPA pretreatment. Saline or 0.2 mg/kg of endotoxin was administered via the airway, and the animals were observed for 4 h. 99mTc-labeled macroaggregated albumin was mixed with saline or endotoxin to obtain a lobar distribution. Lung injury was assessed by the concentration ratio of 125I-labeled albumin in lung tissue to plasma (T/P) and lung wet-dry weight ratio (W/D). We also counted the number of neutrophils in bronchoalveolar lavage (BAL) fluid and fixed lung tissues. T/P, but not W/D, increased in endotoxin-alone and CPA+endotoxin groups compared with the saline control group (p < 0.01). Both T/P and W/D of the CPA+rG-CSF+endotoxin group were significantly higher than those of the endotoxin-alone and CPA+endotoxin groups (p < 0.01). In the CPA+rG-CSF+endotoxin group, histopathologic examination of the lung sections showed neutrophil recruitment into the lung, and neutrophil counts in BAL fluid were elevated. In conclusion, pretreatment with rG-CSF increased sequestration of neutrophils into the lung and exacerbated the lung injury induced by intratracheal endotoxin in CPA-treated guinea pigs.

Acute Disease↗
PubMed2002

Intratracheal endotoxin causes systemic inflammation in ventilated preterm lambs.

Intratracheal endotoxin causes acute inflammation in the adult lung, and injurious styles of mechanical ventilation can result in systemic inflammation derived from the lungs. We asked how ventilated premature and near-term lungs responded to intratracheal endotoxin and if systemic inflammation occurred. Lambs delivered at 130 d gestational age (GA) were treated with surfactant or surfactant plus endotoxin (0.1 mg/kg or 10 mg/kg) (Escherichia coli, serotype O55:B5) and were ventilated for 6 h. Both endotoxin doses resulted in impaired gas exchange and systemic inflammation in the preterm lambs. Lambs at 141 d GA (term 146 d) were given either 10 mg/kg intratracheal endotoxin, 10 mg/kg endotoxin plus high tidal volume ventilation for the first 30 min of life, or 5 microg/kg endotoxin given intravenously. Endotoxin alone (10 mg/kg) caused lung inflammation but no systemic effects after 6 h of ventilation. Lambs given 10 mg/kg endotoxin plus high tidal volume ventilation or 5 microg/kg endotoxin intravenously had decreased gas exchange and systemic inflammation. Endotoxin was detected in the plasma of lambs at 130 d GA but not at 141 d GA. Inflammation in the lungs was more severe in preterm animals. Mechanical ventilation of the endotoxin-exposed preterm lung resulted in systemic effects at a low endotoxin dose and without high tidal volume ventilation.

Animals↗
PubMed1980

Potection from oxygen toxicity with endotoxin. Role of the endogenous antioxidant enzymes of the lung.

Endotoxin treatment of adult rats before hyperoxic exposure significantly increases their survival rate in >95% O(2) (J. Clin. Invest.61: 269, 1978). In this study, we wished to determine: (a) whether endotoxin would protect against O(2) toxicity if it were administered after the animals were already in >95% O(2) for 12-48 h; and (b) the relationship between the endogenous antioxidant enzymes of the lung and the protective effect of endotoxin treatment. Our results showed that adult rats given a single 500 mug/kg dose of endotoxin up to 36 h after the onset of O(2) exposure had significantly increased survival rates and decreased lung fluid accumulation compared to untreated animals in O(2) (P < 0.05). (Survival, 16/49 [untreated rats]; 18/20 [endotoxin at 12 h after the start of O(2) exposure]; 25/26 [endotoxin-24 h]; 15/20 [endotoxin-36 h].)Endotoxin-treated animals in O(2) showed increases in pulmonary superoxide dismutase, catalase, and glutathione peroxidase activities before the usual time of onset of measurable pulmonary edema in untreated animals in O(2). When diethyldithiocarbamate was used to block the superoxide dismutase enzyme rise in the endotoxin-treated rats in O(2), the protective action of endotoxin against pulmonary O(2) toxicity was nullified. In endotoxin-treated, O(2)-exposed mice, there were no lung antioxidant enzyme increases, and no protective effect from O(2) toxicity was achieved. We conclude that, in the rat, a single dose of endotoxin given even 36 h after the onset of hyperoxic exposure results in marked protection against O(2)-induced lung damage; and the increased lung antioxidant enzyme activity in the endotoxin-treated rats appears to be an essential component of this protective action.

Animals↗
PubMed1993

Chylomicrons alter the fate of endotoxin, decreasing tumor necrosis factor release and preventing death.

The hypertriglyceridemia of infection was traditionally thought to represent the mobilization of substrate to fuel the body's response to the infectious challenge. However, we have previously shown that triglyceride-rich lipoproteins can protect against endotoxin-induced lethality. The current studies examine the mechanism by which this protection occurs. Rats infused with a lethal dose of endotoxin preincubated with chylomicrons had a reduced mortality compared with rats infused with endotoxin alone (15 vs. 76%, P < 0.001). Preincubation with chylomicrons increased the rate of clearance of endotoxin from plasma and doubled the amount of endotoxin cleared by the liver (30 +/- 1 vs. 14 +/- 2% of the total infused radiolabel, P < 0.001). In addition, autoradiographic studies showed that chylomicrons directed more of the endotoxin to hepatocytes and away from hepatic macrophages. Rats infused with endotoxin plus chylomicrons also showed reduced peak serum levels of tumor necrosis factor as compared with controls (14.2 +/- 3.3 vs. 44.9 +/- 9.5 ng/ml, mean +/- SEM, P = 0.014). In separate experiments, chylomicrons (1,000 mg triglyceride/kg) or saline were infused 10 min before the infusion of endotoxin. Chylomicron pretreatment resulted in a reduced mortality compared with rats infused with endotoxin alone (22 vs. 78%, P < 0.005). Therefore, chylomicrons can protect against endotoxin-induced lethality with and without preincubation with endotoxin. The mechanism by which chylomicrons protect against endotoxin appears to involve the shunting of endotoxin to hepatocytes and away from macrophages, thereby decreasing macrophage activation and the secretion of cytokines.

Animals↗
PubMed2004

The effect of endotoxin on functional parameters of mammary CID-9 cells.

The effect of endotoxin on mammary CID-9 cells, which differentiate in culture and express beta-casein, was investigated. Cells in culture supplemented with lactogenic hormones and dripped with EMS-Matrix (EMS-drip), were treated daily with endotoxin (0.5-500 microg/ml). Endotoxin at concentrations of less or equal to 10 microg/ml did not affect cell growth and viability up to 5 days post endotoxin treatment. Endotoxin (0.01-10 microg/ml) was added to the culture medium, upon confluence, and functional parameters were examined within 48 h post endotoxin treatment. Nuclear factor-kappaB (NF-kappaB) (p52) increased in nuclear extracts from endotoxin-stimulated cells within 1 h of treatment, while beta-casein mRNA and protein expression decreased in a concentration-dependent manner at 24 and 48 h post treatment. Zymography showed that the 72 and 92 kDa gelatinase activity increased in cells at 24 and 48 h post endotoxin treatment at 10 and 50 microg/ml. At the latter concentration, the active form of 72 kDa gelatinase was induced at 48 h. Interleukin-6 and tumor necrosis factor-alpha levels increased at 1-3 h post endotoxin treatment and peaked at 6 h in cells on plastic and EHS-drip. Nerve growth factor (NGF) levels increased in control and endotoxin-treated cells in a time-dependent manner, and endotoxin increased NGF levels in culture at 6 and 9 h post endotoxin treatment. This study shows that endotoxin activated NF-kappaB, suppressed beta-casein expression and upregulated gelatinases, cytokines and NGF. This model could be used to investigate the role of mammary cells in initiating and propagating inflammation and to test candidate molecules for potential anti-inflammatory properties.

Animals↗
PubMed2000

Reexamination of the effect of endotoxin on cell proliferation and transfection efficiency.

Plasmid DNA purified from bacterial cells can be contaminated with endotoxin to different extents, depending on the purification method. Earlier reports indicate that endotoxin can decrease transfection efficiency in many eukaryotic cell lines; however, the amount of endotoxin required for inhibition is unclear. We determined endotoxin effects in several cell lines and observed that endotoxin levels greater than or equal to 10,000 endotoxin units (EU) were needed to significantly affect cell proliferation and viability; levels greater than 2000 EU/mu g DNA were required to significantly inhibit transfection for all but one (Huh-7) of the cell lines tested. These endotoxin levels are significantly higher than endotoxin contamination in plasmid DNA purified by anion exchange, CsCl2 gradient and endotoxin-free purification technology, but not as high as a crude alkaline lysis preparatory method. Plasmid DNA prepared using anion exchange technology was comparable to endotoxin-free technology in terms of transfection efficiency. Even Huh-7 cells, which are markedly more sensitive to endotoxins, have comparable transfection efficiencies using plasmid DNA purified by either of these two methods. We conclude that for those cell lines commonly used for transfection studies, endotoxin-free, quality DNA is not necessary because significantly higher levels of bacterial endotoxins are required to inhibit either cell proliferation or transfection.

Animals↗
PubMed1989

Endotoxin release from neisseria meningitidis. Relationship between key bacterial characteristics and meningococcal disease.

A method was established in order to measure total and filtrable (CF) endotoxin in cultures of Neisseria meningitidis strains. The Limulus lysate (LAL) test gave results which paralleled those of the standard rabbit pyrogen test and of gas chromatography (GLC), concerning detection of different CF endotoxin levels. Meningococci varied in their ability to produce CF endotoxin. Cultures of similar bacterial densities, whether with a high (E+) or a low (E-) release of endotoxin in CF, had both high yields of endotoxin in sonicated culture suspensions determined by the LAL test. GLC demonstrated only small differences in total LPS contents between E+ and E- strains. This suggests that strains with similar cell wall endotoxin contents may vary in CF endotoxin. Electron microscopy revealed that E+ strains presented a high number of free, outer cell wall fragments (blebs, tubuli, membranes and aggregates of such structures) in surroundings. Few such free, small structures were found around E- strains. The amount of CF endotoxin of E+ strains was in part a function of the number of colony forming units (CFU/ml), and generally followed the growth curve. Because of its moment of appearance, and also based on electron microscopy findings, CF endotoxin appeared mainly to be released from living bacteria. The CF level of endotoxin was low or not detected at all in cultures of E- strains although their cultures reached higher mean CFU-levels than the niveaus required for the detection of CF endotoxin in the E+ strains. The E+ property was strain dependent. Meningococci isolated from CSF or blood had a significantly higher proportion of E+ strains (88.2%) and a higher CF endotoxin titre (greater than or equal to 10(3); 34.5%), than isolates from carriers (32.3% and 10.8%, respectively) (p less than 0.001 and p less than 0.001, respectively). A high mean CFU/ml in cultures seemed to be more often associated with isolates from patients than from carriers, more often with the presence than abscence of capsular polysaccharide (p less than 0.05), and more often with the presence than absence of the E+ property (p = 0.002). E+ strains were mostly serogroupable (i.e. encapsulated), regardless of source of the isolate (99% case and 80% carrier isolates). In contrast, serogroupable bacteria were not necessarily E+ when isolated from carriers (54.8%). The serogroup most apt to cause disease tended to have the highest proportion of E+ strains and the highest level of CF endotoxin.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1987

Rat pulmonary artery restructuring and pulmonary hypertension induced by continuous Escherichia coli endotoxin infusion.

We have studied the effect of continuous endotoxin infusion on rat pulmonary structure and function (69.4 ng/100 gm body weight/min for 24 hours). After 6 days of endotoxin infusion, lack of filling of pre- and intraacinar arteries was evident on pulmonary arteriograms. Microscopy demonstrated lumen narrowing in preacinar arteries and occlusion of intraacinar arteries. Morphometry of patent intraacinar arteries established dilation and increased wall muscle. Widespread alveolar wall injury was evident. After 24 hours of infusion, pulmonary artery pressure was raised (delta 9 mmHg; p less than or equal to 0.001); it then fell but was again increased by day 6 (delta 6 mmHg; p less than or equal to 0.05). Pulmonary vascular resistance was markedly increased at 24 hours (day 0 = 0.1 +/- 0.011 dyne/sec/cm-5; 24 hours endotoxin = 0.572 +/- 0.102 dyne/sec/cm-5; p less than or equal to 0.02). It remained elevated during the infusion period but was not significant. At day 6 the alveolar-arterial oxygen diffusion gradient (A-aDO2) was increased (day 0 = 19.6 +/- 1.39 mmHg, day 6 endotoxin = 33.8 +/- 0.1 mmHg; p less than or equal to 0.001). The arterial oxygen tension (PaO2) was decreased (day 0 = 86.5 +/- 1.8 mmHg, day 6 endotoxin = 74 +/- 2.52 mmHg; p less than or equal to 0.05), as was the arterial carbon dioxide tension (PaCO2) (day 0 = 36.0 +/- 0.73 mmHg, day 6 endotoxin = 30 +/- 1.9 mmHg; p less than or equal to 0.05). Thrombocytopenia occurred during the first 72 hours of infusion (day 0 = 7.41 +/- 0.41 X 10(5)/mm3, day 1 endotoxin = 2.43 +/- 0.30 X 10(5)/mm3, day 3 endotoxin = 2.32 +/- 0.31 X 10(5)/mm3; p less than or equal to 0.001) but by day 6 the platelet count had returned to basal levels (9.9 +/- 0.65 X 10(5)/mm3). Endotoxin increased the number of leukocytes in peripheral blood (day 0 = 12.8 +/- 1.2 X 10(3)/mm3, day 3 endotoxin = 17.0 +/- 1.86 X 10(3)/mm3, day 6 endotoxin = 22.5 +/- 1.8 X 10(3)/mm3; p less than or equal to 0.01 for day 6). Plasma concentrations of 6-keto-prostaglandin F1 alpha decreased during the first 24 hours of infusion (day 0 = 0.56 +/- 0.076 ng/ml, 24 hours endotoxin = 0.27 +/- 0.026 ng/ml; p less than or equal to 0.05) and thromboxane (TX) B2 in the first 15 hours (day 0 = 0.23 +/- 0.058 ng/ml, 15 hours endotoxin = 0.09 +/- 0.14 ng/ml; p less than or equal to 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1983

The synthesis and secretion of granulocyte-monocyte colony-stimulating activity (CSA) by isolated human monocytes: kinetics of the response to bacterial endotoxin.

We studied the kinetics of the synthesis and secretion of granulocyte-monocyte colony-stimulating activity (CSA) by human monocytes stimulated by S. typhi endotoxin. We found that these cells initially secrete copious quantities of CSA when exposed to endotoxin but rapidly become refractory to its stimulatory effect. When monocytes were incubated in liquid suspension cultures, large amounts of CSA were generated during the first 24 hr of culture after the addition of as little as 10 ng/ml of endotoxin to previously unstimulated monocytes. After the addition of endotoxin, CSA secretion abruptly took place after an initial 1 to 2 hr lag phase, and occurred primarily within the first 6 to 12 hr of culture. The addition of puromycin or cycloheximide to the cultures significantly inhibited CSA secretion in response to endotoxin, suggesting that CSA production by stimulated monocytes requires de novo protein synthesis and does not solely result from the release of preformed active CSA. After initial exposure to endotoxin, CSA production by monocytes steadily decreased after 24 hr and ceased after 72 hr. Subsequent reexposure to the same concentration of endotoxin resulted in little CSA production, whereas the refractory state could be overcome by increasing the quantity of endotoxin added. Additional studies demonstrated that refractoriness of monocytes to further CSA production after initial response to endotoxin was not due to a loss of cell viability, degradation of endotoxin, or inhibition of CSA synthesis by soluble metabolites generated by stimulated monocytes. Our data suggest that the capacity of human monocytes to synthesize CSA in response to endotoxin rapidly becomes blunted after initial exposure of the cells to the lipopolysaccharide, but that the refractory state of these cells can be overcome by increasing the concentration of endotoxin. Acquired hyporesponsiveness of cells that produce CSA may in part account for the phenomenon of immediate endotoxin tolerance observed in vivo.

Cell Separation↗
PubMed1982

In vivo quantitation of the rat liver's ability to eliminate endotoxin from portal vein blood.

The in vivo uptake of endotoxin by the liver from portal vein blood was assessed during a single passage through the liver. 51Cr labeled and unlabeled endotoxin were infused in different amounts into the femoral vein of three groups of lead-sensitized rats: a nonoperated, a sham-operated, and a surgically created reversed Eck fistula (REF) group. Whereas in the former two the infused endotoxin encounters the lung as the first filter organ, the liver performs this function in the latter experimental model. The mortality rates observed in control and sham-operated, lead-sensitized rats were found to correlate closely and reproducibly to the degree of endotoxemia. This assay was then applied to determine the amount of endotoxin eliminated by the liver by establishing, in the REF rat, the amounts of endotoxin that escaped hepatic clearance. Following infusion of 1 microgram of endotoxin/hr into REF rats, approximately 985 ng is found to be taken up by the liver; following 2 micrograms, 1965 ng is sequestered; following 3 micrograms, 2810 ng; and after 4 micrograms, 3175 ng is retained by the liver. Hence, the capacity of the liver to eliminate endotoxin from portal vein blood during a single passage increases as the portal vein endotoxin level rises; it approaches a maximum, suggesting that endotoxin's interaction with the Kupffer cells conforms to classical saturation kinetics. A Lineweaver-Burk plot prepared from these data indicates that the maximal in vivo capacity of the liver to remove endotoxin from portal vein blood approximates 1.5 micrograms/gm liver/hr. Data obtained with the use of radiolabeled endotoxin corroborate the information obtained with the bioassay technique. Endotoxin eliminated by the Kupffer cells in these quantities is slowly disintegrated; 4 hr after termination of the endotoxin infusion, less than 4% of the radiolabel is found in the urine and none in the bile. These observations indicate that the Kupffer cell's functional capacity to sequester and detoxify endotoxin is extensive and far exceeds the requirements imposed by physiological and most pathological conditions.

Animals↗
PubMedDate not supplied

Destruction of typical endotoxins by dry heat as determined using LAL assay and pyrogen assay.

The kinetics of destruction by dry heat of two typical endotoxins, Escherichia coli 055:B5 (E. coli endotoxin) and Salmonella abortus equi (S. abortus equi endotoxin), were determined using the Limulus Amebocyte Lysate (LAL) and pyrogen assays. The efficiency of recovery of these endotoxins from carriers using a pyrogen assay was also determined simultaneously. In the LAL assay 0.1-10,000 EU was used and 10-1000 EU in the pyrogen assay. Recoveries of E. coli endotoxin and S. abortus equi endotoxin were, respectively, 49.7-92.0% and 27.0-70.1% by the LAL assay, and 31.1% and 60.6% by the pyrogen assay. Fourier transformation infrared (FT-IR) spectra demonstrated the presence of chemical structural differences between the two endotoxins. By dry heat (200 or 250 degrees C), there were no significant differences in the destruction kinetics between the two endotoxins; either endotoxin can therefore be adapted for use in the endotoxin challenge test. Destruction in the pyrogen assay was significantly quicker than that predicted by the LAL assay for each of the two endotoxins. In this endotoxin destruction system, 3 log cycle reduction (the United State Pharmacopeia (USP) recommendation for the depyrogenation process) could not be obtained by challenge with 10,000 EU of endotoxin under the depyrogenation conditions of 200 degrees C for 60 min (a set of conditions described in the European Pharmacopoeia (EP)), though little pyrogenicity remained. On the other hand, at 250 degrees C for 30 min (a set of conditions described in the EP, USP and Pharmacopoeia of Japan (JP)),a 3 log cycle reduction was achieved without any pyrogenicity remaining.

Drug Contamination↗
PubMed1996

[Effects of intravenous 2-chloroadenosine on endotoxin-induced acute lung injury].

To assess the effects of 2-chloroadenosine (2CA) on acute lung injury caused by endotoxin (lipopolysaccharide), guinea pigs were given 2CA intravenously. Three groups were used: saline control, endotoxin control and 2CA+ endotoxin. In the endotoxin and 2CA+ endotoxin groups, neutrophils accumulated in bronchoalveolar lavage fluid and in lung tissue. However, neutrophil accumulation did not differ significantly between the endotoxin and the 2CA+ endotoxin groups. The number of macrophages in bronchoalveolar lavage fluid was significantly higher in the endotoxin group than in the saline control group, but the difference between the saline control and the 2CA+ endotoxin groups was not significant. The lung wet-dry weight ratio and 125I-albumin lung tissue-plasma ratio, which were used to measure acute lung injury, were significantly higher in the endotoxin group than in the 2CA+ endotoxin and the saline control groups. However, these ratios did not differ between the 2CA+ endotoxin and the saline control groups. These results suggest that 2CA attenuated endotoxin induced acute lung injury in guinea pigs.

2-Chloroadenosine↗
PubMed2006

Particle size distributions and concentrations of airborne endotoxin using novel collection methods in homes during the winter and summer seasons.

UNLABELLED: A comparison study of novel collection methods for airborne bacteria and endotoxin was performed in an environmentally controlled chamber and in pilot-field studies. Airborne particulate matter was collected in swirling liquid impingers, air-monitoring filter cassettes, and with a micro-orifice uniform deposit impactor (MOUDI) to evaluate aerodynamic particle size distributions. Environmentally controlled chamber studies showed that impingers and MOUDI recovered significantly more airborne bacteria than filter cassettes, whereas collection methods for airborne endotoxin were not significantly different. In addition, total airborne bacteria and endotoxin concentrations were measured indoors and outdoors at three homes in Boulder, CO during winter and summer seasons. Indoor concentrations collected with the three different samplers were significantly different for airborne endotoxin, but not for airborne bacteria. Total airborne bacteria indoors and outdoors significantly varied with seasons. Outdoor airborne endotoxin significantly varied with season; no seasonal variation was seen for indoor airborne endotoxin. Indoor and outdoor levels were not significantly different for both airborne bacteria and endotoxin. The largest proportion of endotoxin was associated with airborne particulate matter <1 microm. PRACTICAL IMPLICATIONS: This study compared sampling methods for airborne endotoxin, a potent and nonspecific immune system stimulant which can induce negative health responses. The data from this study showed that swirling liquid impingers and the micro-orifice uniform deposit impactor (MOUDI) recovered significantly more airborne endotoxin than the more widely adapted method of collecting airborne endotoxin on membrane filters, when collection methods were applied in realistic settings (homes). The MOUDI measured the particle size distribution of airborne endotoxin, which can be useful for determining endotoxin respiratory toxicity and its health effects.

Air Microbiology↗
PubMed2003

[Evaluation of the animal model for endotoxin-induced shock].

BACKGROUND: We evaluated our animal model for endotoxin-induced shock and compared its characteristics with those of clinical endotoxic shock. METHODS AND RESULTS: Male Japanese rabbits anesthetized with urethane and ventilated mechanically were assigned to one of two groups: the endotoxin group, receiving intravenous E. coli endotoxin (0.5 mg.kg-1) via the mesenteric vein; control group, receiving 0.9% saline. After the endotoxin injection, the mean arterial pressure, cardiac output, and systemic vascular resistance decreased progressively. Four hours after the endotoxin injection, the levels of both interleukin (IL)-6 and IL-8 in the endotoxin group were higher than those in the control group. Male Wistar rats anesthetized with pentobarbital and ventilated mechanically were assigned to one of two groups: endotoxin group, receiving intravenous E. coli endotoxin (15 mg.kg-1); and control group, receiving 0.9% saline. After the endotoxin injection, the systolic arterial pressure and heart rate decreased progressively. The plasma tumor necrosis factor alpha and IL-6 increased in the endotoxin group. CONCLUSIONS: We could not observe the hyperdynamic state and multiple organ dysfunctions and did not administer vasopressors and antibiotics in our endotoxin shock models, compared with the characteristics of clinical endotoxin shock. Further refinement of our animal models for endotoxin shock is challenging.

Animals↗
PubMed1992

High serum IL-6 level reflects susceptible status of the host to endotoxin and IL-1/tumor necrosis factor.

Patients with high level of serum endotoxin did not necessarily develop into lethal shock, whereas some patients died of septic shock even when their serum endotoxin levels were low. These results indicate that limiting factor which determines the host to be endotoxin shock principally depends on the host susceptibility to endotoxin instead of serum endotoxin level. To understand this susceptible status of the host to endotoxin, we used Propionibacterium acnes primed mouse endotoxin shock model. We found that P. acnes-primed mice responded to low dose of LPS by enhanced production of IL-1 and TNF. And such mice were highly susceptible to the lethal shock inducing effect of IL-1 and/or TNF, which also induced high level of serum IL-6 in these mice. Therefore, measurement of serum IL-6 level provides us with the information of the preceding exposure of the host to either LPS or IL-1 and/or TNF and the highly susceptible status of the host to these stimuli. Based on these results obtained from animal model, we investigated the relationship between serum IL-6 levels and serum endotoxin levels in the patients with malignant hematologic disorders. We found that these patients fell into two groups; an endotoxin susceptible group, equivalent to P. acnes-primed mice, showing high level of serum IL-6 with low level of serum endotoxin, and a nonendotoxin susceptible group, equivalent to P. acnes-nonprimed mice, showing low or undetectable level of serum IL-6 with high level of serum endotoxin. We propose that the measurement of serum IL-6 level in the patients positive for endotoxin is a useful tool in evaluating diagnosis and prognosis of endotoxin shock.

Adolescent↗
PubMed2007

The balance between endotoxin accumulation and clearance during particle-induced osteolysis in murine calvaria.

Bacterial endotoxin may contribute to aseptic loosening of orthopedic implants even in the absence of clinical or microbiological evidence of infection. One potential source of endotoxin during aseptic loosening is systemically circulating endotoxin, derived from intestinal flora, minor infections, or dental procedures, that may bind to wear particles. The current study demonstrates that systemically derived endotoxin accumulates when 'endotoxin-free' titanium and polyethylene particles are implanted on murine calvaria. Time-course experiments and experiments using germ-free mice rule out the possibility that the observed endotoxin accumulation may be due to bacterial contamination. In contrast, endotoxin is cleared from titanium particles that originally carry high amounts of adherent endotoxin. The mechanism of endotoxin clearance is not dependent on induction of a respiratory burst. Taken together, these results indicate that a balance between endotoxin accumulation and endotoxin clearance controls the steady-state level of endotoxin surrounding orthopedic wear particles implanted on murine calvaria. This balance may regulate the rate of osteolysis in the murine calvaria model as well as in patients with aseptic loosening.

Animals↗
PubMed2005

Endotoxin from various gram-negative bacteria has differential effects on function of hepatic cytochrome P450 and drug transporters.

The differential effects of endotoxin derived from Klebsiella pneumoniae, Pseudomonas aeruginosa and Escherichia coli on hepatic cytochrome P450 (CYP)-dependent drug-metabolizing enzyme activity and on the expression of hepatic CYP3A2, CYP2C11, P-glycoprotein and multidrug resistance-associated protein 2 (Mrp2) was investigated in rats. Endotoxin from all three different pathogens significantly decreased the systemic clearance of antipyrine, reflecting reduced hepatic drug-metabolizing enzyme activity 24 h after intravenous injection (0.5 mg/kg). The degree of the decreased systemic clearance by P. aeruginosa endotoxin was smaller than that by both K. pneumoniae and E. coli endotoxin. Western blot analysis revealed that the down-regulation of CYP3A2 by K. pneumoniae and E. coli endotoxin was greater than that by P. aeruginosa endotoxin. However, the down-regulation of CYP2C11 by all three different endotoxin was almost the same. Both K. pneumoniae and P. aeruginosa endotoxin significantly down-regulated P-glycoprotein, but did not down-regulate Mrp2. E. coli endotoxin had no effect on the expression of either P-glycoprotein or Mrp2, probably due to the low dose used. The down-regulation of CYP3A2 by endotoxin was parallel to the decreased systemic clearance of antipyrine. These results suggest that endotoxin has a differential effect on the hepatic CYP-mediated drug-metabolizing enzyme activity, and on the protein levels of hepatic CYP3A2 and P-glycoprotein, probably due to bacterial source-differences in the production of some proinflammatory mediators. Endotoxin appears to regulate coordinately CYP3A2, CYP2C11 and P-glycoprotein, but not Mrp2.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Impact of detection of bacterial endotoxin in menstrual effluent on the pregnancy rate in in vitro fertilization and embryo transfer.

OBJECTIVE: To examine whether bacterial endotoxin is detectable in menstrual effluent and to analyze a possible association between endotoxin levels and a pregnancy rate after IVF-ET. DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): Thirty-eight infertile women undergoing endotoxin assay and IVF-ET. INTERVENTION(S): Endotoxin was assayed by the limulus amoebocyte lysate test. MAIN OUTCOME MEASURE(S): Levels of bacterial endotoxin and a pregnancy rate. RESULT(S): In 38 samples of menstrual effluent taken from 38 women, bacterial endotoxin was detected with a range of 7.1 to >1,000 pg/mL in 37 samples and was not detected in 1 sample. After IVF-ET, pregnancy occurred in 9 of the 38 women. The mean (+/- SD) endotoxin level in these 9 pregnant women was 71.3 +/- 52.5 pg/mL and was significantly lower compared with >236.2 +/- 333.6 pg/mL in the 29 nonpregnant women. All pregnancies occurred in 28 women with an endotoxin level of </=200 pg/mL, whereas no pregnancies occurred in 10 women with an endotoxin level of >200 pg/mL, producing the significantly higher pregnancy rate in the former group than in the latter. CONCLUSION(S): Bacterial endotoxin was detectable in menstrual effluent from infertile women. The pregnancy rate after IVF-ET was significantly higher in women with an endotoxin level of </=200 pg/mL than in women with an endotoxin level of >200.0 pg/mL.

Adult↗