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PubMed1991

Imbalance between plasma levels of thromboxane B2 and 6-keto-prostaglandin F1 alpha during subacute endotoxin-induced hyperdynamic sepsis or multiple organ failure syndrome in sheep.

We compared the time course of plasma and pulmonary lymph levels of thromboxane B2 (TxB2) and 6-keto-prostaglandin (PG)F1 alpha during the development of either the hyperdynamic phase of sepsis or of the multiple organ failure syndrome (MOFS) associated with sepsis in 26 chronically instrumented awake sheep with intravascular catheters and a chronic pulmonary lymph fistula. Using a continuous i.v. infusion of Escherichia coli endotoxin administered at a rate of 20 ng.kg-1.min-1 (group E20, n = 9) resulted in hyperdynamic septic shock with more than 75% of animals surviving after 72 h of continuous endotoxin administration. Infusing endotoxin at a higher dosage (40 ng.kg-1.min-1; group E40, n = 9) resulted in the development of respiratory failure and MOFS with death occurring within 55 hr of endotoxemia. Eight similarly instrumented sheep served as controls. Administration of endotoxin produced within 4 hr in both endotoxin groups a significant increase in arterial plasma concentration of TxB2, which was not significantly different between both endotoxin groups. Thereafter, plasma TxB2 concentrations progressively decreased in the E20 group to reach at 36 hr values significantly lower than those measured in control sheep not given endotoxin. In the E40 group, plasma TxB2 concentrations returned to baseline values during the development of a MOFS. The time course of TxB2 concentrations in pulmonary lymph in both endotoxin groups was similar to that measured in each group in plasma. 6-Keto-PGF1 alpha concentrations in arterial plasma and pulmonary lymph were significantly higher than in controls during the first 20 hr following the start of endotoxin infusion in both endotoxin groups and were not different between these groups. Thereafter, plasma and pulmonary lymph 6-keto-PGF1 alpha concentrations progressively returned to baseline values in the E20 group and remained at these levels up to the end of the study period (72 hr). In the E40 group, plasma 6-keto-PGF1 alpha concentrations also decreased to baseline values during the second day of endotoxemia but then significantly increased in sheep that survived more than 36 hr and developed a hypodynamic septic state. During the first 24 hr of endotoxemia, the plasma TxB2/6-keto-PGF1 alpha ratio was similar in controls and in both endotoxin groups. During the second study day, TxB2/6-keto-PGF1 alpha ratio progressively decreased in both endotoxin groups to reach and maintain values significantly lower than those measured in controls at 36 hr in the E40 group and at 52 hr in E20 group.(ABSTRACT TRUNCATED AT 400 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1985

Dramatic changes in blood gases that are unrelated to arterial pH or cerebral oxygen delivery during endotoxin shock in conscious rats.

In preliminary studies we demonstrated an effect of endotoxin on arterial blood gases that appeared to be related to the dose of endotoxin used and unrelated to changes in arterial pH. In the present study we tested the hypothesis that these changes in blood gases result from decreased oxygen delivery to central respiratory control areas. PO2 significantly rose from a pre-endotoxin value of 91.4 +/- 1.5 (mean +/- SEM) to 97.5 +/- 1.7, 104.0 +/- 0.8, and 108.4 +/- 0.9 at 10, 30, and 60 minutes, respectively, after administration of 6 mg/kg endotoxin and from 93.8 +/- 3.1 to 105.2 +/- 2.6, 118.7 +/- 1.4, and 121.0 +/- 2.8, respectively, after administration of 10 mg/kg endotoxin. PCO2 fell significantly from a pre-endotoxin value of 38.3 +/- 1.2 to 28.6 +/- 0.6 and 24.5 +/- 1.9 at 30 and 60 minutes post-endotoxin, respectively, in 6-mg/kg-treated rats, and from 40.5 +/- 2.1 to 30.7 +/- 4.5, 20.1 +/- 3.9, and 19.3 +/- 1.0, respectively, at 10, 30, and 60 minutes post-10 mg/kg endotoxin. The only significant change (decrease) in pH occurred at 60 minutes after 10 mg/kg treatment. In 10-mg/kg-treated rats, serum lactate rose significantly over time, while HCO-3 decreased. Heart rate was increased significantly (472 +/- 9.6) from a pre-10 mg/kg endotoxin value of 373 +/- 11.8 by 10 minutes post-endotoxin and remained elevated throughout the experiment. Cerebral medullary/pontine blood flow, mean arterial blood pressure, and respiratory rate were not significantly altered by endotoxin administration. Hemoglobin concentration and arterial oxygen content were significantly increased after 10 mg/kg endotoxin. These findings indicate that decreased oxygen delivery to central respiratory control areas is not a cause of the observed dramatic changes in blood gases.

Acid-Base Equilibrium↗

PubMed1994

Platelet-activating factor and endotoxin induce tumour necrosis factor gene expression in rat intestine and liver.

We have shown previously that endotoxin, tumour necrosis factor (TNF) and platelet-activating factor (PAF) are important in the pathogenesis of bowel injury, and that endotoxin and TNF induce PAF formation in bowel tissue. In the present study we investigated the effects of endotoxin and PAF on TNF gene expression. Adult rats were injected with endotoxin (2 mg/kg), PAF (1 microgram/kg) or endotoxin plus PAF, and were killed after 30 min. Endotoxin had little systemic effect. PAF induced transient hypotension and mild bowel injury. Endotoxin plus PAF caused profound shock, severe haemoconcentration, leukopenia and intestinal necrosis. Sham-operated rats had barely detectable TNF mRNA in the liver or intestine. Endotoxin or PAF induced a marked increase in TNF mRNA, especially in the distal ileum and in the liver, but much less in the jejunum. Endotoxin plus PAF did not further increase TNF mRNA, probably due to development of tissue injury. Serum TNF levels in animals treated with endotoxin, PAF and endotoxin plus PAF were elevated. Endotoxin induces TNF gene expression probably via both PAF-dependent and PAF-independent pathways, since TNF mRNA formation was only partially blocked by PAF antagonist.

Animals↗

PubMed1963

MODIFICATION OF HOST RESPONSES TO BACTERIAL ENDOTOXINS. I. SPECIFICITY OF PYROGENIC TOLERANCE AND THE ROLE OF HYPERSENSITIVITY IN PYROGENICITY, LETHALITY, AND SKIN REACTIVITY.

Evidence is presented suggesting that the apparent non-specificity of pyrogenic tolerance observed with Gram-negative bacterial endotoxins is due to related antigenic determinants associated with the macromolecular toxins. This is based on results obtained in rabbits from pyrogenic cross-tolerance tests with selected endotoxins. In these tests, purified endotoxins from Escherichia coli (COO8) and Chromobacterium violaceum (CV) gave results one might expect with non-reciprocal cross-reacting antigens in classical immune systems. Additional evidence for an immune mechanism in tolerance is suggested by the highly significant anamnestic response observed. Lipid A, a toxic derivative of the purified COO8 endotoxin, failed to induce pyrogenic tolerance against the parent toxin. These results are explained by assuming that endotoxins have two interdependent activities associated with different portions of the macromolecule; one is assumed to be responsible for the primary toxicity, and the other is involved in secondary toxicity. The latter is dependent on the hypersensitive state of the host. Additional evidence for the role of hypersensitivity in secondary toxicity is based on the observation that adult rabbits are highly sensitive to the pyrogenic, lethal, and skin-reacting activities of endotoxin in contrast to young animals which are more resistant to all of these attributes of toxicity. In adults, the host responses to pyrogenicity, lethality, and skin reactivity could be partially inhibited by the early exposure of the animals to massive doses of endotoxin equivalent to a LD(50). The pyrogenic tolerance shown in these animals was specific indicating that the inhibition of the hypersusceptibility to endotoxin involved an immunological mechanism. A mechanism of endotoxin tolerance is proposed and discussed based on the induction of specific antibodies capable of assisting the RES in the clearance and destruction of endotoxin. It is suggested that the present inconsistencies relative to the chemical nature and biological activities of endotoxins might be explained on the basis of these two activities and the failure to recognize the importance of the immunological state of the host in which the toxins are tested.

Animals↗

PubMed1990

The effect of endotoxin on 1,2-dimethylhydrazine-induced colonic tumors in rats.

The effect of endotoxin on colon tumors was studied in male Sprague-Dawley rats. Colon tumors were induced in weanling rats by the administration of 20 weekly subcutaneous injections of 1,2-dimethylhydrazine (DMH). When colon tumors were detected by colonoscopy in 80% of the rats around week 24 after DMH injection, the animals were divided randomly into two groups. One group served as the control. The other group received six endotoxin (Escherichia coli) treatments every fifth day. The first dose was 50 micrograms/100 g (intraperitoneally); the remaining doses were 100 micrograms/100 g (subcutaneously). Rats were killed 2 weeks after the last endotoxin injection. Endotoxin treatments resulted in larger colon tumors. The median tumor size was 71 mm2 for endotoxin-treated and 31 mm2 for untreated rats (P less than 0.02). Endotoxin treatments also resulted in a significantly higher incidence (P less than 0.05) of ulcer development in the small intestine, that is 47% in the endotoxin-treated versus 23% in the untreated rats. After a single subcutaneous injection of endotoxin (100 micrograms/100 g), the colon mucosal reduced glutathione (GSH) level was raised by 21% at 16 hours, reached a peak on day 2, then decreased to baseline by day 4. The increased GSH level in the colon mucosa was maintained up to the third endotoxin injection. By the fifth injection, no increase in the GSH level was observed. These results suggest that the growth of colon tumors in rats induced by DMH could be enhanced by endotoxin treatments. The enhanced tumor growth may be due to an increase in the colon GSH level and/or other mediators released by macrophages as a result of endotoxin treatments.

1,2-Dimethylhydrazine↗

PubMed1992

Endotoxins inhibit endocytotic catabolism of low-density lipoproteins in Hep G2 cells.

The effects of endotoxins on the uptake and degradation of low-density lipoproteins in Hep G2, a well-differentiated human hepatoma cell line, were studied. The results showed that incubation of Hep G2 cells with 125I-labeled low-density lipoprotein in the presence of endotoxins caused decreased uptake and degradation of 125I-labeled low-density lipoprotein. The inhibitory effects of endotoxins on the uptake and degradation of 125I-labeled low-density lipoprotein were dose and time dependent. With a monoclonal low-density lipoprotein receptor antibody, it was found that endotoxins interfered with both low-density lipoprotein receptor-mediated and non-low-density lipoprotein receptor-mediated uptake. If, however, the cells were pretreated with endotoxins for 1 or 24 hr and then incubated with new medium without endotoxins, no inhibitory effect on the subsequent uptake and degradation of 125I-labeled low-density lipoprotein occurred. Endotoxins had no toxic effects on Hep G2 cells as judged by [3H]thymidine incorporation and by determination of cell growth. Also, endotoxins did not under our experimental conditions induce oxidative modification of low-density lipoprotein. Furthermore, reisolated low-density lipoprotein that had previously been incubated with endotoxin was catabolized to a lower extent by Hep G2 cells than was control low-density lipoprotein. We speculate that the inhibitory effect of endotoxins on cellular low-density lipoprotein catabolism is due to the formation of endotoxin-low-density lipoprotein complexes, which interfere with the binding of low-density lipoprotein to the cell surface.

Biological Transport↗

PubMed1998

Endotoxin pretreatment in vivo increases the mitochondrial respiratory capacity in rat hepatocytes.

Administration of sublethal doses of endotoxin produces tolerance to subsequent oxidative stress in diverse animal models. Although endotoxin induces antioxidant enzymes, particularly manganous superoxide dismutase (Mn-SOD), the phenomenon of tolerance remains incompletely understood. Previously I determined that endotoxin treatment in rats increased lung mitochondrial respiration-dependent (i.e., independent of Mn-SOD) scavenging of superoxide anion. Because nonenzymatic scavenging of superoxide anion correlates with the mitochondrial membrane energy gradient, I hypothesized that endotoxin increases the mitochondrial transmembrane potential. Endotoxin treatment (500 micrograms/kg intraperitoneally 48 h earlier) increased the hepatocyte mitochondrial transmembrane potential as determined by two separate methods: the intramitochondrial sequestration of triphenylmethylphosphonium (electrical potential or delta psi) and the fluorescence intensity of the hepatocyte mitochondria when stained with rhodamine-123 and examined by confocal microscopy. These findings suggest that endotoxin treatment increased the total mitochondrial membrane potential per hepatocyte. In parallel, endotoxin treatment increased the fluorescence intensity of hepatocyte mitochondria after staining with 10-N-nonyl-acridine orange, a dye that binds to the mitochondrial inner membrane independently of the transmembrane potential. This suggests that an increase in mitochondrial inner membrane mass is responsible for the net increase in inner membrane potential per cell following endotoxin pretreatment. These findings complement previous studies in which endotoxin treatment increased the mitochondrial-specific antioxidant Mn-SOD and support the more recent finding that endotoxin treatment also increased nonenzymatic scavenging of superoxide by lung mitochondria. Taken, together, these observations suggest that mitochondrial biogenesis, and the subsequent increase in both enzymatic and nonenzymatic scavenging of superoxide anion, is a central feature of endotoxin-mediated tolerance to oxidative stress.

Aminoacridines↗

PubMed1992

Effects of in vivo endotoxin infusions on in vitro cellular immune responses in humans.

Studies of the immune response of patients following major injury have identified significant abnormalities, some of which may be due to the effects of endotoxin. To evaluate the effect of endotoxin on the immune system without conflicting variables, we studied 18 normal, healthy male volunteers each on two occasions. In one study, Escherichia coli endotoxin was administered intravenously at a dose of 4 ng/kg. In the other, saline was given. Blood for immune function studies was obtained at either 0, 4, or 24 hr (seven volunteers), 0, 1, and 4 hr (five volunteers), or 0, 4, and 6 hr (six volunteers) postinfusion. Peripheral blood mononuclear cells (PBMC) were isolated and adjusted to the same concentration. Measurements following endotoxin infusion were compared with those of the same volunteers following saline infusion and with those from normal ambulatory laboratory volunteers. Interleukin 1 (IL-1) production by adherent cells was significantly reduced at 1 hr post endotoxin infusion. Significant decreases in number of mononuclear cells, response to phytohemagglutinin (PHA), and production of IL-2 and IL-1 were observed by 4 hr after endotoxin infusion. No significant changes in percentages of monocytes, lymphocytes, or CD3, CD4, or CD8 lymphocytes were observed at any time. By 24 hr postinfusion all values had returned to normal or, in some cases, supranormal levels. Response to PHA by PBMC from volunteers 4 hr following endotoxin was completely restored by in vitro addition of recombinant human IL-2 but was only marginally improved by IL-1. In vitro addition of indomethacin to PBMC cultures responding to PHA reduced the suppression observed after in vivo endotoxin but also was not as effective as IL-2. In a fourth study, seven volunteers were treated as above either with two doses (800 mg each) of the cyclooxygenase inhibitor ibuprofen before endotoxin infusion or with ibuprofen alone. Ibuprofen pretreatment completely restored the PBMC response to PHA to normal and caused a significant decrease in the endotoxin-induced suppression of IL-2 production. However, the decrease in circulating PBMC number and adherent cell secretion of IL-1 was not affected by inhibition of the cyclooxygenase pathway. These results suggest that endotoxin has immunomodulatory effects on both adherent mononuclear-cell and T-lymphocyte function and that more than one mechanism is involved.

Adult↗

PubMed1994

Increased prostaglandin I2 and thromboxane A2 production by rat dental pulp after intravenous administration of endotoxin.

The effect of systemic endotoxin (lipopolysaccharide from Escherichia coli 0111:B4) on prostaglandin I2 (PGI2) and thromboxane A2 (TXA2) production by rat dental pulp was investigated. Intravenous injection of endotoxin increased ex vivo production of both PGI2 and TXA2 by the pulp tissue, when determined by radioimmunoassay. A significant effect on PGI2 and TXA2 production was observed with endotoxin doses of greater than 2 and 0.4 mg/kg, respectively. A significant increase was also observed at 30 min after injection of 10 mg/kg endotoxin, reaching a maximum after 60 min for both PG and TX production. Endotoxin (10 mg/kg for 60 min) also increased TXA2 but not PGI2 production in lung tissue, but had no effect in jejunal tissue. Indomethacin (10 microM) completely inhibited PGI2 and TXA2 production by the pulp of physiological saline- and endotoxin-treated rats. Further, arachidonic acids (10 microM) significantly increased PG and TX production by the pulp of saline- but not of endotoxin-treated rats. Endotoxin (100 micrograms/ml) had no in vitro effect on PG or TX production when incubated with isolated pulp, lung and jejunal tissues, suggesting that the endotoxin-induced increases in PG and TX production are an indirect effect. The endotoxin-induced increase in TXA2 production, but not in PGI2 production, by the pulp tissue was significantly suppressed by WEB 2170, a platelet-activating factor (PAF) antagonist. These results indicate that arachidonate metabolism in pulp tissue is susceptible to endotoxaemia in comparison with the lung and jejunum, and further suggest that the endotoxin-induced increase in, at least, TXA2 production by the pulp is mediated by PAF.

Animals↗

PubMed1989

Arachidonic acid turnover in peritoneal macrophages is altered in endotoxin-tolerant rats.

Peritoneal macrophages from endotoxin-tolerant rats have been found to exhibit depressed metabolism of arachidonic acid (AA) to prostaglandins and thromboxane in response to endotoxin. The effect of endotoxin tolerance on AA turnover in peritoneal macrophages was investigated by measuring [14C]AA incorporation and release from membrane phospholipids. Endotoxin tolerance did not affect the amount of [14C]AA incorporated into macrophages (30 min-24 h). However, the temporal incorporation of [14C]AA into individual phospholipid pools (15 min-24 h) was altered. In endotoxin-tolerant macrophages, [14C]AA incorporation into phosphatidylcholine (PC) (2, 4, 24 h) and phosphatidylethanolamine (PE) (8 h) was increased, while the incorporation into phosphatidylserine (PS) (2-24 h) was reduced (P less than 0.005) compared to control macrophages. There was no change in [14C]AA incorporation into phosphatidylinositol (PI). Following 2 or 24 h of incorporation of [14C]AA, macrophages were incubated (3 h) with endotoxin (50 micrograms/ml) or A23187 (1 microM), and [14C]AA release was measured. Endotoxin-tolerant macrophages released decreased (P less than 0.05) amounts of [14C]AA in response to both endotoxin and the calcium ionophore A23187 compared to controls. Control macrophages in response to endotoxin released [14C]AA from PC, PI and PE. In contrast, tolerant cells released [14C]AA only from PC (P less than 0.05). A23187 released [14C]AA from all four pools in the control cells, but only from PC and PE in the tolerant cells. These data demonstrate that endotoxin tolerance alters the uptake and release of AA from specific macrophage phospholipid pools. These results suggest that changes in AA turnover and/or storage are associated with endotoxin tolerance.

Animals↗

PubMed1992

Modification of alpha-adrenoceptor-mediated pressor responses by NG-nitro-L-arginine methyl ester and vasopressin in endotoxin-treated pithed rats.

Pithed rats were used to compare the abilities of vasopressin and NG-nitro-L-arginine methyl ester (L-NAME) to prevent the early (1 h after starting an endotoxin infusion) E. coli endotoxin-induced impairment of pressor responsiveness to noradrenaline, cirazoline, BHT 933 and to sympathetic stimulation (T8). L-NAME increased arterial blood pressure and augmented pressor responses to noradrenaline and to sympathetic nerve stimulation to a similar degree in control and endotoxin-treated rats. The response to the alpha 1-adrenoceptor agonist cirazoline was augmented by L-NAME in endotoxin-treated rats only, whereas the response to the alpha 2-adrenoceptor agonist BHT 933 was unaffected. Vasopressin (0.64 I.U. kg-1 h-1) prevented the hypotension that resulted from endotoxin administration and produced a similar increase in blood pressure to that produced by L-NAME. This dose of vasopressin also augmented pressor responses to noradrenaline and sympathetic nerve stimulation similarly in both control and endotoxin-treated rats. Sodium nitroprusside, in a dose that mimicked the degree of hypotension caused by endotoxin, also impaired pressor responsiveness to cirazoline; this impairment was prevented by co-infusion of vasopressin. Thus the effects of L-NAME in preventing the early phase of endotoxin-induced impairment of vascular responsiveness may be related to its hypertensive properties, due to inhibition of the constitutive form of nitric oxide synthase, rather than inhibition of endotoxin-induced nitric oxide synthase. These data suggest that early endotoxin-induced impairment of vascular reactivity probably involves factors other than nitric oxide. The well documented effect of endotoxin in inducing nitric oxide synthase probably explains the later, more sustained loss of vascular responsiveness.

Adrenergic alpha-Agonists↗

PubMed1989

Clearance of gut-derived endotoxins by the liver. Release and modification of 3H, 14C-lipopolysaccharide by isolated rat Kupffer cells.

This paper describes experiments that were designed to study postuptake modification by isolated rat Kupffer cells of a 3H,14C-biosynthetically labeled endotoxin purified from Escherichia coli J5 as assessed by cesium chloride isopyknic density gradients and gel permeation chromatography. Pulse-chase experiments demonstrated that half as much of the endotoxin's lipid, relative to polysaccharide, was released by the cells. Density gradients revealed that native endotoxin equilibrated at a density of 1.412 g/ml, whereas endotoxin retained by Kupffer cells equilibrated at densities of 1.274 and 1.295 g/ml. Gel permeation chromatography indicated that endotoxin retained by Kupffer cells formed a larger micelle than either exocytosed or native endotoxin. Endotoxin exocytosed by Kupffer cells fractionated into two peaks, one with a smaller and one with a larger apparent micelle size than native endotoxin but both smaller than the retained lipopolysaccharide. Both systems indicated that the Kupffer cell modified endotoxin by enriching the lipid content of the molecule and shortening the length of the O-antigen. Thus, the Kuffer cell, in its mode of action on the endotoxin molecule, appears to play a prominent role in the initial phase of a biochemical process for endotoxin clearance and detoxification.

Animals↗

PubMed1995

Removal of endotoxins by affinity sorbents.

Histidine, histamine and polymyxin B affinity sorbents were employed for the removal of Escherichia coli-derived endotoxins. Their effectiveness was compared with those of poly-L-lysine-Sepharose and DEAE-Sepharose. All sorbents reduced the concentration of endotoxins from an E. coli culture filtrate to tolerable levels. However, their effectiveness was not higher than that of the anion exchanger, which displayed clearance rates of up to 15,000. Endotoxin removal from protein solutions depended on the net charge of the desired protein. Lysozyme as a model for positively charged proteins enhanced endotoxin removal. In contrast, only low initial contamination levels (< 34 EU/ml) were reduced to tolerable levels from bovine serum albumin (BSA) as the negatively charged protein model owing to competition of BSA and endotoxins for adsorption sites. Hence also a low BSA recovery was observed after the treatment whereas the lysozyme recovery was almost 100%. At pH values below the isoelectric point of BSA, endotoxin removal was also more effective. The best conditions for the decontamination were found at neutral pH and low ionic strength (< or = 20 mM phosphate). Ionic forces between ligands and endotoxins are dominant at this ionic strength; hydrophobic interactions are not very effective. Hence the selectivities of all sorbents towards endotoxins are not exceptionally high. DEAE-anion exchangers are the most suitable sorbents for the removal of endotoxins from solutions accommodating positively charged proteins owing to their low cost and high capacity. Poly-L-lysine-Sepharose was most effective for the removal of small amounts of endotoxins from solutions of negatively charged proteins. The "affinity ligands" histamine, histidine and polymyxin B were effective for the removal of endotoxins from E. coli filtrate; however, their effectiveness decreased dramatically in the presence of BSA and it was lower than for poly-L-lysine- and DEAE-Sepharose in the presence of lysozyme.

Adsorption↗

PubMed2005

Airborne endotoxin in homes with domestic animals: implications for cat-specific tolerance.

BACKGROUND: Although endotoxin is known to increase symptoms in allergic individuals, early exposure might decrease sensitization. Similarly, the presence of an animal in the home has been associated with decreased sensitization to animal allergens. It has been suggested that the effect of animals could be explained by increased endotoxin exposure. OBJECTIVE: We sought to investigate the effects of domestic animals on airborne endotoxin. METHODS: By using a silent particle collector, air was sampled over 24 hours in homes with or without animals. The total volume sampled was approximately 1000 m3, which provides quantities of allergen and endotoxin that can easily be measured with standard assays. RESULTS: The quantity of endotoxin ranged from less than 0.5 to more than 500 pg/m3, whereas cat and dog allergen ranged from less than 0.002 to more than 5 ng/m3. Overall, the quantity of airborne endotoxin was not higher in homes with at least one animal. However, airborne endotoxin levels were significantly lower in homes with a cat compared with homes with a dog (P < .001). In keeping with this, there was a significant correlation between airborne Can f 1 and airborne endotoxin (r = 0.50, P < .01) but not between endotoxin and Fel d 1 (r = 0.17, P = .27). CONCLUSIONS: The results demonstrate that endotoxin is present in the air of almost all homes. Although higher levels were seen in homes with a dog, similar levels might be present in homes with no animals. The results argue that the effects of cat ownership cannot be explained by increased exposure to endotoxin.

Air Pollutants↗

PubMed2005

Early life host-bacteria relations and development: long-term individual differences in neuroimmune function following neonatal endotoxin challenge.

Neonatal animals have a proportionately greater risk, relative to the adult animal, of developing a bacterial infection. Research has revealed that such infections can influence biological processes long after the actual infection has been resolved. Indeed, studies examining the long-term alterations induced by early-life infection, simulated using endotoxin, have indicated that some aspects of the systemic inflammatory response in the adult animal are susceptible to modification. Available evidence suggests that altered inflammatory activities observed in the neonatally endotoxin challenged adult may be the result of potentiated hypothalamic pituitary adrenal (HPA) activity, specifically increased corticosterone production. Few studies, however, have examined whether altered corticosterone production is actually associated with changes in systemic inflammation in the neonatally endotoxin challenged adult animal. The aim, therefore, of the current study was to simultaneously examine the relationship between altered inflammatory activities and corticosterone production in the neonatally endotoxin challenged adult rat. Our findings demonstrate no significant differences exist between adults neonatally treated with saline or endotoxin in terms of their production of corticosterone following endotoxin challenge. While not appearing to influence the production of corticosterone neonatal endotoxin challenge did result in a marked attenuation in the adult's febrile response following endotoxin challenge. Interestingly, circulating levels of IL-1beta and TNF-alpha were found to be equivalent in neonatal treatment groups following endotoxin administration in adulthood, indicating that the reduction in fever was unlikely to be the result of altered pro-inflammatory cytokine production. Further, no differences were found between neonatal treatment groups in net food consumption, water consumption or weight loss following endotoxin challenge in adulthood. Collectively, these findings demonstrate that neonatal endotoxin challenge does not affect a blanket down regulation of inflammatory processes but rather appears to induce highly specific alterations in the adult male Fischer-344 rat.

Age Factors↗

PubMed2006

Measurements of endotoxin on ambient loaded PM filters after long-term storage.

At present there exist unsolved questions, whether endotoxin measurements on PM filters show valid measurements after long-term storage of loaded PM filters. As part of the TRAPCA study we collected particles with a 50% aerodynamic cut-off diameter of 2.5 microm (PM(2.5)) at 40 outdoor sites and particles less than 10 microm in size (PM(10)) at a subset of these sites (N=12) in Munich. The PM filters were cut in halves and endotoxin was measured in the extract of one filter half 2-3 years after PM collection. Here we present the results of repeated endotoxin measurements, where the association between previously measured endotoxin concentrations, measurements from stored eluates, and measurements in extracts of the second filter halves were determined. No statistically significant changes were seen between our old measurements and those from the stored eluates. Additionally, no change was observed between previously measured endotoxin concentrations and those from the stored set of filter halves. We found an average increase of 5% between our old measurements and those from the stored eluates and of 19% between the old measurements and those from the stored set of filter halves. The correlations between the previously measured endotoxin concentrations and the repeated measurements from the stored eluates were high (r=0.789) for EU/m(3) PM(2.5). Since endotoxin was evaluated from the same set of filter halves, it is obvious that storage over three years did not substantially effect the correlation of the endotoxin content. Regarding the outliers from previous measurements unsymmetric endotoxin spots on one out of 48 filter halves could be determined. Apart from this we conclude that the endotoxin is homogenously distributed on the filter halves and that endotoxin levels, which were repeatedly measured from filters stored over three years, could be determined validly.

Air Pollutants↗

PubMed1998

Endotoxin-induced atrial natriuretic factor release: in vivo and in vitro studies.

OBJECTIVE: We evaluated the effects of coliform endotoxin on the circulating levels of atrial natriuretic factor and renal function. To understand the direct effects of endotoxin in the release of atrial natriuretic factor by cardiac tissue, studies in isolated rat atria were performed. STUDY DESIGN: In vivo studies were used. Anesthetized dogs were studied, with one group receiving isotonic saline solution (n = 6) and the other group receiving 50 microg/kg of coliform endotoxin (n = 7) as a continuous infusion over a 4-hour period. Cardiovascular parameters, renal function, and circulating levels of atrial natriuretic factor were measured at specified time intervals. In another set of experiments with in vitro studies left atria from Sprague-Dawley rats were isolated and perfused. In the control group (n = 9) the standard Krebs perfusate was used. In the endotoxin group (n = 9) coliform endotoxin was added at a concentration of 250 microg/mL to the standard perfusate. Atrial pressure was used as an index of stretch, and atrial natriuretic factor was measured from the perfusate. RESULTS: Administration of endotoxin resulted in decreased blood pressure (P < .05) with a concomitant increase in heart rate. Renal artery flow, however, showed an increase (P < .05) initially followed by a return to its baseline value, with a sustained increase occurring in the saline solution control group. A significant (P < .05) and sustained increase in the circulating levels of atrial natriuretic factor after endotoxin infusion did not prevent the decrease in fractional sodium excretion (P < .05) and creatinine clearance despite an increase in the urinary output. Serum sodium, serum potassium, and osmolalities, however, remained relatively stable. The study pertaining to isolated atria showed that in the presence of low atrial pressures, addition of endotoxin had no significant effect on the release of atrial natriuretic factor. With the increase in atrial pressure atrial natriuretic factor release was significantly higher in the group directly exposed to endotoxin compared with the control group. CONCLUSIONS: These studies demonstrate that the slow infusion of coliform endotoxin results in increased circulating levels of atrial natriuretic factor. This increase is in part due to the direct effect of endotoxin on the heart as indicated by studies in isolated atria. Our data suggest that atrial natriuretic factor in endotoxemia acts in an integrative manner with other hormones on a variety of target organs to modulate cardiovascular function and fluid balance.

Animals↗

PubMed1995

Triglyceride-rich lipoproteins improve survival when given after endotoxin in rats.

BACKGROUND: Triglyceride-rich lipoproteins have been shown to bind bacterial endotoxin and inhibit its activity in vitro and to protect animals from death when administered before a lethal injection of endotoxin. We now demonstrate that triglyceride-rich lipoproteins can neutralize the toxic effects of endotoxin already in circulation. METHODS: Rats were infused with a lethal dose of endotoxin, followed at various time intervals by an infusion of either mesenteric lymph containing nascent chylomicrons (1 gm chylomicron triglyceride/kg) or an equal volume of normal saline solution. Survival was measured at 48 hours. The experiment was then repeated, substituting the synthetic triglyceride-rich lipid emulsion (1 gm/kg) for chylomicrons. We also measured the clearance and tissue distribution of radioiodinated endotoxin in rats treated subsequently with chylomicrons or saline solution. RESULTS: Chylomicron infusions significantly improved survival when given up to 30 minutes after a lethal dose of endotoxin (p < 0.05). Chylomicrons accelerated endotoxin clearance from the blood and increased endotoxin uptake by the liver. The synthetic triglyceride-rich lipid emulsion significantly improved survival when given up to 15 minutes after a lethal dose of endotoxin (p < 0.05). CONCLUSIONS: Triglyceride-rich lipoproteins and synthetic triglyceride-rich lipid emulsions significantly improve survival of rats when given after a lethal dose of endotoxin. Lipoprotein treatment accelerates endotoxin clearance to the liver, which may account for the observed protection. These data suggest a possible therapeutic role for triglyceride-rich lipoproteins or synthetic lipid emulsions in the treatment of the endotoxemia of gram-negative sepsis.

Animals↗