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PubMed2002

Development of a highly sensitive in vitro assay method for biological activity of endotoxin contamination in biological products.

The pyrogen test in rabbits has been replaced by the bacterial endotoxin test. The endotoxin test, however, showed a considerable discrepancy with pyrogenicity and was, therefore, assumed to have an efficacy limitation in directly predicting harmful biological effects of endotoxin. We developed a sensitive in vitro assay method by making use of tumour necrosis factor alpha (TNF-alpha) induction in RAW264.7 cells, which showed a fine correlation with pyrogenicity in rabbits. RAW264.7 cells maintained by serial subculture under an endotoxin-free condition have gained the similar level of sensitivity as the endotoxin test to allow extensive dilutions of a drug for eliminating adverse effects on the cells. The in vitro TNF-alpha induction assay was shown to be capable to detect quantitatively a synergistic effect of a drug and endotoxin. The synergy is assumed necessary to be taken into consideration to define the limit value for the endotoxin test for guaranteeing the similar level of safety as by the pyrogen test.

Animals↗
PubMed1993

Aged mice are resistant to the hepatotoxic effects of endotoxin and galactosamine.

The ability of concurrent intraperitoneal injections of endotoxin (0.1 micrograms/kg) and galactosamine (700 mg/kg) to produce liver damage was determined in fasted C57Bl/6 mice of different ages: 2 months (young), 6 months (mature), and 24 months (aged). Liver damage was assessed after 6 hr by measurement of plasma alanine aminotransferase activity (ALAT, mumole/liter/min) and by histological examination for mature and aged mice. Control mice, those treated with saline, galactosamine, endotoxin, or hydrazine alone, had ALAT activities which ranged from 13 to 72 (n = 21). Plasma ALAT activities were increased to hepatotoxic values in some, but not all, mice injected with both endotoxin and galactosamine. For young mice, 7/11 had increased plasma ALAT activities; for mature mice, 5/8 had increased plasma ALAT activities and substantial centrilobular necrosis, whereas for aged mice, 0/7 had increased ALAT activities and none had centrilobular necrosis. Basophilic staining of the cytoplasm was increased by administration of endotoxin and/or galactosamine in both mature and aged mice whether or not necrosis was present. A 5-hr pretreatment with hydrazine sulfate (80 mg/kg) substantially decreased the ALAT release caused by endotoxin and galactosamine in mature mice. Hydrazine pretreatment prevented centrilobular necrosis in mature mice and decreased basophilic cytoplasmic staining in aged mice. The results demonstrate that aged mice are resistant to the hepatotoxic effects of endotoxin and galactosamine which were observed in both young mice and mature mice. Also, hydrazine sulfate pretreatment will protect against the hepatotoxic effects as well as the lethal actions of endotoxin and galactosamine.

Aging↗
PubMed1997

Pathogenicity of Serpulina hyodysenteriae: in vivo induction of tumor necrosis factor and interleukin-6 by a serpulinal butanol/water extract (endotoxin).

Lipopolysaccharide (LPS) of Gram-negative bacteria is a classic inducer of inflammatory cytokines. In the present experiments, LPS-like (phenol/water extract) or endotoxin-like (butanol/water extract) preparations from Serpulina hyodysenteriae were examined for their ability to induce serum tumor necrosis factor (TNF) or interleukin (IL)-6 bioactivity in mice and swine. Serpulina hyodysenteriae endotoxin (butanol/water extract) elicited increased serum TNF activity in mice, although serpulinal endotoxin was at least 10 times less potent than the LPS preparations of E. coli or S. typhimurium on a weight basis for induction of TNF bioactivity. S. hyodysenteriae LPS induced lower levels of serum TNF in mice than S. hyodysenteriae endotoxin. In contrast, pigs injected with S. hyodysenteriae endotoxin demonstrated no increase in serum TNF activity. However, an induction of IL-6 bioactivity was observed in serum samples from pigs injected with serpulinal endotoxin. In pigs, the serpulinal preparations were five times less potent (on a weight basis) than E. coli or S. typhimurium LPS for induction of IL-6 bioactivity. These data indicate that serpulinal endotoxin, although less bioactive than E. coli or S. typhimurium LPS, is nonetheless capable of inducing the in vivo production of specific pro-inflammatory cytokines.

Animals↗
PubMed1994

Involvement of neuronal processes and nitric oxide in the inhibition by endotoxin of pentagastrin-stimulated gastric acid secretion.

Administration of E. coli endotoxin (1 mg kg-1, i.v.) abolished the acid response induced by the i.v. infusion of pentagastrin (8 micrograms kg-1 h-1) in the continuously perfused stomach of the anaesthetized rat. Local serosal application of tetrodotoxin (36 ng per rat) completely restored acid responses to pentagastrin in endotoxin-treated rats. However, pretreatment with atropine (0.5 mg kg-1, s.c.), capsaicin (20, 30, and 50 mg kg-1, s.c. 2 weeks before the study) or guanethidine (16 mg kg-1, s.c. 3 and 16h before) did not influence the inhibitory effects of endotoxin. Continuous i.v. infusion with NG-nitro arginine methyl ester (L-NAME, 10 mg kg-1 h-1) restored the secretory responses to pentagastrin in endotoxin treated rats. The effects of L-NAME were reversed by L-arginine (100 mg kg-1 h-1, i.v.), but not by its enantiomer D-arginine (100 mg kg-1 h-1, i.v.). The secretory responses elicited by pentagastrin (10(-10)-10(-6) M) in the isolated lumen perfused stomach of the rat were not influenced by incubation (100 min) with endotoxin (10 micrograms ml-1). These observations with tetrodotoxin indicate that inhibition of acid secretion by endotoxin in vivo involves neuronal activity, while inhibition of NO synthesis had a comparable inhibitory action. Activation of a systemic non-adrenergic non-cholinergic neuronal pathway involving NO could thus mediate the acute acid inhibitory effects of endotoxin.

Animals↗
PubMed1992

Heart sarcolemmal Ca2+ transport in endotoxin shock: I. Impairment of ATP-dependent Ca2+ transport.

Effects of endotoxin administration on the ATP-dependent Ca2+ transport in canine cardiac sarcolemma were investigated. The results show that the sidedness of the sarcolemmal vesicles was not affected but the ATP-dependent Ca2+ transport in cardiac sarcolemma was decreased by 22 to 46% (p less than 0.05) at 4 h following endotoxin administration. The kinetic analysis indicates that the Vmax for ATP and for Ca2+ were decreased by 50% (p less than 0.01) and 32% (p less than 0.01), respectively, while the Km values for ATP and Ca2+ were not significantly affected after endotoxin administration. Magnesium (1-5 mM) stimulated while vanadate (0.25-3.0 microM) inhibited the ATP-dependent Ca2+ transport, but the Mg(2+)-stimulated and the vanadate-inhibitable activities remained significantly lower in the endotoxin-treated animals. These data demonstrate that endotoxin administration impairs the ATP-dependent Ca2+ transport in canine cardiac sarcolemma and that the impairment is associated with a mechanism not affecting the affinity towards ATP and Ca2+. Additional experiments show that the Ca2+ sensitivity of the Ca(2+)-ATPase activity was indifferent between the control and endotoxic groups suggesting that endotoxic injury impairs Ca2+ pumping without affecting Ca(2+)-ATPase activity. Since sarcolemmal ATP-dependent Ca2+ transport plays an important role in the regulation of cytosolic Ca2+ homeostasis, an impairment in the sarcolemmal ATP-dependent Ca2+ transport induced by endotoxin administration may have a pathophysiological significance in contributing to the development of myocardial dysfunction in endotoxin shock.

Adenosine Triphosphate↗
PubMed1993

Changes in the blood endotoxin concentration after digestive surgery.

Blood endotoxin concentrations measured in 57 patients with digestive disorders pre- and postoperatively, were found to peak one day after surgery, then gradually return to the preoperative level. The plasma endotoxin concentration was not significantly different in patients with and without liver cirrhosis before surgery, but was significantly higher in the cirrhosis group one day after surgery. The preoperative endotoxin concentration did not correlate with the white blood count (WBC), platelet count, or routine biochemical liver function tests, however, a significant negative correlation was observed between the plasma endotoxin and fibronectin concentrations. The ability of plasma to inactivate endotoxin was quantified by serial measurements of the endotoxin concentration following the addition of a known quantity to each patient's plasma. The plasma from normal subjects quickly inactivated endotoxin, but inactivation was decreased in the plasma from patients with liver failure.

Digestive System Diseases↗
PubMed1987

The efficacy of dexamethasone and flunixin meglumine in treating endotoxin-induced changes in calves.

Eicosanoids have been implicated in the pathophysiology of endotoxic shock. Drugs which alter eicosanoid production such as corticosteroids and non-steroidal anti-inflammatory drugs (NSAID) are beneficial in treating endotoxic shock. Experiments were conducted to investigate the efficacy of dexamethasone, a corticosteroid, and/or flunixin meglumine, a NSAID, in treating endotoxin-induced changes in calves. Fourteen male calves were assigned to one of four treatment groups: group 1, endotoxin-untreated; group 2, endotoxin-flunixin meglumine treated; group 3, endotoxin-dexamethasone-treated; group 4, endotoxin-flunixin meglumine and dexamethasone-treated. Each calf was given three intravenous and intraperitoneal injections of E. coli endotoxin. Hemodynamic, blood gas, blood chemical and eicosanoid level determinations were obtained. Thirty minutes after endotoxin injection, pulmonary artery pressure (PAP) increased and cardiac output (CO) decreased compared with baseline, corresponding to increased thromboxaneB2 levels in groups 1 and 3. These groups exhibited a decreased mean arterial pressure (MAP) at three and five hours corresponding to increased 6-keto-prostaglandinF1 alpha. The MAP, PAP and CO of group 4 remained near baseline for the entire six hours, except for a late drop in MAP. Lactic acid levels were significantly increased and arterial bicarbonate levels were reduced by six hours in all groups except for group 4. These results indicate that the combination treatment of flunixin meglumine and dexamethasone prevents many of the metabolic derangements observed during endotoxic shock in calves.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Induction of prostaglandin synthesis-dependent suppressor cells with endotoxin: occurrence in patients with thermal injuries.

The induction of lymphocyte suppressor activity with bacterial endotoxin is well documented. While most of the evidence has been obtained using animal models and has required large doses of endotoxin, we have demonstrated that additions of as little as 1.0 ng of chromatographically purified endotoxin [from Escherichia coli 055:B5, E. coli 0111:B4, Pseudomonas aeruginosa (Fisher-Devlin immunotype 1), Serratia marcescens, or Salmonella minnesota] to human mixed lymphocyte or to mitogen-stimulated cultures produced statistically significant suppression. In each case, endotoxin was most suppressive when present in the culture system prior to the introduction of the alloantigen or mitogen. Suppressive effects were dependent upon the participation of peripheral blood monocytes and could be blocked by the addition of the prostaglandin synthetase inhibitor indomethacin or meclofenamate sodium. Prostaglandin production by monocytes appeared to induce a population of "short-lived" suppressor cells, identified by the immediate and delayed addition of lymphocyte cocultures to endotoxin-preincubated cells. The suppressive behavior of endotoxin-primed lymphocytes was identical to the behavior of burn patient serum-primed lymphocytes or to lymphocyte populations derived from a subpopulation of burn patients whose serum was Limulus positive. We, therefore, feel that endotoxin plays a significant immunologic role in these patients.

Adult↗
PubMed1977

Fever produced in the rat by intracerebral E. coli endotoxin.

E. coli endotoxin introduced into the brain ventricles or into various brain areas raises the body temperature of conscious rats. Endotoxin-sensitive sites were found within the anterior hypothalamus and the lower brainstem. The increase in temperature (delta T) after microinjection of endotoxin into the anterior hypothalamic nucleus was dose-dependent. Endotoxin injected into the ventricles produced monophasic hyperthermia, but microinjections into the anterior hypothalamus produced monophasic or biphasic types of hyperthermia. The second and third microinjections of endotoxin into the anterior hypothalamic nucleus subsequently caused higher responses in delta T, but not in the rate of temperature change. The effects of the fourth and furter microinjections were the same as those of the third, and no tolerance developed for 24 days. The observations of behaviour, vegetative reactions, skin temperature, and carbon dioxide production indicated that the rise in the rat body temperature induced by endotoxin represents fever and that the heat is gained, at an ambient temperature of 22 degrees C, mainly through skin vessel vasoconstriction. Aspirin abolished and reversed fever induced by endotoxin, while hydrocortisone was without effect.

Animals↗
PubMed1979

Thromboxane A2 biosynthesis during endotoxin-induced aggregation of platelets from normal and sensitized guinea-pigs.

Endotoxin lipopolysaccharides Escherichia coli O26:B6 and E. coli O127:B8 were weak inducers of aggregation in normal guinea-pig platelet-rich plasma (PRP), even in the presence of Ca2+. Indomethacin hardly inhibited endotoxin-induced aggregation, indicating that biosynthesis of thromboxane A2 (TXA2) was of little importance. In accordance with this conclusion TXA2 was not detectable by means of bioassay during endotoxin-induced aggregation in normal guinea-pig PRP. Pretreatment of the guinea-pigs with endotoxin sensitized their PRP to endotoxin. This was due to a humoral factor with a selectively directed towards the polysaccharide moiety of endotoxin. The combination of this factor with endotoxin indued a marked biosynthesis of TXA2 and concomitant platelet aggregation.

Animals↗
PubMed1983

Molecular mechanisms in endotoxin fever.

Two important concepts are presented in this review. First, endotoxin fever, like all fevers, is mediated by a host product, leukocytic pyrogen (LP). The mechanism by which LP production is initiated by endotoxin is discussed and evidence is provided which clearly distinguishes the biological and physical differences between LP and endotoxins. The second concept is that many of the molecular and neurochemical mechanisms by which LP causes fever by its action on the hypothalamic thermoregulatory center are also observed when endotoxins are introduced into the central nervous system. Thus, there may be experimental and clinical situations in which endotoxins can directly affect the hypothalamus and initiate fever. Although this bi-modal effect of endotoxin on the production of fever can occur, the importance of LP in mediating endotoxin and other fevers cannot be overstated.

Animals↗
PubMed1996

Role of endotoxin-like contaminants in the apparent anti-inflammatory activity of bovine superoxide dismutase.

Bovine CuZn superoxide dismutase (SOD: 1, 3 and 10 mg/kg) dose-dependently reduced carrageenan-induced paw edema in rats when administered intravenously 30 min before irritant injection. However, heat-treated SOD (10 mg/kg) was as effective as native SOD (10 mg/kg) although the enzymic activity was reduced to 9.7%. Examination of the contaminants of the native SOD revealed a fairly large amount of endotoxin-like activity, 47 ng as Escherichia coli endotoxin per mg, and 59.6% of this activity remained after heat treatment. Bovine CuZn SOD (1, 3 and 10 mg/kg), which contained negligible endotoxin-like materials and 1.5 times more enzyme units, had no effect on edema under the same conditions. Furthermore, Escherichia coli endotoxin (10, 100 and 1000 ng/kg) reduced edema dose-dependently. These results suggest that contamination by endotoxin-like materials is responsible for the anti-inflammatory action of the SOD preparation we observed. Hence, the anti-inflammatory action of contaminating endotoxin-like materials may lead to misinterpretation as a protective effect of SOD unless stringent precautions are taken against endotoxin-like contaminants in the SOD under examination.

Animals↗
PubMed1986

Enhanced endotoxin clearance in reversed Eck fistula rats during a tolerant stage.

The effects of tolerance to Escherichia coli endotoxin on the clearance activity of the hepatic reticuloendothelial system was examined using the experimental animal model of the reversed Eck fistula (REF). Compared with clearance rate of 51Cr-labeled endotoxin in the normal REF-rat, in the tolerant reversed Eck fistula animals, there was three fold increase in the clearance of endotoxin in the liver. The enhanced endotoxin uptake of the hepatic reticuloendothelial system was observed when the medium containing serum from tolerant animals was infused into the non-tolerant liver with a Harvard pump before the clearance studies, using 51Cr-labeled endotoxin administered via the femoral vein. Heat treatment of tolerant serum at 56 degrees C for 45 min destroyed the enhancing effect. These results suggest that during endotoxin tolerance, humoral factors, particularly complement, play an important role in the uptake of endotoxin from portal vein blood. A direct stimulation of the hepatic reticuloendothelial system may also occur.

Animals↗
PubMed1994

Removal of endotoxin from antibody preparations for clinical use. Assessment of polymyxin-sepharose CNBr affinity chromatography.

Despite attempts to maintain asepsis, good manufacturing practices, and the use of terminal sterilization by millipore filtration, the nuclear practitioner is always worried about the possibility of endotoxin contamination. Methods, such as ion-exchange chromatography, have been tried for removing endotoxins during the preparation of radiolabeled antibodies, and so on. As suggested by Stevenson (1990), we evaluated the Issekutz technique (1) of endotoxin removal by affinity chromatography using a polymyxin cyanogen bromide (CNBr) Sepharose column. The endotoxin content of millipore filtrates of heat killed/sonicated suspensions of Pseudomonas pyocyaneus, E. coli were measured using a Sigma (St. Louis, MO) Endotoxin Assay Kit before and after filtration through such columns and compared with the results obtained using gel exclusion and ion-exchange columns of the same length and diameter. Reduction of endotoxin content to undetectable levels by the polymyxin column was observed. The use of such columns for terminal endotoxin removal analogous to terminal sterilization is advocated especially when developing a radiopharmaceutical such as radiolabeled antibodies for in house use.

Antibodies, Monoclonal↗
PubMed1997

Effect of endotoxin administration on the severity of acute pancreatitis in two experimental models.

CONCLUSIONS: Endotoxemia can transform acute pancreatitis (AP) into a more severe form of the disease in models of AP provoked by common pancreatico-biliary duct ligation or L-arginine injection. BACKGROUND: It has been shown that systemic endotoxemia is a common feature in severe AP. The effect of endotoxemia on the course of experimental pancreatitis is unknown. METHODS: AP was induced by common pancreatico-biliary duct ligation (experiment 1) and i.p. injection of 250 mg/100 g body wt of L-arginine (experiment 2). Test animals of both experiments received i.p. injections of 0.5 and 1.0 mg/100 g body wt of endotoxin at the induction of AP. Saline-treated and only endotoxin-dosed animals served as controls for both experiments. Mortality rates and pancreatic histology were investigated at 48 h. RESULTS: The mortality rate was significantly elevated (60%, p < 0.05) in experiment 1 when 1.0 mg/100 g of endotoxin was given. In experiment 2, the mortality rate was also increased (30%) at this dose of endotoxin without reaching significance. Histologic changes were more severe in both groups of AP treated by the two doses of endotoxin than without it. Acinar necrosis and hemorrhage were highly elevated (p < 0.01) in both experiments when AP was combined with 1.0 mg/100 g body wt of endotoxin. The animals receiving only endotoxin showed only slight inflammatory and necrotic changes.

Acute Disease↗
PubMedDate not supplied

Evaluation of hepatic dysfunction in endotoxin pretreated rats using tolbutamide as a marker.

The pharmacokinetics of tolbutamide (TB) have been studied in endotoxin pretreated rats with the aim of evaluating TB as a marker for endotoxin effects. Endotoxin dose of 10 mg/kg resulted in a 50% rate of mortality. TB was i.v. administered 24 h. after endotoxin dosing. Clearance (Cl) decreased by approximately 2/3 of its value, area under the curve (AUC) and half-life (t1/2) in the pretreated animals were an average 1.5 times the values for the respective controls. Volume of distribution (Vd) increased by 10% approximately. These findings suggest that endotoxin pretreatment may cause hepatic damage by producing a decrease in Cl and an increase in the t1/2 of TB. But, SGOT levels in pretreated animals were not significantly different. This phenomenon may be explained by the increase in plasma protein binding of TB during endotoxin pretreatment, which decreases the free fraction of the drug in plasma available for metabolism. Endotoxin increased tmax of hydroxy-TB, while no change in Cmax was observed. Since tmax is inversely related to the formation and elimination rates of hydroxy-TB, an increase in tmax may be due to the decrease in both elimination rates. No change in Cmax may be due to the decrease in the rate of formation which is equivalent to the decrease in the rate of elimination of hydroxy-TB.

Animals↗
PubMed1999

Endotoxin impairs the engraftment of rat islets transplanted beneath the kidney capsule of C57BL/6-mice.

The primary objective of this investigation was to determine the effect of endotoxin on islet xenograft survival within the first three days after transplantation. Pancreatic islets from Lewis rats were prepared under endotoxin-free conditions with Liberase (Boehringer) and purified by centrifugation on endotoxin-free Ficoll/Histopaque. After overnight incubation, with or without 10 microg/ml endotoxin, the islets were transplanted beneath the kidney capsule of normoglycemic C57Bl/6-mice. Three days later, kidneys were removed and their insulin content were measured. We could demonstrate significant differences (P<0.01) in insulin recovery between lipopolysaccharide-free and lipopolysaccharide-containing grafts. In case of endotoxin contaminated islets, we found only 13+/-2% (n=9) of the original insulin content, in contrast to 53+/-7% (n=9) when endotoxin-free islets where grafted. In experiments with islets isolated by use of conventional (lipopolysaccharide-containing) collagenase, and then cultured in endotoxin-free medium, insulin recovery three days after transplantation was 36+/-1% (n=13).

Animals↗
PubMed2004

Severe vagal response after endotoxin administration in humans.

OBJECTIVE: Endotoxin administration to humans is a common means to study systemic inflammation. Worldwide, thousands of volunteers have received endotoxin, and adverse events are rarely reported. The aim of this report was to increase awareness of specific risks of the intravenous administration of endotoxin to human volunteers. DESIGN: Report of four cases who developed severe bradycardia or protracted asystole after administration of endotoxin. Interviews with investigators at three large centers that conduct normal volunteer endotoxin studies. SETTING: Clinical research unit. CASES: Four subjects developed severe bradycardia or protracted asystole, approximately 1 h after administration of endotoxin. Further analyses revealed that the subjects had a history of vasovagal syncope or a positive head-tilt test, indicating increased vagal sensitivity. Relative volume depletion associated with fasting overnight may have predisposed these subjects to this condition. CONCLUSIONS: These responses are very rare and are likely due to the cardioinhibitory Bezold-Jarisch reflex. A thorough screening regarding a history of vagal sensitivity and liberal oral or intravenous fluid administration prior to and during the endotoxin challenge may decrease the risk of these events.

Adult↗