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PubMed1998

IL-1beta, IL-6, TNFalpha, fetal fibronectin, and endotoxin in the lower genital tract of pregnant women with bacterial vaginosis.

BACKGROUND: In our studies on women with bacterial vaginosis (BV) in early pregnancy a strong association has been found between BV and the levels of endotoxin or interleukin-1alpha (IL-1alpha) in the lower genital tract. In the present study we investigated if an association could be found between BV and other cytokines (IL-1beta, IL-6, tumor necrosis factor alpha, TNF) or fetal fibronectin (FFN). The cytokine-inducing capacity of endotoxins present in the cervical mucus was explored in a monocytic cell assay. METHODS: Cervical mucus or cervicovaginal fluid was collected from women with (BV) and without BV (nonBV) attending a family planning unit for first trimester abortion. The concentrations of IL-1beta, IL-6, TNF and FFN were determined by quantitative enzyme immunoassays. TNF was determined in 63 women (BV, n=25) out of whom 37 (BV, n=11) were analyzed for IL-1beta and the remaining 26 for IL-6 (BV, n=14). FFN was determined in another 36 women (BV, n= 19). The cytokine-inducing capacity of endotoxin-containing cervical mucus and purified endotoxin of Prevotella bivia were studied by an in vitro cell assay using a human monocytic cell line (THP-1). RESULTS: IL-lbeta and IL-6 were found in almost all women. The levels of IL-1beta, but not IL-6, TNF or FFN, were significantly increased in women with BV compared with the nonBV women (p<0.05). Purified endotoxin from P. bivia, and cervical mucus from BV women containing high levels of endotoxin were able to induce a cytokine response (IL-6) in monocytic cells in vitro. CONCLUSION: BV is associated with increased levels of IL-1beta in the lower genital tract of pregnant women in the first trimester. The ability of BV-associated endotoxins to induce cytokine production in monocytic cells may partly explain the increased IL-1beta levels.

Adult↗
PubMed1999

[Bile acids and endotoxins: physico-chemical defense of the body].

The toxic effects of endotoxin--the cell wall component of Gram negative intestinal bacteria--under experimental conditions can be induced only when they are administered parenterally. However, in naturally occurring enteroendotoxemic diseases (e.g. septic and various shocks, etc.), the endotoxin absorbs from the intestinal tract. The cause and mode of translocation was unknown. The generally used experimental shock models differ from natural diseases only in the mode by which endotoxin enters the blood circulation. If the common bile ducts of rats were chronically cannulated (bile deprived animals) perorally administered endotoxin was absorbed from the intestinal canal into blood circulation and provoked endotoxin shock. The translocation of endotoxins and consequent shock can be prevented by sodium deoxycholate or natural biles. The bile acids can split the endotoxin macromolecule (atoxic fragments). A similar destructive detergent action might will be a significant factor against potential infectious agents with lipoprotein outer structure (e.g. so-called "big" viruses). This defense mechanism of macrooganisms based on the detergent activity of bile acids is called as physico-chemical defense system. On the basis of this knowledge the bile acids might be used in the prevention and therapy of some clinical processes (e.g. hepatorenal syndrome; psoriasis).

Animals↗
PubMed1994

Macrophage endotoxin tolerance. Tumor necrosis factor and interleukin-1 regulation by lipopolysaccharide pretreatment.

OBJECTIVE: To correlate cytokine gene expression with the release of protein product by murine peritoneal macrophages rendered tolerant by sequential endotoxin stimulation in vitro. DESIGN: In vitro investigation of the regulation of endotoxin-stimulated cytokine production following endotoxin pretreatment using cytokine bioassays, polymerase chain reaction, and Northern blot analyses. SETTING: In vitro cell culture model of sequential endotoxin stimulation of murine macrophages. INTERVENTIONS: Macrophages were pretreated with 0 or 100 ng/mL of lipopolysaccharide (LPS1) for 24 hours and then stimulated with 0 or 100 ng/mL of LPS (LPS2) for 4 or 24 hours. After stimulation, supernatant tumor necrosis factor (TNF) and interleukin-1 (IL-1) levels were measured by bioassay. Total RNA was extracted and messenger RNA (mRNA) corresponding to TNF and IL-1 was amplified by reverse transcription-polymerase chain reaction or analyzed by Northern blot. RESULTS: Endotoxin pretreatment resulted in the augmentation of IL-1 (mean +/- SD, 78 +/- 9 vs 596 +/- 42 pg/mL, P < .01) and the inhibition of TNF (274 +/- 63 vs 61 +/- 3 pg/mL, P < .01) release 4 hours after stimulation with 100 ng/mL of LPS2. A similar pattern of cytokine release was observed 24 hours after LPS2 stimulation. Pretreatment produced an increased IL-1 message in response to 100 ng/mL of LPS2. The TNF message was detectable in all groups receiving LPS2 alone, but the highest levels of TNF mRNA were seen in LPS1-pretreated cells stimulated with LPS2. CONCLUSIONS: Endotoxin pretreatment produced increased IL-1 message that paralleled the augmentation of IL-1 protein, whereas abundant TNF message was present even though TNF protein release was significantly inhibited. In this model of in vitro endotoxin tolerance, pretreatment initiates divergent pathways of cytokine regulation.

Animals↗
PubMed1994

Distinct patterns of nitric oxide production in hepatic macrophages and endothelial cells following acute exposure of rats to endotoxin.

Hepatic macrophages and endothelial cells play an important role in the clearance of endotoxin from the portal circulation. These cells are activated by endotoxin to release reactive mediators including superoxide anion, hydrogen peroxide, and nitric oxide, which have been implicated in hepatic inflammation and tissue injury. In the present studies we analyzed mechanisms regulating the production of nitric oxide by hepatic macrophages and endothelial cells following in vivo exposure to endotoxin. Rats were injected intravenously with Escherichia coli lipopolysaccharide (LPS, 5 mg/kg). Cells were isolated from the animals 48 h later by in situ perfusion of the liver with collagenase and pronase followed by differential centrifugation and centrifugal elutriation. We found that macrophages and endothelial cells from both untreated and endotoxin-treated rats readily synthesized nitric oxide following in vitro stimulation with interferon-gamma (IFN-gamma) and LPS alone and in combination. This response was dependent on l-arginine and was blocked by two nitric oxide synthase inhibitors, NG-monomethyl-l-arginine and l-canavanine. Macrophages produced more nitric oxide in response to LPS or LPS plus IFN-gamma than endothelial cells. In addition, nitric oxide production by both cell types in response to LPS plus IFN-gamma was increased after treatment of rats with endotoxin. Macrophages appeared to be more sensitive than endothelial cells to the in vivo effects of this inflammatory stimulus. Northern and Western blot analysis demonstrated that nitric oxide production by macrophages and endothelial cells in response to LPS plus IFN-gamma was due to increased expression of an inducible form of nitric oxide synthase (iNOS) mRNA and protein. Using fluorescence image analysis, iNOS protein was found to be localized in the cytoplasm of the cells. Treatment of rats with endotoxin was associated with increased expression of iNOS protein in the macrophages. The phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA) also stimulated nitric oxide production by macrophages and endothelial cells from endotoxin-treated rats, although not as effectively as LPS and IFN-gamma. Macrophages were more responsive than endothelial cells to TPA. Furthermore, depletion of the cells of glutathione using buthionine sulfoximine had no major effect on nitric oxide production by macrophages but resulted in small but significant inhibition in endothelial cells. This suggests that this sulfhydryl-containing tripeptide does not regulate intracellular levels of reactive nitrogen intermediates in activated macrophages.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Oxidoreductases↗
PubMed2001

Actions of endotoxin and morphine.

In summary, our current studies show that treatment with a bacterial endotoxin, lipopolysaccharide (LPS), induces the expression of mu opioid receptors in the rat mesentery. This induction may be mediated through IL-1's actions on mu opioid receptors. Morphine stimulates the expression of adhesion molecules in human brain microvascular endothelial cells (HBMEC) isolated from pathological tissues. Under pathological conditions, mu opioid receptor-dependent pathways may be modulated through the induction of mu opioid receptors, especially in endothelial cells. Treatment with morphine increases [14C]-inulin permeability of an in vitro microvascular endothelial cell barrier, and decreases endothelial cell viability. Morphine pre-treatment potentiates the effects of LPS on endothelial cell viability, and on LPS induction of IL-1beta secretion from 1alpha, 25-dihydroxy-vitamin D3-treated HL-60 human leukemia cells. Previously, it was suggested that an opioid-dependent pathway may be involved in the recovery from endotoxin shock (D'Amato and Holaday, 1984). Induction of mu opioid receptors by treatment with high doses of endotoxin suggests that mu opioid receptor-dependent pathways may be involved in mediating the response to endotoxins. Taken together, these data provide valid evidence for an association between endotoxins and opioid actions. These studies suggest that opioid-dependent pathways in disease or in endotoxin exposure may be modified by cytokine-induced expression of opioid receptors in endothelial cells. In a pathological condition, an alteration of the opioid-dependent pathway may be expected. When morphine is used for its therapeutic values, it may, indeed, potentiate LPS' effects in an adverse manner. From a clinical perspective, these data indicate that morphine and an endotoxin, such as LPS, may interact in a positive 'feedback type of reaction, and thereby modulate the body's immune responses with unexpected and detrimental results.

Animals↗
PubMed1996

The preventive effects of OK432 on endotoxin-induced liver injury: liver protection by the modulation of hepatic macrophage function.

The present study was conducted to clarify whether endotoxin-induced liver injury could be improved by modulating the function of hepatic macrophages using OK432, an immunostimulant derived from Streptococcus. OK432 elevated the capacity of hepatic macrophages to produce superoxide and tumor necrosis factor (TNF), and enhanced the mRNA expression of interleukin-1-alpha, -beta, and TNF-alpha in liver nonparenchymal cells (NPC). However, intravenous (iv) preadministration of OK432 reduced the mRNA expression of TNF-alpha in liver NPC enhanced by the endotoxin injection, decreased the serum level of GOT and lactic dehydrogenase (LDH), and improved the survival rate of endotoxin-injected rats. Histological examination revealed a significant reduction in cell vacuolization and focal necrosis in the livers of the endotoxin-injected rats pretreated with OK432. These results indicate that hepatic macrophages play a crucial role in endotoxin-induced liver injury, and that TNF-alpha is one of the factors most likely to be implicated in the development of endotoxin-induced liver injury. Thus, it is suggested that the administration of OK432 provides liver protection by modulating the responsiveness of hepatic macrophages against endotoxin.

Animals↗
PubMed1991

Relationship of airborne endotoxin and bacteria levels in pig farms with the lung function and respiratory symptoms of farmers.

Previous studies have demonstrated a high prevalence of respiratory and other symptoms and a decrement in lung function among pig farm workers, although the relationships with specific agents present in the work environment remain obscure. This study was therefore undertaken to investigate the relationship between symptoms, lung function and airborne endotoxin, ammonia and dust levels in piggeries. Information on symptoms, lung function, endotoxin, ammonia and dust levels was available for 183 pig farmers who worked in 136 farms. For 62 farms information was present on the levels of bacteria and gram-negative bacteria. For these 62 farms, endotoxin exposure measurements were taken in more than one stable. In general, no significant correlations were found between lung function and chronic respiratory symptoms, or dust and ammonia levels. The endotoxin concentration in stables was negatively related to most lung function variables, but only for the subgroup of 62 farmers was a statistically significant relationship found between endoxtoxin exposure and FEV1. A borderline statistically significant and negative relationship was found between the endotoxin concentration and the FVC. Symptoms experienced during or shortly after work showed odds ratios larger than one with the levels of bacteria, gram-negative bacteria and endotoxin, indicating a positive relationship. No consistency in the relationship between symptoms and dust levels was found. The results suggest that endotoxins and (gram-negative) bacteria probably play an important role in the development of symptoms and lung function changes among pig farmers.

Adolescent↗
PubMed2000

Ketamine suppresses endotoxin-induced NF-kappaB expression.

PURPOSE: Ketamine reduces endotoxin-induced production of proinflammatory cytokines, including tumour necrosis factor-alpha (TNF), in several types of inflammatory cells, including monocytes and macrophages. Transcription of the genes that encode production of these proinflammatory cytokines is regulated by nuclear factor-kappa B (NF-kappaB). Cytoplasmic B protein is activated by endotoxin (LPS) as well as by TNF, allowing B protein to migrate into the cell nucleus to activate gene transcription for these inflammatory mediators. Because NF-kappaB is likely involved in brain injury and inflammatory neurodegenerative disease, such as multiple sclerosis, we examined whether ketamine inhibits LPS-induced activation of NF-kappaB in human glioma cells in vitro and intact mouse brain cells in vivo. METHODS: Endotoxin-induced NF-kappaB expression in both the human glioma cells in vitro and the intact mouse brain cells in vivo was determined by electrophoretic mobility shift assays (EMSA) of nuclear extracts and measurement of NF-kappaB expression by densitometry. Endotoxin was injected intracerebroventricularly in vivo and intact brain was harvested. Klenow fragment labeling was used to identify NF-kappaB protein for both the in vivo and vitro experiments. RESULTS: Endotoxin treatment increased NF-kappaB expression (P < 0.05) both in vivo and vitro compared with control (untreated) cells. Ketamine suppressed endotoxin-induced neuronal NF-kappaB activation in a dose-dependent manner (P < 0.05, except for the 10(-5) M concentration in vitro) both in vivo and vitro. CONCLUSION: Ketamine inhibits endotoxin-induced NF-kappaB expression in brain cells in vivo and vitro and it is suggested that this may have implications in the neuroprotective effects of ketamine reported by other investigators.

Animals↗
PubMed2006

Effects of AM281, a cannabinoid antagonist, on circulatory deterioration and cytokine production in an endotoxin shock model: comparison with norepinephrine.

PURPOSE: The purpose of this study was to examine the comparative effects of AM281, a cannabinoid antagonist, and norepinephrine (NE) on systemic hemodynamics, and renal and mesenteric artery blood flow in an endotoxin shock model. METHODS: The study was designed to include two sets of experiments: (1) measurements of changes in systemic hemodynamics and organ artery blood flows (n = 20), and (2) measurements of biochemical variables (n = 20). For each set of experiments, male 7-week-old Wistar rats were randomly divided into four groups: group 1, controls (n = 5); group 2, receiving lipopolysaccharide (LPS: Escherichia coli endotoxin, 10.0 mg.kg(-1) intravenous bolus) (n = 5); group 3, receiving intravenous LPS and NE (continuous infusion at 0.2 microg.kg.min(-1)) (n = 5); group 4, receiving LPS and AM281 (0.1 mg.kg.min(-1)) (n = 5). Systemic hemodynamics, regional artery blood flow changes, and biochemical variables were assessed before treatment and 1 and 3 h after treatment. RESULTS: Infusion of NE or AM281 prevented endotoxin-induced decreases in systemic arterial pressure, aortic blood flow, carotid artery blood flow, and renal artery blood flow. Both AM281 and NE inhibited endotoxin-induced increases in cytokine production, with significant differences observed among the three groups at 1 and 3 h after treatment. Endotoxin-induced decreases in mesenteric arterial blood flow were restored by AM281 but not by NE. AM281 improved arterial oxygenation and reduced lactate overproduction and body temperature elevation induced by endotoxin. CONCLUSIONS: Although NE and AM281 both prevented endotoxin-induced deterioration of systemic hemodynamics, AM281 yielded better preservation of mesenteric blood flow and attenuation of cytokine production than NE.

Adrenergic alpha-Agonists↗
PubMed1996

Interaction of lipopolysaccharide endotoxin produced from Escherichia coli with D-tubocurarine at the nicotinic2 receptor and adenosine 3':5' cyclic monophosphate during physiological contraction in skeletal muscle.

In this report the murine model of endotoxicosis was used to evaluate hyposensitivity to the neuromuscular relaxant D-tubocurarine (dTC). This hyposensitivity was expressed in terms of a decreased potency to dTC. A rightward shift of the dose-response curve due to endotoxin was observed. Mice were subjected to cumulative intraperitoneal doses of Escherichia coli endotoxin over a 2-wk period. The interaction between endotoxin and dTC was examined during an acute (1 wk) and chronic (2 wk) period of endotoxicosis. Muscle twitch analyses were performed and samples of gastrocnemius muscle were assayed for adenosine 3':5' cyclic monophosphate (cAMP) by [125I]radioimmunoassay. A parallel shift in the dose-response curve occurred in the endotoxin group subjected to doses corresponding to one-third the dose evoking 50% lethality for 2 wk. Both skeletal muscle tension and cAMP levels decreased as cumulative endotoxin doses increased. A relationship between decreasing cAMP levels and increasing dTC and effective dose required to achieve 50% muscle paralysis values was thought to be evoked by the agonistic activity of E. coli endotoxin leading to desensitizing of adenylate cyclase. The perturbations of the classical second messenger cAMP system by endotoxin may be responsible for skeletal muscle dysfunction observed in immunocompromised patients.

Animals↗
PubMed1988

Beneficial effects of dextran 70 versus Ringer's acetate on pulmonary function, hemodynamics and survival in a porcine endotoxin shock model.

The effects of Dextran 70 with NaCl as against Ringer's acetate on hemodynamics, gas exchange, oxygen transport and survival were evaluated in a porcine model of pulmonary and circulatory insufficiency induced by a continuous i.v. endotoxin infusion over 6 h. Dextran and Ringer's acetate were infused continuously to maintain baseline mean left atrial pressure (MLAP) throughout the endotoxin period. Twelve pigs receiving endotoxin + Ringer's acetate displayed a progressive 45% decline in cardiac output (Qt) and a two peaked increase in pulmonary vascular resistance (PVR) with a late increase of 250%. Venous admixture (Qva/Qt) increased progressively more than 6-fold and extravascular lung water (EVLW) increased by 55%. Mean arterial blood pressure (MAP) fell by 25%, oxygen delivery by 40%, base excess (BE) ranged between - 4.5 and - 9 mmol.1(-1) at the end of the endotoxin period and 4 of 12 animals died. Polymorphonuclear cell count (PMNs) fell rapidly by 90% and was severely decreased throughout the endotoxin period. Contrastingly, the 12 pigs that received endotoxin + Dextran maintained Qt near baseline and PVR was significantly lower in this group. Qva/Qt increased progressively more than 4-fold, but was significantly lower than in the Ringer's group as was the increase in EVLW (23%). MAP only decreased by 10%, oxygen delivery only decreased by 20%. BE ranged between - 1.0 and - 3.0 at the end of the endotoxin period and all animals survived. PMNs fell by 90% at 0.5 h but subsequently tended to return towards baseline. PMNs were significantly increased compared with the Ringer's group. The amount of Ringer's acetate necessary to maintain a stable MLAP averaged 4.6 times the Dextran volume. The superiority of Dextran as compared with Ringer's acetate in this endotoxemic shock model seems to be consequent to better rheological effects combined with pharmacological interactions with granulocytes.

Animals↗
PubMed2006

Glibenclamide attenuates the antiarrhythmic effect of endotoxin with a mechanism not involving K(ATP) channels.

The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.

Action Potentials↗
PubMed1999

Treatment with recombinant bactericidal/permeability-increasing protein to prevent endotoxin-induced mortality in bile duct-ligated rats.

BACKGROUND: Operation in patients with obstructive jaundice is associated with substantial morbidity because of increased susceptibility to endotoxin (lipopolysaccharide) and the inflammatory cascade. Different interventions to reduce endotoxemia and cytokine induction, and resulting complications, have been studied. Bactericidal/permeability-increasing protein (BPI) is a naturally occurring endotoxin-binding protein produced in neutrophils. It binds endotoxin, neutralizing the activity and inhibiting cytokine production by mononuclear cells. In experimental endotoxemia in animals and in healthy human volunteers, BPI has shown a protective effect. The aim of this study was to determine whether BPI could protect against increased endotoxin sensitivity in rats with obstructive jaundice and reduce endotoxin-induced mortality. STUDY DESIGN: Male Wistar rats were used. Intraperitoneal Escherichia coli 2mg/kg was given 1 week after sham operation or bile duct ligation (BDL). Three groups were studied: sham, BDL with placebo, and BDL with 5 mg/kg recombinant BPI21. RESULTS: BDL rats were jaundiced (mean bilirubin 186 micromol/L; no difference between BDL rats without or with BPI). Bilirubin remained less than 1 micromol/L in sham-operated rats (p = 0.002). Endotoxin levels were 3.4pg/mL in sham controls and 3.1 pg/mL in BDL rats before administration of lipopolysaccharide (p = NS). Two hours after administration, levels were 615.4ng/mL in placebo BDL rats and 10 times less in BPI-treated BDL rats, at 60.2ng/mL (p=0.03). The same trend was found at 6 hours. At 24 hours, mortality was 1 of 6 in sham-operated rats (15%) versus 8 of 11 in untreated BDL rats (75%). BPI intervention reduced the death rate to 1 of 12 BDL rats (8%) (p = 0.003). CONCLUSIONS: Intraperitoneal recombinant BPI21 in rats having BDL reduced endotoxin-induced mortality from 75% to 8%, a death rate comparable to that in nonjaundiced rats. BPI could be an interesting perioperative treatment in clinical obstructive jaundice.

Animals↗
PubMed2001

Endotoxin increases paracellular permeability of isolated rat hepatocyte couplets.

Hyperbilirubinemia is frequently associated with endotoxemia. Regurgitation of bile constituents including bilirubin into the sinusoidal space is prevented by tight junctions which maintain paracellular permeability between hepatocytes. To investigate the mechanism of endotoxin-associated hyperbilirubinemia, we have studied the changes in paracellular permeability of primary hepatocyte couplets treated with endotoxin. In addition, we examined the effects of ursodeoxycholic acid (UDCA), which has been widely used for various liver diseases, on endotoxin-associated changes in paracellular permeability. The paracellular permeability of hepatocyte couplets was evaluated by paracellular penetration of fluorescein isothiocyanate (FITC)-dextran with molecular weights of 3, 10 and 70K using confocal laser scanning microscopy. Endotoxin increased the paracellular penetration of FITC-dextran 3 and 10K. These changes were prevented by treatment with UDCA. There was little paracellular penetration of FITC-dextran 70K under any conditions. These results suggested that endotoxin increased the paracellular permeability of hepatocyte couplets and these changes were prevented by treatment with UDCA. Furthermore, bile regurgitation through the paracellular route is involved in endotoxin-associated hyperbilirubinemia, and UDCA might be a potential therapeutic agent for endotoxin-associated hyperbilirubinemia.

Journal Article↗
PubMed1999

Impaired glucocorticoid receptor function evolves in aberrant physiological responses to bacterial endotoxin.

The consequences of glucocorticoid receptor (GR) dysfunction for neuroimmunoendocrine responses to an inflammatory challenge were studied in transgenic mice expressing antisense RNA directed against the GR [GR-impaired (GR-i) mice]. Mice were implanted intraperitoneally with a biotelemetry transmitter to monitor body temperature and locomotion. GR-i mice showed decreased locomotion and body temperature during the dark phase of the diurnal cycle. Intraperitoneal administration of saline caused a rapid increase in body temperature in control mice, which was terminated within 90 min. In GR-i mice, however, body temperature remained elevated for about 6 h. Intraperitoneal injection of endotoxin (10 micrograms/mouse) produced a biphasic fever in control mice. However, in endotoxin-injected GR-i mice, body temperature was not significantly different from their saline-injected controls during the first 6 h. Body temperature then increased and remained elevated during the night period. Both strains showed hypolocomotion after endotoxin. In a second experiment, mice were injected intraperitoneally with saline or endotoxin and killed after 1, 3, 6 or 24 h. In GR-i mice, endotoxin caused an augmented rise in plasma ACTH, but not in corticosterone levels. The endotoxin-induced increase in serum levels of interleukin-1 beta and interleukin-6 was not different between the strains. However, whereas in control mice tumour necrosis factor-alpha levels were below detection at the time points studied, substantial levels of this cytokine were found in the serum of GR-i mice 1 h after endotoxin administration. It may be concluded that life-long impairment of GR evolves in aberrant physiological and humoral responses to an acute inflammatory challenge. These findings expand our understanding about the neuroendocrine and physiological disturbances associated with stress-related disorders.

Adrenocorticotropic Hormone↗
PubMed1999

Surface plasmon resonance studies resolve the enigmatic endotoxin neutralizing activity of polymyxin B.

Polymyxin B (PMB), a cyclic cationic peptide antibiotic, despite its severe side effects continues to occupy a premiere position for treating endotoxicosis. Its mode of neutralization of endotoxin has remained elusive for the last three decades. Several synthetic peptide mimics of PMB, capable of binding endotoxin, have been made. However, the binding ability alone appears to be a deceptive indicator of endotoxin neutralizing activity as molecules with similar binding propensities could either sequester or opsonize the toxin. Hence identification of additional physical parameters which describe adequately the outcome of PMB-endotoxin interaction become imperative. Surface plasmon resonance (SPR) studies reported here show that several mimics of PMB despite exhibiting lipopolysaccharide binding affinities comparable with it but, unlike it, do not sequester the endotoxin. These studies thus provide a striking illustration of the difference in the behavior of PMB, vis a vis its mimics toward the endotoxin lamellae, and define further, in chemical terms, mechanism of the action of PMB and allow us to posit that the design of molecules as effective antidotes for sepsis should incorporate the ability to sequester endotoxin specifically.

Amino Acid Sequence↗
PubMed1960

Functional and metabolic properties of polymorphonuclear leucocytes. II. The influence of a lipopolysaccharide endotoxin.

The effects of a purified bacterial lipopolysaccharide endotoxin on homogenous populations of rabbit polymorphonuclear leucocytes have been studied in vitro under defined conditions. Employing a 500-fold range of concentration (0.1 to 50.0 microg./ml.), it was shown that endotoxin enhanced the rate at which staphylococci were killed by leucocytes. The mechanism underlying the increased killing was found to be a direct stimulation of the phagocytic activity of the leucocyte and not mediated by the release of bactericidins or opsonins from the treated cells. In the presence of 10 per cent serum all concentrations of endotoxin enhanced phagocytosis, whereas at lower serum concentrations, the higher doses of lipopolysaccharide inhibited the phagocytic activity of the cells. Similar concentrations of endotoxin were capable of increasing the utilization of glucose and the production of lactic acid. Endotoxin treated leucocytes exhibited no change in oxygen consumption, and only a slight depression in glycogen synthesis. It appeared that endotoxin could interact and alter the functional and metabolic properties of leucocytes in the absence of serum. The demonstration of enhanced phagocytic activity of endotoxin-treated cells was dependent upon the particular opsonic requirements for the organism under study.

Animals↗
PubMed1986

Effect of gamma interferon on cachectin expression by mononuclear phagocytes. Reversal of the lpsd (endotoxin resistance) phenotype.

IFN-gamma permits the endotoxin-induced production of cachectin by C3H/HeJ (endotoxin resistant) macrophages, apparently by facilitating endotoxin-induced cachectin biosynthesis at both transcriptional and posttranscriptional levels. IFN-gamma cannot induce cachectin biosynthesis by itself, nor does it markedly enhance cachectin production by endotoxin-induced peritoneal macrophages obtained from endotoxin-responsive mice. Elucidation of the precise mechanism through which IFN-gamma influences cachectin biosynthesis may permit a better understanding of the molecular events that follow endotoxin-induced activation of macrophages. Moreover, the permissive effect of IFN-gamma on cachectin biosynthesis might elicit enhanced endotoxin sensitivity in vivo.

Animals↗