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 649 records · Page 36Linked to original sources
PubMed1992

Complications in obstructive jaundice: role of endotoxins.

Surgical treatment of patients with obstructive jaundice is associated with a high postoperative morbidity and mortality. A correlation was suggested between endotoxins and the observed complications. The mechanism by which endotoxins affect the negative outcome in operated jaundiced patients was, however, not clear, nor was the mechanism of clinically used preventive treatments. Several experiments were therefore performed in rats with biliary obstruction, to investigate whether and how endotoxins are active. The role of endotoxins was studied in a model in which endotoxins were absent. In germfree rats (free of bacteria and thus of endotoxin) the effect of biliary obstruction was studied and compared with biliary obstruction in conventional rats. To substantiate further the role of endotoxin, anti-endotoxin treatments (oral lactulose or internal drainage) were tested in rats with obstructive jaundice undergoing a severe surgical trauma. It is shown that endotoxins are responsible for complications (suppression of cellular immunity, kidney function, mortality) and that these complications can be prevented with an anti-endotoxin treatment. These results may have implications for preoperative treatment of jaundiced patients.

Animals↗
PubMed1982

Effects of endotoxin upon rat hepatic microsomal drug metabolism in vivo and in vitro.

1. Bacterial endotoxin, a soluble lipopolysaccharide, has been studied to ascertain its effects in vivo and in vitro on the hepatic drug-metabolizing enzymes of adult male and female rats. 2. 24 h after a single 1 X 0 or 2 X 0 mg/kg i.p. dose of endotoxin, hexobarbital sleeping time was significantly increased in adult male rats. Significant inhibition of liver microsomal cytochrome P-450 occurred after 6 h and continued only until 24 h after endotoxin administration, while injection of inactivated endotoxin did not result in any significant decrease of hepatic mixed-function oxidase enzymes or cytochrome P-450. In contrast, rho-nitrophenol-UDP-glucuronyltransferase enzyme activity was unaffected by these levels of endotoxin. 3. Electron-microscopic examination of rat liver hepatocytes did not reveal any significant change in ultrastructure 24 h after a single i.p. dose of endotoxin. 4. Endotoxin failed to depress the phenobarbitone- or 3-methylcholanthrene-induced forms of cytochrome P-450 and the dependent mono-oxygenase enzymes. Simultaneous administration of phenobarbital and endotoxin resulted in 100% mortality of rats. Combination of 3-methylcholanthrene and endotoxin did not block the induction of cytochrome P-448 or dependent benzo[a]pyrene hydroxylase activity. 5. Addition of endotoxin in vitro resulted in significant inhibition of hepatic microsomal cytochrome P-450 and aminopyrine N-demethylase activity only on preincubation with an NADPH-generating system supplemented with EDTA.

Animals↗
PubMedDate not supplied

Neutrophils pretreated with granulocyte colony-stimulating factor (G-CSF) are not related to the severity of endotoxin-induced lung injury.

Neutrophils play an important role in mediating acute lung injury that is characteristic of adult respiratory distress syndrome. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase neutrophil counts and to enhance their biological functions. This study investigated the effects of neutrophils pretreated with G-CSF on endotoxin-induced lung injury in conscious sheep. Nineteen sheep were chronically instrumented with a lung lymph fistula and vascular catheters for monitoring. Sheep were randomly allocated into three groups: group 1-sheep were infused only with endotoxin; group 2-G-CSF (250 micrograms/day) was administered intravenously for 5 days prior to endotoxin; and group 3-G-CSF (125 micrograms) was administered just before endotoxin. In each group, sheep received E. coli endotoxin (1 microgram/kg) for 30 min and observations were made for 5 h after endotoxin administration. Circulating leukocyte counts before endotoxin markedly increased in group 2 and significantly decreased in group 3, when compared with the level in group 1 (9700 +/- 900 (SEM) in group 1, 49,900 +/- 10,000 in group 2, and 3600 +/- 600/microL in group 3). In each group, circulating leukocyte counts significantly decreased 1 h after endotoxin administration and then returned to baseline values. However, there were no significant differences in either pulmonary hemodynamic or lung lymph responses to endotoxin among the groups. The results indicate that G-CSF does not adversely affect physiologic responses of the lung to endotoxin in sheep.

Animals↗
PubMed1995

A comparative study of the accurate measurement of endotoxin in liposome-encapsulated hemoglobin.

We have examined three different methods of endotoxin determination utilizing the Limulus Amebocyte Lysate (LAL) assay to accurately determine endotoxin levels in Liposome Encapsulated Hemoglobin (LEH), 1) the gel-clot method, 2) chromogenic spectroscopic-based LAL, and 3) the turbidimetric method which determines endotoxin levels in solutions based on the time needed to reach a specific degree of turbidity. Both the chromogenic and turbidimetric methods require significant dilution of the LEH preparation before accurate measurement can be made. We have tested the levels of endotoxin in LEH solutions using these methods and measured LEH, liposome, and hemoglobin samples spiked with known amounts of endotoxin. A comparison of the three methods shows that the absolute value of endotoxin measured in LEH by the three methods can vary significantly. However, within any one assay the spiked amount of endotoxin in the sample can be accurately measured. The accuracy of these methods may also be complicated by the binding of endotoxin to LEH. This was evident by mixing free endotoxin with LEH followed by centrifugation to separate the LEH. Biological activity of endotoxin bound to LEH was measured by exposure to RAW264.7 followed by the expression of tumor necrosis factor.

Chromogenic Compounds↗
PubMed2000

Role of nitric oxide in endotoxin-induced hepatic microvascular dysfunction in rats chronically fed ethanol.

BACKGROUND: Nitric oxide (NO) appears to be involved in the pathogenesis of endotoxin-induced liver injury. However, little is known about how NO acts on the hepatic microcirculation, especially in alcohol-fed animals. We examined the roles of NO in endotoxin-induced hepatic microvascular dysfunction in control and ethanol-fed rats. METHODS: One lobe of the liver was observed with an intravital microscope. Flow velocity of fluorescein isothiocyanate-labeled erythrocytes in sinusoids was measured with an off-line velocimeter. Portal pressure and mean arterial pressure also were measured. RESULTS: After administration of endotoxin to control, the flow velocity decreased after 30 min. Portal pressure increased after 45 min. However, in ethanol-fed rats, both the flow velocity and portal pressure temporarily increased in the early phase. Thereafter, the flow velocity decreased and portal pressure increased. At 30 min after administration of the endotoxin, pretreatment with 10 mg/kg of an NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA), enhanced the endotoxin-induced decrease in the velocity of erythrocytes in the midzonal region of both control and ethanol-fed rats. Although 0.5 mg/kg of L-NMMA enhanced the endotoxin-induced reduction of erythrocyte velocity in the midzonal region of ethanol-fed rats, L-NMMA enhanced the endotoxin-induced reduction of erythrocyte velocity in the pericentral region of control rats. At 60 min after the endotoxin administration, L-NMMA did not affect the endotoxin-induced decrease of erythrocyte velocity in either control or ethanol-fed rats. Although 10 mg/kg of L-NMMA increased mean arterial pressure both in control and ethanol-fed rats, 0.5 mg/kg of L-NMMA did not change mean arterial pressure in either control or ethanol-fed rats. CONCLUSIONS: These results suggest that NO is involved in endotoxin-induced hepatic microvascular dysfunction, which may contribute to the sequential liver injury, especially in alcohol-fed animals.

Animals↗
PubMed2001

Evaluation of exposure to airborne bacterial endotoxins and peptidoglycans in selected work environments.

The aim of this study was to assess workers' exposure to endotoxins and peptidoglycans, as well as associations between workers' reported symptoms and the detected bacterial exposures. From the filter samples, biologically-active endotoxins were analysed with the Limulus amebocyte lysate (LAL) assay. The total amount of endotoxins was analysed as 3-hydroxy (OH) fatty acids with a gas chromatography-mass spectrometry (GC-MS) assay, which was also used to assess peptidoglycans as muramic acid. Biologically-active endotoxins related better to the self-reported symptoms than total endotoxins. Specific 3-OH-14:0 fatty acid in the total endotoxin samples associated better with the symptoms than other 3-OH fatty acids. Half of the surveyed 77 workers reported respiratory symptoms, 27% eye symptoms, and 10% fever or shivering. The proportion of workers with respiratory symptoms was greater when the concentration of endotoxins was over 25 ng/m3. These endotoxin levels were occasionally found in the air of most studied occupational environments. The muramic acid concentrations of peptidoglycans were highest (medians over 100 ng/m3) in the garbage-handling plant and in the grain/vegetable storage houses. The LAL assay for endotoxins, as well as the GC-MS assay analysing muramic acid for peptidoglycans or specific 3-OH fatty acids for endotoxins, seem to be suitable methods for evaluating workers' exposure to airborne bacteria.

Adolescent↗
PubMed1992

In vivo effects of endotoxin on intraepithelial mucosubstances in rat pulmonary airways. Quantitative histochemistry.

Bacteria-induced bronchopneumonias are often characterized by an influx of neutrophils and excess mucus in pulmonary airways. This study determined how endotoxin, a component of gram-negative bacteria and a potent inflammatory agent, affects the ultrastructure of the mucociliary apparatus and the amount of stored intraepithelial mucosubstances in the main axial airways within the lung. Rats were intranasally instilled, once a day for 3 days, with endotoxin or saline (controls). Animals were sacrificed 1, 2, or 7 days after the last instillation. Microdissected intrapulmonary axial airways (generations 8-11) from the right caudal lobes of infusion-fixed lungs were processed for light and electron microscopy. Morphometric techniques were used to determine the volume densities (Vs) of histochemically stained intraepithelial mucosubstances and numerical densities of airway epithelial cells. There were marked increases, compared with controls, in the amount of intraepithelial mucosubstances in the intrapulmonary axial airways at generations 8 and 11 in the right caudal lobes from endotoxin-instilled rats sacrificed 1, 2, and 7 days after the last instillation. There were significantly greater numbers of surface epithelial cells per length of basal lamina (i.e., hyperplasia) in endotoxin-exposed airways compared with airways from controls. This endotoxin-induced hyperplasia was due primarily to an increase in the number of mucus-secretory cells, which in endotoxin-exposed epithelium were columnar and contained numerous, large confluent, electronlucent, secretory granules composed of acidic and neutral glycoproteins. In contrast, secretory cells in airway epithelium from controls were cuboidal and contained small discrete, electron-dense, granules composed of only neutral glycoproteins. The numbers of ciliated cells and basal cells were similar in both control and endotoxin-exposed epithelium. Only endotoxin-exposed epithelium, however, contained atypical epithelial cells with numerous basal bodies, few cilia, and few apical secretory granules. These results indicate that repeated airway instillations of endotoxin induce an increase in the amount of intraepithelial mucosubstances, secretory cell hyperplasia, and excess luminal mucus in pulmonary airways. Therefore, endotoxin released from gram-negative bacteria may be partially responsible for the structural alterations, in the airway surface epithelium, which result in the excess luminal mucus observed in bacteria-induced bronchopneumonias.

Animals↗
PubMed1990

Effects of canine endotoxin shock on lymphocytic beta-adrenergic receptors.

To determine whether beta-adrenergic receptors on circulating lymphocytes are impaired during endotoxemia and the precise role of catecholamines in this process, we allocated 16 dogs to three groups: I) control-saline vehicle (n = 5), II) endotoxin--Escherichia coli endotoxin 1.0 mg/kg iv bolus (n = 6), and III) endotoxin + propranolol--E. coli endotoxin 1.0 mg/kg after pretreatment with propranolol, 1.5 mg/kg iv bolus followed by a continuous infusion, 30 micrograms/kg per min, (n = 5). Five hours after endotoxin injection, lymphocytic beta-adrenergic receptor number and sodium fluoride (NaF)-stimulated cyclic AMP accumulation were reduced by 41 +/- 6% and 25 +/- 7% of baseline values, respectively, which were significantly different from those observed in the control group (both P less than .01). Propranolol pretreatment prevented the endotoxin-induced reduction in lymphocytic beta-adrenergic receptor number (P less than .02 compared with the endotoxin group), but not the decrease in NaF-stimulated cyclic AMP accumulation (P less than .01 compared with the control group). Myocardial beta-adrenergic receptor number was reduced in the endotoxin group compared with that observed in the control group (P less than .06). These changes were associated with a decreased chronotropic response to isoproterenol in the endotoxin group compared with the control group (P less than .05). We conclude that decreased lymphocytic beta-adrenergic receptor number in endotoxin shock is caused by circulating catecholamines, whereas alterations distal to the receptors may be due to other mechanisms.

Animals↗
PubMed1990

Airborne endotoxin concentrations in various work areas within two cotton textile mills in the People's Republic of China.

As part of a multidisciplinary longitudinal approach to assess the roles of airborne cotton dust and endotoxins in affecting the respiratory health of cotton textile workers, this study was designed to quantify the endotoxin contamination of airborne vertically elutriated and total dusts. Yarn preparation areas (opening through fine spinning) were studied at two cotton textile mills which had been studied 5 years previously in Shanghai. People's Republic of China, Filter, with vertically elutriated (VE) or total dusts were mailed to the United States and endotoxin analyses were performed for each filter in duplicate with the quantitative chromogenic modification of the Limulus amebocyte lysate assay. Dusts from all areas of the textile mills contained endotoxins. Endotoxin burdens in VE dusts from the carding area were similar in both milk while the endotoxin contamination of total dust from carding in Mill 1 was over threefold greater than that of total dust from carding in Mill 2. All other areas differed between milk in both VE and total dust endotoxin burdens. Mean endotoxin levels in VE dusts from all areas of both mills were well above the reported threshold of 90 EU/m3 for acute pulmonary function effects in humans. Comparison of selected areas of both mills from the present study with the same work areas from the previous study showed that, in general, the airborne endotoxin burden was higher than levels found 5 years ago in these two mills. The data suggest that even with reduced or unchanged gravimetric dust levels in these two cotton textile mills, airborne endotoxin levels were higher and provided an increased potential for adverse respiratory response in exposed workers.

Air Pollutants, Occupational↗
PubMed1990

Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity.

Rabbits were given polyclonal anti-tissue factor (TF) immunoglobulin G (IgG) before an injection of endotoxin to test the hypothesis that TF triggers disseminated intravascular coagulation (DIC) after endotoxin. The rabbits had been prepared with cortisone to develop DIC after one injection of endotoxin. Anti-TF IgG substantially reduced the falls in fibrinogen, factors V and VIII, and platelets noted in control rabbits given preimmune IgG before endotoxin. At autopsy 24 hours later, fibrin was present in glomerular capillaries of 4 of 5 control rabbits, but in none of 11 rabbits given anti-TF IgG. DIC was also induced in a second group of rabbits by the infusion, over 4 hours, of 1 microgram/kg of purified, reconstituted rabbit brain TF. This resulted in striking falls in plasma fibrinogen, factors V, and VIII that were diminished, but not prevented by prior treatment with anti-TF IgG. Circulating activated factor VII, induced by either TF infusion or endotoxin, could not be detected after DIC. Mean plasma extrinsic pathway inhibitor (EPI) activity did not fall significantly after endotoxin, and only to about 65% of the preinfusion after infusion of TF. Thus, DIC induced by both agents proceeded despite nearly normal plasma EPI levels. Because EPI neutralizes factor VIIa/TF in vitro only after a short lag period, the DIC that persisted for up to 6 hours after injection of endotoxin suggests that TF activity continued to be generated during this period on cells to which the circulating blood was exposed. All animals given endotoxin became ill with cyanosis, tachypnea, cold ears, and diarrhea, regardless of whether they had received anti-TF IgG to attenuate DIC. Infusion of TF caused some animals to die acutely with pulmonary arterial thromboses, but surviving animals did not appear ill. The findings support the hypothesis that exposure of blood to TF triggers DIC after endotoxin, but is not important for the pathogenesis of endotoxin-induced shock.

Animals↗
PubMed1986

Release of eicosanoids from white blood cells, platelets, smooth muscle cells, and endothelial cells in response to endotoxin and A23187.

Endotoxin produces numerous pathophysiologic changes in animals, including vascular endothelial cell damage and hematologic changes. Direct effects of endotoxin on arachidonic acid metabolism and the release of eicosanoids from endothelial cells and neutrophils have been reported. A rapid release of these autocoids occurs when cells are incubated with endotoxin, and this appears to be one of the earliest endotoxin-induced changes. Some of these eicosanoids may result in beneficial effects, and others may result in detrimental effects. This study was to determine the release of eicosanoids from white blood cells, platelets, smooth muscle cells, and endothelial cells in response to varying amounts of endotoxin and the calcium ionophore A23187. The results indicate that endotoxin has a major direct effect on vascular endothelial cells and smooth muscle cells as indicated by its ability to increase the synthesis of predominately i6-keto-PGF1 alpha by these cells. These effects were seen within a dose range of endotoxin that is lethal in horses. Very high concentrations of endotoxin (100 micrograms/ml) were required to stimulate a small increase in the production of i6-keto-PGF1 alpha and iLTC4 by freshly isolated neutrophils. Stimulation of cells with A23187 revealed that, of the eicosanoids measured, the one produced predominately by endothelial cells and smooth muscle cells was 6-keto-PGF1 alpha, by platelets was TxB2, and by neutrophils was LTC4 (LTB4 was not measured). A mixture of all white blood cells including platelets when incubated with A23187 produced large amounts of TxB2, LTB4, and LTC4 with smaller amounts of 6-keto-PGF1 alpha. The results indicate that endotoxin directly affects cells and stimulates them to produce thromboxane and prostacyclin, but very high concentrations of endotoxin were required to stimulate neutrophils to produce rather small increases in iLTC4.

6-Ketoprostaglandin F1 alpha↗
PubMed1987

Renal microthrombosis following endotoxin infusion may be mediated by lipoxygenase products.

Renal microvascular thrombosis following endotoxin infusion was assessed by measuring accumulation of 125I-labeled fibrinogen and transmission electron microscopy. Endotoxin shock was induced in unanesthetized Sprague-Dawley rats using 14 mg/kg Escherichia coli endotoxin (Difco) infused intravenously over a 5-hour period. Fifteen minutes after infusion of endotoxin was started, intravenous treatment was initiated. Two-thirds of the treatment was given over a period of 20 minutes followed by the remaining dose over the next 2 hours. Five rats received methyl prednisolone sodium succinate (Solu-Medrol) (U-9,088) (39.5 mg/kg). Six rats received a Solu-Medrol analog (methyl prednisolone 21(N-Methyltaurosuberate), sodium salt) (U-67,590A) (61.08 mg/kg). Six rats received a 5-lipoxygenase inhibitor (1-naphthalenol,2,3,diethyl-4-methoxy-acetate) (U-66,855) (20 mg/kg). Six rats received a prostacyclin analog (pentanoic acid, 5- less than hexahydro-5-hydroxy-6-(3-hydroxy-1-octenyl)-3a-methyl-2(1H)- pentalenylidene greater than -calcium salt, hydrate) (U-61,431F) (0.04 mg/kg). Six rats received a thromboxane synthase inhibitor (2-benzofurancarboxylic acid, 5-(3-pyridinylmethyl), sodium salt monohydrate) (U-63,557A) (18 mg/kg). Eight endotoxin-infused rats received only normal saline. Six control rats received no endotoxin infusion, only saline. Composition and location of thrombi were assessed by transmission electron microscopy. Glomerular thrombosis was quantitated by determination of whole blood equivalents of 125I fibrin/g of tissue. Electron microscopy and radioactive quantitation demonstrated microthrombosis in the nontreated endotoxin group. The thrombi contained fibrin, platelets, erythrocytes, and leukocytes. The extent of thrombosis was significantly elevated compared to saline-treated controls. Three treated groups (U-9,088, U-67,590A, and U-66,855) all had significantly less thrombosis than the nontreated endotoxin rats. Two treated groups (U-63,557A and U-61,431F) developed glomerular thrombosis similar to untreated endotoxin rats. The results suggest that endotoxin stimulation of procoagulant activity and microthrombosis may be mediated by production of arachidonic acid metabolites via the lipoxygenase pathway.

Animals↗
PubMed1986

Emigration and accumulation of PMN-leukocytes induced by endotoxin, interleukin 1 and other chemotactic substances.

This publication describes polymorphonuclear leukocyte (PMN) emigration and accumulation, which is prerequisite for their defensive function in infected tissues. The extravasated PMNs can kill microorganisms, but in this process they also release proteolytic enzymes and other cell constituents which can alter and even injure the tissues, primarily the microcirculation. In the first part of the paper in vivo quantitation of the acute inflammatory reaction is described with emphasis on PMN emigration and accumulation. With 51Cr-labeled PMNs the kinetics of their emigration induced by a number of chemotaxins and chemotaxinigens was found to be similar, peaking in 1-4 hour old lesions and returning to baseline values thereafter. The most potent substance tested was endotoxin, which induced a PMN influx at a molar concentration a least 3 orders of magnitude lower than the other substances tested, implying the these substances are not the primary endogenous mediators of endotoxin induced inflammation. Next we describe an observation which shed considerable light on the mechanisms underlying PMN emigration. When a chemotaxin or endotoxin was injected intradermally and after varying periods of time reinjected into the same site, the PMN influx into those sites was diminished, compared to sites not previously injected, i. e. injected for the first time. This tachyphylaxis or diminished responsiveness was attributed to a downregulation of receptors, presumably on endothelial cells, coupled to a facilitatory mechanism. Other mechanism proposed to terminate emigration of PMNs during inflammatory reaction were unlikely, based on our experimental findings. Endotoxin is not chemotactic in vitro but it induces PMN emigration when injected intradermally. Hence the third part of the publication deals with PMN emigration induced by interleukin 1 and its significance for endotoxin-induced inflammation. IL 1 is the only chemotaxin which induces PMN accumulation at a concentration comparable to that of endotoxin and considerably lower than the other chemotaxins. There was cross tachyphylaxis between endotoxin and IL 1 and vice versa. The PMN influx into IL 1 sites injected 6 hours earlier with IL 1 or with endotoxin was diminished compared to IL 1 sites injected into normal skin. Sites injected first with IL 1 and then with a low dose of endotoxin also exhibited cross tachyphylaxis. FMLP or LTB4 injected into sites pretreated with endotoxin did not exhibit cross tachyphylaxis, i. e. the PMN influx was similar to sites injected for the first time with these chemotaxins.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1979

Platelet and fibrinogen production: relative sensitivities to endotoxin.

The relative sensitivities of platelet and fibrinogen production to endotoxin were determined in male New Zealand rabbits. E. coli endotoxin was administered in single intravenous doses of 0.1 to 50.0 mu/g/kg body mass. 75SeM was injected 5, 12, or 18 hr after endotoxin, and the percent incorporation into platelets and fibrinogen was used to measure thrombopoiesis and fibrinogen synthesis. Leukopenia occurred after the infusion of endotoxin at all dose levels; the lowest dose that caused thrombocytopenia was 0.5 microgram/kg. Endotoxin was detected with the Limulus test in plasma of animals that received 5 to 50 microgram/kg. The stimulation of fibrinogen and platelet production, as well as the postinfusion decrease in platelet count, correlated directly with the log of the dose of endotoxin infused. The lowest dose of endotoxin that stimulated platelet and fibrinogen production was 0.5 microgram/kg. In animals that received this dose of endotoxin, increased fibrinogen production was detected only when 75SeM was injected 5 hr later. In animals injected 5, 12, or 18 hr later. Increased platelet production was detected at these two doses only when 75SeM was injected 18 hr after endotoxin. The data indicate that fibrinogen and platelet production have similar sensitivities to endotoxin, although the time course of stimulation is different for these two blood components.

Animals↗
PubMed1984

The mediated effect of endotoxin and lead upon hepatic metabolism.

A test was made of the possibility that gram-negative bacterial cell wall lipopolysaccharides acted directly on key glucoregulatory enzymes in rat liver cytosol to cause the characteristic hypoglycemia of severe endotoxemia. Fasted male rats were sensitized to endotoxin by the simultaneous intravenous injection of lead acetate. The minimum systemic dosage of endotoxin necessary to perturb the normal pattern of hepatic glycolytic intermediates was determined by serial testing with diminishing dosages of endotoxin. The hepatocyte concentration of endotoxin was then calculated from this minimum dosage by use of literature data on the fraction of endotoxin delivered to liver cells after a systemic intravenous injection of radiochromium labeled lipopolysaccharides. Accepting a molecular weight of 118,000 daltons for the smallest endotoxin monomer capable of evoking a physiologic response, the molar amount of endotoxin present in 1 gram of hepatocytes was readily calculated. The concentration of glucoregulatory enzymes in parenchymal cells was then estimated from other literature sources. It was found that the amount of endotoxin in the hepatocytes was insufficient to combine directly with even 1 per cent of the quantity of a single key glucoregulatory enzyme in liver parenchyma. Since a one to one stoichiometric reaction between endotoxin and enzyme could not occur in the liver cytosol, a direct interaction mechanism between agonist and biocatalyst can be ruled out. It is concluded that bacterial endotoxin must act on hepatic glucoregulation by an indirect mechanism presumably based upon the release and operation of mediators.

Animals↗
PubMed1981

Insulin-like action of endotoxin: antagonism by steroidal and nonsteroidal anti-inflammatory agents.

Studies were undertaken to evaluate the direct insulin-like action of S enteritidis endotoxin on glucose oxidation in the rat epididymal fat pad and to assess antagonism by steroidal and nonsteroidal anti-inflammatory agents. In vitro administration of endotoxin at concentrations of 500, 100, 50, and 10 micrograms/ml significantly increased adipose tissue glucose oxidation by 115, 92, 55, and 32%, respectively. Exposure of the fat pads to endotoxin (100 microgram/ml) for timed incubations of 120 to 5 min, all produced significant increments in glucose oxidation. The insulin-like action of endotoxin was significantly less in Ca2+ free-KRB plus EGTA. Cotreatment of the fat pads with endotoxin and the steroidal anti-inflammatory agents, dexamethasone and methylprednisolone, as well as the nonsteroidal anti-inflammatory agent, indomethacin, significantly antagonized endotoxin-stimulated glucose oxidation. Dexamethasone antagonism was not significant if it was added after endotoxin treatment. Testosterone, a steroid with no anti-inflammatory activity, did not antagonize endotoxin's insulin-like action. The data provide further evidence of the direct insulin-like action of endotoxin and suggest that the protective effect of dexamethasone, methylprednisolone, and indomethacin may be due, in part, to a direct antagonism of endotoxin at the tissue level.

Adipose Tissue↗
PubMed1981

Endotoxin protects against chlorpromazine-induced cholestasis in the isolated perfused rat liver.

Induction of endotoxin tolerance or acute chlorpromazine treatment caused a decrease in bile and perfusate flow in the isolated perfused rat liver. The primary effects of each appeared to be on the bile acid-independent fraction of bile. Both the induction of endotoxin tolerance and the in vitro treatment of the perfused rat liver with endotoxin partially blocked the adverse effects of chlorpromazine on bile formation and perfusate flow. Although the "protective" effects of the in vitro endotoxin treatment were dose-dependent, the protection afforded by endotoxin tolerance was greater. Preincubation of isolated hepatocytes with endotoxin, before the addition of chlorpromazine, caused dose-dependent reductions in the chlorpromazine-induced release of aspartate transaminase. However, neither the incubation of endotoxin with chlorpromazine, before addition of membranes isolated from control rats, nor isolation of membranes from endotoxin-tolerant rats affected the inhibitory effects of chlorpromazine on sodium, potassium-, or magnesium-activated adenosine triphosphatase. If endotoxin exerts its protective effects at the membrane level, these data suggest that endotoxin is able to protect the intact, but not the isolated, hepatocyte membrane or that inhibition of adenosine triphosphatases by chlorpromazine is not important in the adverse effects of chlorpromazine on the perfused rat liver and isolated rat hepatocytes.

Animals↗
PubMed1995

Paradoxical effects of IL-10 in endotoxin-induced uveitis.

Uveitis, or intraocular inflammation, can be provoked in laboratory rodents by the local or systemic injection of bacterial endotoxin. Many of the inflammatory effects of endotoxin are potentially due to the induction of cytokine synthesis. IL-10 is a cytokine that potently inhibits the synthesis of many cytokines, including IL-1 and TNF-alpha. We have assessed the ability of IL-10 to inhibit endotoxin-induced uveitis in rabbits and mice. The intravitreal injection of 1 micrograms of human recombinant IL-10 was extremely effective in rabbits in reducing the inflammation produced by the intravitreal injection of 250 ng of Escherichia coli endotoxin, as judged by the reduced accumulation of cells and protein in the aqueous humor. Locally injected IL-10 was similarly effective in blocking the ocular inflammatory effects of intravitreally injected endotoxin in a mouse model. If the injection of IL-10 was delayed subsequent to the endotoxin injection, the reduced inflammatory effects in the rabbit model were diminished. In contrast to its ability to inhibit the local inflammatory effect of endotoxin in the eye, IL-10 did not reduce the inflammation induced by a local ocular injection of 400 U of human recombinant IL-alpha. Paradoxically, in a mouse model of uveitis subsequent to intraperitoneally injected endotoxin, the simultaneous injection of 1 micrograms of IL-10 and endotoxin potentiated the ocular inflammation, as judged by the number of leukocytes seen in histologic sections. This effect was dose dependent, since eye inflammation was markedly inhibited by 100 micrograms of IL-10 injected i.p. These observations are compatible with the hypothesis that locally injected IL-10 acts by reducing cytokine synthesis in these uveitis models. Intraperitoneally injected IL-10 can either inhibit or suppress endotoxin-induced eye inflammation in a dose-dependent manner.

Animals↗