Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “ENDOTOXINS”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 883 records · Page 49Linked to original sources
PubMed2002

Role of Zn(2+) in oxidative stress caused by endotoxin challenge.

The role of Zn(2+) in oxidative stress during endotoxemia was investigated. In rats fed a Zn(2+)-deficient diet (Zn(2+) concentration of less than 1.5 mg/kg) for 8 weeks, the Zn(2+) level in the serum was about 62% lower than that in rats fed a Zn(2+)-adequate diet (Zn(2+) concentration, 50 mg/kg). The Zn(2+) level in serum 18 h after administration of endotoxin (6 mg/kg, i.p.) to Zn(2+)-deficient diet rats was markedly lower than that of the endotoxin/Zn(2+)-adequate diet group. Lipid peroxide formation in the liver of Zn(2+)-deficient diet rats was markedly increased 18 h after endotoxin injection compared with that in the endotoxin/Zn(2+)-adequate diet group. Metallothionein in the liver of endotoxin/Zn(2+)-adequate diet rats was increased more than 17-fold by endotoxin administration, while a markedly lower level of metallothionein was observed in the endotoxin/Zn(2+)-deficient diet group. On the other hand, treatment with ZnSO(4) (100 microM) significantly increased endotoxin (1 microg/ml)-induced tumor necrosis factor-alpha (TNF-alpha) production in J774A.1 cells. Our results clearly demonstrated that treatment with ZnSO(4) significantly inhibited the endotoxin-induced increase in intracellular Ca(2+) level in J774A.1 cells. However, a cell membrane-permeable Zn(2+) chelator, N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN, 1 microM), did not affect the endotoxin-induced TNF-alpha production or Ca(2+) level in J774A.1 cells. In addition, we investigated whether Zn(2+) can suppress nitric oxide (NO) generation and cytotoxicity in endotoxin-treated cells. Treatment with ZnSO(4) (50 microM) significantly inhibited endotoxin-induced NO production in J774A.1 cells, but did not affect endotoxin-induced cytotoxicity. These findings suggest that zinc may play an important role, at least in part, in the oxidative stress during endotoxemia.

Animals↗
PubMed2001

Rapid in vivo induction of leukocyte tissue factor mRNA and protein synthesis following low dose endotoxin administration to rabbits.

INTRODUCTION: Disseminated intravascular coagulation in humans is frequently associated with Gram-negative bacterial sepsis. Therefore, to examine the role and time frame of the in vivo induction of tissue factor (TF) by bacterial endotoxin, a reverse transcription polymerase chain reaction and a solid-phase ELISA assay were developed to monitor the in vivo production in rabbits, of TF mRNA and TF antigen by peripheral blood leukocytes (PBL). METHODS: : Healthy rabbits were injected intravenously with either 1, 10 or 50 microg/kg of Salmonella endotoxin. Blood samples were obtained both before endotoxin administration and at various time points thereafter, up to 24 h. Some experiments were also done to determine whether all-trans retinoic acid would ameliorate the signs of the endotoxin-induced disseminated intravascular coagulation. RESULTS: PBL counts dropped significantly within 2 h of rabbits receiving the endotoxin, recovering to baseline levels by 24 h. Platelet counts decreased gradually over this same time frame. Fibrin deposition was noted in renal glomerular capillaries at 24 h. An increase (P<0.001) in PBL-associated TF mRNA levels was observed 2 h post-endotoxin (10 microg/kg, n = 8), followed by a gradual decline over the subsequent 24 h. The average increase in TF mRNA at 2 h was approximately 4.6-fold (P<0.001) over that seen at time 0. The amount of mononuclear cell associated TF antigen demonstrated a peak at 2 h post-endotoxin (10 microg/kg, n = 13), with levels approximately 9.6-fold greater than (P<0.001) baseline. Pre-treatment of rabbits with all-trans retinoic acid significantly (P<0.001) ameliorated the PBL-associated increase in TF mRNA and TF antigen levels. CONCLUSION: These results suggest that low dose endotoxin (10 microg/kg) faithfully reproduces the non-overt activation of coagulation observed in primates and human volunteers, supporting the hypothesis that TF expression is involved in the in vivo initiation and propagation of disseminated intravascular coagulation. Moreover, all-trans retinoic acid may be effective in modulating in vivo the TF transcription induced by endotoxin.

Animals↗
PubMed1996

High affinity endotoxin-binding and neutralizing peptides based on the crystal structure of recombinant Limulus anti-lipopolysaccharide factor.

Lipid A, the conserved portion of endotoxin or lipopolysaccharide, is the major mediator of septic shock, and therefore endotoxin-neutralizing molecules could have important clinical applications. The crystal structure of recombinant Limulus anti-lipopolysaccharide factor (rLALF) (Hoess, A., Watson, S., Siber, G. R., and Liddington, R. (1993) EMBO J. 12, 3351-3356), has been used to design synthetic peptides comprising different parts of the exposed amphipathic loop in the proposed endotoxin-binding domain of rLALF. We investigated the minimal requirements of rLALF for endotoxin and lipid A binding with linear 10-mer peptides. Only one linear peptide, corresponding to amino acids 36-45 of rLALF, was able to bind lipid A and endotoxin above background levels. Cyclic peptides, however, bind lipid A and endotoxin with high affinity, presumably by mimicking the three dimensional characteristics of the exposed hairpin loop. The cyclic peptide including amino acids 36-47, LALF-14, has a lipid A binding activity comparable to the high affinity endotoxin-binding peptide polymyxin B. LALF-14 has an improved serum half-life compared with its linear counterpart, and it is not toxic for cultured human monocytes or red blood cells. In mice, it blocks tumor necrosis factor-alpha induction after endotoxin challenge. The characterization of the minimal endotoxin-binding domain of rLALF and, importantly, its structure provided a basis for designing small molecules that could have prophylactic and/or therapeutic properties in humans for the management of septic shock.

Animals↗
PubMed1984

Distribution of cardiac output, oxygen consumption and lactate production in canine endotoxin shock.

Endotoxin causes shock accompanied by compensatory changes such as redistribution of cardiac output and increased oxygen extraction. We studied these effects in anaesthetised dogs (etomidate: 4 mg X kg-1 X h-1, n = 14) randomly assigned to a control (n = 6) and a shock group (endotoxin 1.5 mg X kg-1; n = 8). We measured left ventricular pressure, LVEDP and LVdP/dt (Millar microtip), mean systemic, central venous and pulmonary artery pressure (Statham P23Db), cardiac output (thermodilution), organ flow (microspheres, 15 micron, 5 labels), bloodgases (PO2, PCO2), pH and lactate. All measurements were performed before and at 60, 90, 120 and 150 min after endotoxin or saline. Sixty minutes after endotoxin mean systemic pressure, LVdP/dt and cardiac output had decreased (by 60, 50 and 35%), while heart rate had increased (by 30%). Arterial PO2 was lower after endotoxin (-29%), haematocrit and mixed venous PCO2 were higher (+16 and +38%) and arterial pH had decreased from 7.34 to 7.14. After endotoxin perfusion of heart and adrenals did not change but muscle perfusion increased (by 33% at t = 90). Endotoxin caused vasoconstriction in spleen and kidneys: the percentage of cardiac output to these organs thus decreased (by 50 and 69%). Sixty minutes after endotoxin we found vasodilatation in the hepatic arterial, pancreatic, and gastrointestinal beds. Later the percentage of cardiac output to these beds decreased. Systemic arterio-venous shunting fell (from 6.5 to 0.7%). Systemic and splanchnic oxygen extraction increased (by 66 and 71% at t = 60): oxygen consumption hardly changed; 60 min after endotoxin it tended to decrease. During shock serum lactate rose (by 167% at t = 60) before oxygen consumption fell. Myocardial oxygen consumption did not alter during shock but the tension time index decreased.

Animals↗
PubMed1988

Effect of insulin on myocardial contractility during canine endotoxin shock.

During endotoxin shock the heart becomes less responsive to the stimulatory effect of insulin on glucose uptake. In the present study we sought to determine if the heart was also less responsive to the positive inotropic effect of insulin during non-cardiogenic endotoxin shock. Responses of the heart to insulin were assessed under conditions of hyperinsulinaemic (4U.min-1), euglycaemic clamp (INS). Adult mongrel dogs, weighing 20-25 kg, were anaesthetised and instrumented to measure differences in substrate concentrations between arterial and coronary sinus blood, circumflex artery blood flow (using electromagnetic flow probe), haemodynamic variables, and left ventricular posterior wall thickness (using sonomicrometry). The first derivative of left ventricular pressure with respect to time was measured and its maximal value (LV dP/dtmax) used as an index of cardiac performance. Myocardial contractility was measured using the end systolic pressure-dimension relationship. Endotoxin shock was induced by Salmonella typhimurium (1 mg.kg-1 intravenously), and resulted in depression of myocardial performance but increased contractility. INS caused a twofold elevation in myocardial glucose uptake in control animals while in endotoxin shocked dogs it was unable to elevate glucose uptake above the pre-endotoxin level. In control animals INS caused both increased cardiac contractility and performance. In the endotoxin shock group INS was unable to increase LVdP/dtmax above the basal, pre-endotoxin level and did not cause any significant change in myocardial contractility. We suggest that the heart becomes less responsive to the positive inotropic as well as metabolic effects of insulin during endotoxin shock. Changes in LV dP/dtmax can be attributed to the changing loading conditions that occur during endotoxin shock.

Animals↗
PubMed2001

Endotoxin enhancement of ozone-induced mucous cell metaplasia is neutrophil-dependent in rat nasal epithelium.

Ozone, the primary oxidant gas in photochemical smog, causes neutrophilic inflammation and mucous cell metaplasia (MCM) in the nasal transitional epithelium (NTE) of rats and monkeys. Bacterial endotoxin is another common airborne agent that induces acute neutrophilic inflammation, but not MCM, in NTE. It does, however, enhance ozone-induced MCM in rat nasal airways (Fanucchi et al., 1998, Toxicol. Appl. Pharmacol. 152, 1-9). In the present study, F344 rats exposed to filtered air or 0.5 ppm ozone (8 h/day for 3 days) were intranasally instilled with sterile saline or 100 microg endotoxin 24 h and 48 h after the third ozone exposure. To determine the role of neutrophilic inflammation in endotoxin-induced potentiation of the MCM caused by ozone, half of the rats were depleted of circulating neutrophils prior to saline or endotoxin instillations. Rats were killed 6 h or 3 days after the last intranasal instillation, and nasal tissues were processed for (1) light microscopy and morphometric analysis to determine the number of infiltrating neutrophils and the volume amount (density) of stored mucosubstances in the NTE, and (2) quantitative RT-PCR analysis of steady-state mucin gene (rMuc-5AC) mRNA levels in the NTE. Endotoxin induced a transient influx of neutrophils in both air- and ozone-exposed rats that was completely blocked by neutrophil depletion. Endotoxin increased rMuc-5AC mRNA levels in the NTE of ozone-exposed rats. Neutrophil depletion, however, had no effect on endotoxin-induced upregulation of mucin gene mRNA levels. Endotoxin enhanced the ozone-induced increase in stored mucosubstances (4-fold increase), but only in neutrophil-sufficient rats. These data indicate that endotoxin enhancement of ozone-induced upregulation of rMuc-5AC mRNA levels is neutrophil-independent, while its effects on intraepithelial production and storage of mucus glycoproteins is dependent on the presence of neutrophils.

Air Pollutants↗
PubMed2002

Role of endotoxin in NF-kappaB activation by ethanol in rat hepatocytes.

BACKGROUND: Endotoxin plays an important role in the progression of alcoholic liver injury. However, the role of endotoxin in acute activation of NF-kappaB by ethanol remains unclear. METHODS: In primary rat hepatocyte cultures treated with ethanol and/or endotoxin, the DNA-binding activity of NF-kappaB in the nuclear extract was estimated by electrophoretic mobility shift assay. After pretreatment of a CYP2E1 inhibitor, 4-methyl pyrazole or diallyl sulfide, NF-kappaB activity was also measured in the same manner. RESULTS: Ethanol or endotoxin caused activation of NF-kappaB in primary rat hepatocytes. Taking 50 mM of ethanol and endotoxin together raised the rapid increase in NF-kappaB activation, but both 100 mM of ethanol and endotoxin treatment reduced the increase. Addition of diallyl sulfide decreased the activity at rapid phase but increased it after 60 min, whereas addition of 4-methyl pyrazole caused no change of the activity at rapid phase but raised it after 60 min. Pretreatment with both endotoxin and a CYP2E1 inhibitor raised the activation of NF-kappaB constantly after ethanol addition. These findings suggest that endotoxin plays a critical role in the metabolism-independent activation of NF-kappaB by ethanol. CONCLUSIONS: Endotoxin raised metabolism-independent activation of NF-kappaB by high ethanol in rat hepatocytes.

Animals↗
PubMed2006

Effects of extracorporeal treatment with Lixelle on the mortality and inflammatory responses to endotoxin-induced shock in rats.

Endotoxemia and endotoxic shock are common problems in intensive care units and are associated with a very high mortality. Several previous studies have shown that Lixelle, which absorbs beta2-microglobulin for the treatment of dialysis-related amyloidosis, is also useful for the adsorption of inflammatory cytokines and endotoxins. The current study examined the use of Lixelle and its effects on the mortality and inflammatory responses to endotoxin-induced shock in rats. Male Sprague-Dawley rats were anesthetized and assigned to one of four groups (N = 13 per group): Escherichia coli endotoxin (15 mg/kg, i.v.) alone (endotoxemic); direct hemoperfusion apheresis without Lixelle for 120 min (direct hemoperfusion (DHP) alone); Lixelle treatment with Lixelle for 120 min immediately after endotoxin injection (Lixelle treatment); or Lixelle treatment with Lixelle for 120 min 2 h after endotoxin injection (Lixelle post-treatment). Hemodynamics and plasma lactate and cytokine concentrations were measured during observation. Mortality was assessed up to 8 h after the endotoxin injection. The mortality rates at 8 h after endotoxin injection were 92%, 85%, 23% and 46% for the endotoxemic, DHP-alone, Lixelle treatment, and Lixelle post-treatment groups, respectively. Elevated plasma cytokine concentrations were less conspicuous in the Lixelle treatment group than in the other three groups. Thus, Lixelle treatment drastically reduced the high mortality and the inflammatory responses in endotoxin-exposed rats. Moreover, Lixelle post-treatment also suppressed hypotension and a high mortality, although the inflammatory responses were the same as for endotoxin alone. These findings indicate that Lixelle treatment might be an effective therapy for endotoxemia and endotoxic shock.

Adsorption↗
PubMed1995

Effect of hypertriglyceridemia on endotoxin responsiveness in humans.

Triglyceride-rich lipoproteins can inhibit endotoxin activity in vitro and in rodents. We sought to determine whether Intralipid, a triglyceride-rich fat emulsion which in contact with plasma functions similarly to endogenous lipoproteins, can alter the human response to endotoxin. Intralipid inhibited endotoxin-induced cytokine production in human whole blood in vitro in a dose-dependent manner, with maximal inhibition (up to 70%) being achieved at a concentration of 10 g/liter. In healthy men, a bolus intravenous injection of endotoxin (lot EC-5; 20 U/kg of body weight) was given midway through a 4-h infusion (125 ml/h) of either 5% glucose (n = 5) or 20% Intralipid (n = 5). The infusion of Intralipid led to an increase in triglyceride levels in serum from 95 +/- 16 to 818 +/- 135 mg/dl prior to endotoxin administration, i.e., levels that importantly reduced cytokine production in endotoxin-stimulated whole blood. However, in vivo hypertriglyceridemia did not influence inflammatory responses to endotoxin (fever, release of tumor necrosis factor and soluble tumor necrosis factor receptors, and leukocytosis) or even potentiated endotoxin responses (release of interleukins 6 and 8 and neutrophil degranulation). Hypertriglyceridemia does not inhibit the in vivo responses to endotoxin in humans.

Adult↗
PubMed1998

Pasteurella haemolytica A1-derived leukotoxin and endotoxin induce intracellular calcium elevation in bovine alveolar macrophages by different signaling pathways.

Leukotoxin and endotoxin derived from Pasteurella haemolytica serotype 1 are the primary virulence factors contributing to the pathogenesis of lung injury in bovine pneumonic pasteurellosis. Activation of bovine alveolar macrophages with endotoxin or leukotoxin results in the induction of cytokine gene expression, with different kinetics (H. S. Yoo, S. K. Maheswaran, G. Lin, E. L. Townsend, and T. R. Ames, Infect. Immun. 63:381-388, 1995; H. S. Yoo, B. S. Rajagopal, S. K. Maheswaran, and T. R. Ames, Microb. Pathog. 18:237-252, 1995). Furthermore, extracellular Ca2+ is required for leukotoxin-induced cytokine gene expression. However, the involvement of Ca2+ in endotoxin effects and the precise signaling mechanisms in the regulation of intracellular Ca2+ by leukotoxin and endotoxin are not known. In fura-2-acetoxymethyl ester-loaded alveolar macrophages, intracellular Ca2+ regulation by leukotoxin and endotoxin was studied by video fluorescence microscopy. Leukotoxin induced a sustained elevation of intracellular Ca2+ in a concentration-dependent fashion by influx of extracellular Ca2+ through voltage-gated channels. In the presence of fetal bovine serum, endotoxin elevated intracellular Ca2+ even in the absence of extracellular Ca2+. Leukotoxin-induced intracellular Ca2+ elevation was inhibited by pertussis toxin, inhibitors of phospholipases A2 and C, and the arachidonic acid analog 5,8,11,14-eicosatetraynoic acid. Intracellular Ca2+ elevation by endotoxin was inhibited by inhibitors of phospholipase C and protein tyrosine kinase, but not by pertussis toxin, or the arachidonic acid analog. To the best of our knowledge, this is the first report of Ca2+ signaling by leukotoxin through a G-protein-coupled mechanism involving activation of phospholipases A2 and C and release of arachidonic acid in bovine alveolar macrophages. Ca2+ signaling by endotoxin, on the other hand, involves activation of phospholipase C and requires tyrosine phosphorylation. The differences in the Ca2+ signaling mechanisms may underlie the reported temporal differences in gene expression during leukotoxin and endotoxin activation.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1977

Glucose utilization and role of blood in endotoxin shock.

The present study was conducted to explore influences modifying glucose uptake in canine blood administered LD100 E. coli endotoxin. Particular emphasis was given to assay the role of the white blood cell (WBC) in glucose utilization. Significant increases in glucose uptake and lactic acid production, attributed to increased activity of the WBC, were observed 1-3 h after endotoxin was added to blood in vitro. Although a net increase in glucose utilization was noted, endotoxin simultaneously exerted adverse effects by depressing glucose uptake below predicted values (Q10 = 2.12 with LD100 endotoxin vs. 2.78 in saline controls) and increasing WBC mortality rate. Blood from dogs pretreated with sublethal doses of endotoxin in vivo utilized glucose at an accelerated rate when subjected to endotoxin in vitro. Excess glucose was consumed because of elevated numbers of white blood cells although additional glucose requirements after endotoxin were independent of temperature between the ranges of 34-41 degrees C. All animals pretreated with daily sublethal injections of endotoxin for 3 days survived superlethal doses of endotoxin.

Animals↗
PubMed2002

Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue.

E5564, a synthetic lipid A analogue, is a selective, highly active antagonist of endotoxin-mediated activation of immune cells. Preclinical research has indicated that E5564 can block endotoxin-mediated induction of cytokines and endotoxin or Gram-negative bacterial-induced death in animal models. Recent phase I clinical trials have focused on the ability of E5564 to block responsiveness to endotoxin. This was done in two ways: in vivo challenge of human volunteers with 4 ng/kg endotoxin, and by use of an ex vivo assay which utilizes blood drawn from volunteers administered E5564 and challenged with endotoxin at concentrations that ranged from 50 pg/ml to 10 ng/ml. In vivo, > or = 100 microg of E5564 completely blocked signs, symptoms and cytokines induced by concomitantly-administered endotoxin. In contrast, subjects receiving a 50 microg dose of E5564 demonstrated a graded response; cytokines were inhibited > or = 95%, but many signs and symptoms of endotoxemia were still evident. E5564 demonstrated a long pharmacokinetic half-life (> 30 h); however, ex vivo analysis indicated that while single doses of 350 microg induced a nearly complete block of the effects of 1 ng/ml endotoxin immediately upon E5564 administration, antagonistic activity declined rapidly (t(1/2) < 1 h). Similar results were obtained in vivo using a delayed endotoxin challenge. These results have driven us to examine antagonistic activity of E5564 in vivo and ex vivo after administration by continuous infusion or twice-daily dosing. Results from these multiple-dose studies indicate that under these conditions of administration, plasma levels of E5564 can be predictive of long-term pharmacodynamic activity.

Animals↗
PubMed2003

Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis.

Endotoxin is considered to be a systemic (immunological) stressor eliciting a prolonged activation of the hypothalamo-pituitary-adrenal (HPA) axis. The HPA-axis response after an endotoxin challenge is mainly due to released cytokines (IL-1, IL-6 and TNF-alpha) from stimulated peripheral immune cells, which in turn stimulate different levels of the HPA axis. Controversy exists regarding the main locus of action of endotoxin on glucocorticoid secretion, since the effect of endotoxin on this neuro-endocrine axis has been observed in intact animals and after ablation of the hypothalamus; however, a lack of LPS effect has been described at both pituitary and adrenocortical levels. The resulting increase in adrenal glucocorticoids has well-documented inhibitory effects on the inflammatory process and on inflammatory cytokine release. Therefore, immune activation of the adrenal gland by endotoxin is thought to occur by cytokine stimulation of corticosteroid-releasing hormone (CRH) production in the median eminence of the hypothalamus, which, in turn stimulates the secretion of ACTH from the pituitary. Acute administration of endotoxin stimulates ACTH and cortisol secretion and the release of CRH and vasopressin (AVP) in the hypophysial portal blood. During repeated endotoxemia, tolerance of both immune and HPA function develops, with a crucial role for glucocorticoids in the modulation of the HPA axis. A single exposure to a high dose of LPS can induce a long-lasting state of tolerance to a second exposure of LPS, affecting the response of plasma TNF-alpha and HPA hormones. Although there are gender differences in the HPA response to endotoxin and IL-1, these responses are enhanced by castration and attenuated by androgen and estrogen replacement. Estrogens attenuate the endotoxin-induced stimulation of IL-6, TNF-alpha and IL-1ra release and subsequent activation in postmenopausal women. There appears to be a temporal and functional relation between the HPA-axis response to endotoxin and nitric oxide formation in the neuro-endocrine hypothalamus, suggesting a stimulatory role for nitric oxide in modulating the HPA response to immune challenges.

Adrenocorticotropic Hormone↗
PubMed2003

Endotoxin tolerance: is there a clinical relevance?

Beeson (1946) first defined endotoxin tolerance as a reduced endotoxin-induced fever following repeated injections of typhoid vaccine. Freudenberg and Galanos (1988) demonstrated that endotoxin tolerance that can protect against a lethal challenge of lipopolysaccharide (LPS) involves the participation of macrophages. Evans and Zuckerman (1991) reported a role for glucocorticoids in endotoxin tolerance. Prostaglandins, interleukin-(IL-)10, and transforming growth factor-beta are other players of in vivo endotoxin tolerance. Dramatic reduction of plasma tumor necrosis factor (TNF) (Mathison et al. 1990) and other cytokines in response to LPS parallels endotoxin tolerance. The reduced capacity to produce TNF and other cytokines can be mimicked in vitro by pretreatment of monocytes or macrophages with LPS. It is not a specific phenomenon and can be induced by other agents or events. Cross-tolerance between LPS, TLR2 specific ligands, IL-1 and TNF has been regularly reported. A similar loss of LPS-reactivity has been repeatedly reported in leukocytes of septic patients and in patients with non-infectious systemic inflammation response syndrome (SIRS; e.g. surgery, trauma, cardiac arrest and resuscitation, etc.). Studies on cellular signaling within leukocytes from septic and SIRS patients reveal numerous alterations of the activation pathways reminiscent of those observed in endotoxin-tolerant cells. While endotoxin tolerance prevents severity of infections and ischemia-reperfusion damage, it has been suggested that the immune dysregulation observed in SIRS patients was associated with an enhanced sensitivity to nosocomial infections. In conclusion, in vitro and in vivo endotoxin tolerance, either experimental or due to clinical status, are similar but not identical.

Animals↗
PubMed2003

The dose-related effects of ketamine on mortality and cytokine responses to endotoxin-induced shock in rats.

In our previous study, ketamine administration was found to inhibit hypotension, metabolic acidosis, and cytokine responses in endotoxemia. However, only a few studies have indicated whether ketamine has the dose-related beneficial effects after endotoxin injection. Our objective was to clarify the dose-related effects of ketamine on mortality and cytokine responses to endotoxemia in rats. Sixty-five rats were divided at random among five equal groups: Group C was given saline alone. Group E was given endotoxin alone (Escherichia coli endotoxin; 10 mg/kg, IV). Group L received a a low dose of ketamine (5 mg.kg(-1).h(-1), IV), Group M a medium dose of ketamine (10 mg.kg(-1).h(-1), IV), and Group H a high dose of ketamine (20 mg.kg(-1).h(-1), IV), all exposure to endotoxin. After endotoxin injection, hemodynamics, acid-base status, mortality rate, and plasma concentrations of tumor necrosis factor alpha and interleukin 6 were assessed for each of the five groups. Endotoxin injection produced progressive hypotension, metabolic acidosis, and a large increase in plasma cytokine concentrations. Mortality rates 8 h after endotoxin injection were 0% for group C, 92% for group E, 48% for group L, 0% for group M, and 32% for group H. Ketamine administration thus clearly had a beneficial effect on mortality rates, with that for group M lower than for groups L and H (P < 0.05). The cytokine responses to endotoxin were somewhat suppressed in group M but not in group L. Ketamine administration dose-independently inhibited hypotension, metabolic acidosis, and cytokine responses in rats injected with endotoxin.

Animals↗
PubMed1996

Grain dust and endotoxin inhalation challenges produce similar inflammatory responses in normal subjects.

STUDY OBJECTIVE: To compare the physiologic and inflammatory response following inhalation of corn dust extract (CDE) and lipopolysaccharide (LPS) solutions in normal subjects. DESIGN: Randomized, double-blind crossover design. PARTICIPANTS: Fourteen healthy, nonatopic, nonasthmatic, never-smoking volunteers. INTERVENTIONS: On separate visits, subjects underwent a series of four inhalation challenges to LPS or CDE, each containing either a high (6 micrograms/mL) or low (0.9 microgram/mL) endotoxin concentration, and administered at equal Xolumes. RESULTS: Chest tightness, cough, dyspnea, and sputum production were experienced following both LPS and CDE exposures and with similar frequency at both high and low endotoxin concentrations. LPS and CDE inhalations caused acute declines in FEV1, and the changes in FEV1 from baseline following exposure to both inhalants were not significantly different at both high and low endotoxin concentrations. Following exposure to the high-endotoxin LPS and CDE, no consistent differences in total cell and cytokine (tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta [IL-1 beta], IL-6, IL-8) concentrations were seen between exposures, although the neutrophil concentration was greater following the LPS exposure (p = 0.01). BAL cellularity and cytokine concentrations following the low-endotoxin LPS and CDE exposure revealed no differences, except for IL-1 beta, which was greater following LPS exposure (p = 0.05). The high-endotoxin LPS and CDE exposures resulted in greater increases in BAL neutrophils and cytokines in comparison to its respective low-endotoxin exposure. CONCLUSIONS: At exposure levels of endotoxin, LPS and CDE result in similar symptoms, changes in airflow, and increases in BAL inflammatory cells and mediators. Moreover, the physiologic and inflammatory response to LPS and CDE appears to be related to the exposure level of endotoxin.

Adult↗
PubMed1995

Endotoxin Detection in Pharmaceuticals and Medical Devices with Kinetic-QCL, a Kinetic-Quantitative Chromogenic Limulus Amebocyte Lysate Assay.

The observation that endotoxin caused gelation in extracts of Limulus amebocytes has been expanded to the development of an in vitro kinetic, quantitative chromogenic LAL assay (Kinetic-QCL) for the detection of endotoxin in aqueous fluids. Within the last 15 years, the use of Limulus amebocyte lysate to detect and control the presence of pyrogenic substances in pharmaceuticals and medical devices has gained wide international acceptance. Both the United States and European Pharmacopoeias contain descriptions of and requirements for the LAL Bacterial Endotoxin Test. Both pharmacopoeias have begun to remove the rabbit pyrogen test requirement in a majority of drug monographs and have substituted endotoxin limits to be determined by LAL. The use of LAL has proved invaluable in controlling the level of endotoxin in finished product. The endotoxin contribution of raw materials and packaging material can be monitored as well. In-process testing at critical production steps can identify additional sources of endotoxin contamination, and depyrogenation processes can be validated by quantitating the degradation of endotoxin challenges. The speed, reproducibility, sensitivity, and economics of the Kinetic-QCL assay, in conjunction with the ppropriate equipment and software, over both the in vivo rabbit pyrogen test and the more traditional LAL gel-clot assay allow a more in-depth approach to the control of endotoxin in pharmaceuticals and medical devices.

Journal Article↗
PubMed1987

Cardiorespiratory alterations produced by centrally administered thyrotropin-releasing hormone during canine endotoxin shock.

Endogenous opiates have been implicated in the pathophysiology of endotoxin, hemorrhagic, and spinal shock. Blockade of these compounds with peripherally or centrally administered naloxone has been shown to produce beneficial effects. More recently, it has been suggested that thyrotropin-releasing hormone (TRH) may be able to block the detrimental effects of endogenous opiate compounds without removing their analgesic effects. Improved cardiovascular function during endotoxin shock has been demonstrated in rat and primate models; however, this drug has not been tested in the canine endotoxin shock model. The present study was designed to determine if TRH administered through ventriculocisternal (VC) perfusion could significantly improve cardiorespiratory function during canine endotoxin shock. Cardiac output, arterial pressure, end-tidal CO2, heart rate, respiratory rate, pulse pressure, and total peripheral resistance were determined for three separate groups of animals. One group of animals received TRH only and served as a drug control. One of the remaining groups received endotoxin only, while the other group received endotoxin plus TRH. The results of the study suggest that TRH administered centrally is capable of improving cardiac output during endotoxin shock. No significant difference was found in any of the other parameters measured. Based on these findings, it can be concluded that TRH has a minimal effect during canine endotoxin shock. The discrepancy between these results and those from other endotoxin shock models may result from species variation, TRH metabolism and sensitivity, and/or anesthetic effect.

Animals↗