Intravenous Injection Of Endotoxin Research Articles

Multi-Cellular Activation In Vivo by Endotoxin in Humans – Limited Protection by Adenosine Infusion

The influence of adenosine infusion (40 microg/kg/min for 4 h) on inflammatory and hemostatic parameters was investigated in healthy males without (n = 10) or with (n = 11) intravenous endotoxin injection (4 ng/kg). Without endotoxin, adenosine elevated circulating leukocytes and circulating platelet-leukocyte aggregates. Endotoxin activated platelets and leukocytes in vivo. Platelet activation was seen as slightly increased platelet P-selectin expression, decreased platelet counts, and elevated plasma soluble P-selectin (from 39.6 +/- 3.4 to 68.9 +/- 6.6 ng/ml, P<0.01). Leukocyte activation was evidenced by increased CD1 lb expression (from MFI of 0.54 +/- 0.02 to 2.21 +/- 0.17; P<0.01) and plasma elastase levels (from 25.3 +/- 2.5 to 169.3 +/- 22.5 ng/ml: P <0.01). Endotoxin also enhanced platelet and leukocyte responsiveness to in vitro stimulation. Endotoxin induced von Willebrand factor secretion (from 92 +/- 8 units to 265 +/- 19 units at 4 h; P <0.001) and enhanced thrombin generation in vivo. Endotoxin induced leukocytosis and thus increased circulating platelet-leukocyte, mainly platelet-neutrophil, aggregates. Adenosine caused slight attenuation of platelet reactivity to agonist stimulation, enhanced the endotoxin-induced leukocytosis, and detained more platelet-leukocyte aggregates in circulation, but did not attenuate endotoxin-induced neutrophil elastase secretion, von Willebrand factor secretion, or thrombin generation. Thus, endotoxemia induces multi-cellular activation in vivo. Adenosine inhibits leukocyte adhesion and extravasation, and mildly attenuates platelet responsiveness and soluble P-selectin release. Adenosine has the potential of becoming a therapeutic antiinflammatory drug, but an optimal treatment strategy needs to be developed.

The effect of CP-96,345, a non-peptide substance-P antagonist, on thermoregulation and the development of endotoxin-fever in rats

1. Substance-P (SP) has been shown to induce a regulated rise in body temperature when injected into one of the lateral cerebral ventricles of rats. 2. The non-peptide antagonist of SP (CP-96,345) decreased the SP-induced rise in core temperature and, when given prior to an intravenous endotoxin injection, it also attenuated the febrile response to endotoxin.

Receptor Clearance Obscures the Magnitude of Granulocyte-Macrophage Colony-Stimulating Factor Responses in Mice to Endotoxin or Local Infections

AbstractMarrow cells from mice lacking high-affinity receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF; βc−/− mice) were shown to bind and internalize much less GM-CSF than cells from normal (βc+/+) mice. βc−/− mice were used to determine the effect of negligible receptor-mediated clearance on detectible GM-CSF responses to the intravenous injection of endotoxin or the intraperitoneal injection of casein plus microorganisms. Unlike the minor serum GM-CSF responses to endotoxin seen in βc+/+ mice, serum GM-CSF levels rose 30-fold to 9 ng/mL in βc−/− mice even though loss of GM-CSF in the urine was greater than in βc+/+ mice. Organs from βc−/− and βc+/+ mice had a similar capacity to produce GM-CSF in vitro, as did peritoneal cells from both types of mice when challenged in vitro by casein. However, when casein was injected intraperitoneally, βc−/− mice developed higher and more sustained levels of GM-CSF than did βc+/+ mice. The data indicated that receptor-dependent removal of GM-CSF masks the magnitude of GM-CSF responses to endotoxin and local infections. Because of this phenomenon, serum GM-CSF concentrations can be a misleading index of the occurrence or nonoccurrence of GM-CSF responses to infections.

Receptor Clearance Obscures the Magnitude of Granulocyte-Macrophage Colony-Stimulating Factor Responses in Mice to Endotoxin or Local Infections

Marrow cells from mice lacking high-affinity receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF; βc−/− mice) were shown to bind and internalize much less GM-CSF than cells from normal (βc+/+) mice. βc−/− mice were used to determine the effect of negligible receptor-mediated clearance on detectible GM-CSF responses to the intravenous injection of endotoxin or the intraperitoneal injection of casein plus microorganisms. Unlike the minor serum GM-CSF responses to endotoxin seen in βc+/+ mice, serum GM-CSF levels rose 30-fold to 9 ng/mL in βc−/− mice even though loss of GM-CSF in the urine was greater than in βc+/+ mice. Organs from βc−/− and βc+/+ mice had a similar capacity to produce GM-CSF in vitro, as did peritoneal cells from both types of mice when challenged in vitro by casein. However, when casein was injected intraperitoneally, βc−/− mice developed higher and more sustained levels of GM-CSF than did βc+/+ mice. The data indicated that receptor-dependent removal of GM-CSF masks the magnitude of GM-CSF responses to endotoxin and local infections. Because of this phenomenon, serum GM-CSF concentrations can be a misleading index of the occurrence or nonoccurrence of GM-CSF responses to infections.

Sequential measurements of chemokines in urosepsis and experimental endotoxemia.

Chemokines are a superfamily of small chemotactic proteins. While increased levels of interleukin-8 have been measured in serum and urine during urinary tract infection, little is known about other chemokines in this condition. Monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and interferon-gamma inducible protein (IP)-10 were measured in 30 patients with culture-proven urosepsis during a 3-day follow-up and in 11 healthy humans after intravenous injection of endotoxin (4 ng/kg). Urine and serum levels of MCP-1, MIP-1beta, and IP-10, but not of MIP-1alpha were elevated in patients on admission, and decreased after initiation of antibiotic treatment. Endotoxin administration to healthy subjects induced increases in plasma and urine concentrations of all four chemokines. These data indicate that clinical and experimental gram-negative infection in humans is associated with enhanced production of chemokines that act mainly on mononuclear cells and that these chemokines are at least in part locally produced.

TUMOR NECROSIS FACTOR ALPHA IS INVOLVED IN THE INDUCTION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 BY ENDOTOXIN

Treatment with endotoxin leads to a rise in plasminogen activator inhibitor-1 (PAI-1) both in vivo and in vitro. Although a recent study insists that inhibition of tumor necrosis factor alpha (TNFα) does not reduce the induction of PAI-1 by endotoxin in rats, we imagine that TNFα is involved in the induction of PAI-1 by endotoxin, because endotoxin treatment induces TNFα and administration of TNFα induces PAI-1 both in vitro and in vivo. In order to confirm this hypothesis, we have measured plasma PAI activity and PAI-1 mRNA in liver after endotoxin treatment with or without pretreatment by polyclonal rabbit antiserum against murine TNFα. Chronically cannulated Sprague-Dawley rats received intravenous injection of endotoxin (10 μg/kg) 10 min after administration of anti-TNFα antibody (Antibody Group) or same volume of control rabbit serum (Control Group). PAI activity was measured by Coatest PAI®, ans PAI-1 mRNA was measured semi-quantitatively by high-performance liquid chromatography after reverse transcription and polymerase chain reaction. Increases in PAI activity 4 h after endotoxin treatment were significantly smaller in the Antibody Group than in the Control Group, while increases in PAI-1 mRNA were significantly smaller at 2 h in the Antibody Group. These results suggest that TNFα is responsible, at least in part, for the induction of PAI-1 by endotoxin in vivo. © 1997 Elsevier Science Ltd

Dantrolene, an inhibitor of intracellular calcium release, fails to increase survival in a rat model of intra-abdominal sepsis.

Increased release of intracellular calcium has been implicated in cell death and organ failure in endotoxemia and sepsis. We sought to test this hypothesis in a rat model of antibiotic-treated intraperitoneal sepsis with the use of dantrolene sodium, a specific inhibitor of intracellular calcium release. A prospective, randomized controlled trial. An experimental animal laboratory in a university hospital. Two hundred fourteen male Sprague-Dawley rats. Rats were rendered septic by intraperitoneal implantation of sterile feces mixed with live Escherichia coli and allocated to control, vehicle, or dantrolene treatment. A separate group of rats had arterial catheters implanted to allow blood sampling for determination of circulating tumor necrosis factor (TNF)-alpha and lactate concentrations. Additional rats were randomized to receive vehicle or dantrolene after intravenous injection of endotoxin. Over the 7-day study period, survival was significantly worse among rats that received dantrolene at a dose of 10 mg/kg, irrespective of whether treatment was started before or after induction of peritonitis. Mean whole blood lactate for each group peaked at 6 hrs after induction of infection. There were no significant differences in lactate concentration among the groups at any of the time points examined. Similarly, there were no differences among any of the groups for circulating concentrations of TNF-alpha. In rats challenged with endotoxin, dantrolene affected neither survival nor circulating concentrations of TNF-alpha. We conclude that dantrolene decreases survival in bacterial sepsis and has no effect on survival in endotoxemia in rats. The importance of excessive intracellular calcium release in sepsis remains to be elucidated.

Interaction between norepinephrine and prostaglandin E2 in the preoptic area of guinea pigs.

The release of norepinephrine (NE) and prostaglandin E2 (PGE2) in the preoptic-anterior hypothalamus (POA) by systemically administered pyrogens suggests that both substances may mediate the febrile response. To investigate their possible interaction, we measured directly the levels of PGE2 in the extracellular fluid of the POA of conscious guinea pigs microdialyzed intrapreoptically with exogenous NE over the entire course of their febrile response to endotoxin. Acidified and buffered NE (NEa, NEb), artificial cerebrospinal fluid (aCSFa, aCSFb), and vehicle (Veha, Vehb) were tested. All but aCSFb depressed the febrile response to endotoxin. The microdialysis of aCSFa, aCSFb, Veha, Vehb, and NEa did not change basal preoptic PGE2 levels. However, NEb, at a dose that by itself did not affect body temperature (Tb), caused a large elevation in preoptic PGE2. The intravenous injection of endotoxin increased the level of PGE2 in the POA. NEb potentiated this increase, whereas NEa, aCSFa, and Vehb reduced it; Veha reduced it for the first 60 min and enhanced it for the last 90 min of the experiment. Thus these data suggest that the low pH of the NE solute and/or its Veh may confound the observed effects of NE on the Tb and preoptic PGE2 induced by endotoxin. We surmise that this is due to a neurotoxic action of the antioxidants and the acidity of the solution on thermosensitive neurons in the POA. Hence, the results of experiments using exogenous, usually acidified, NE preparations that often also contain additives should be interpreted with caution.

Induction mechanism of small intestinal lesions caused by intravenous injection of endotoxin in rats.

The pathogenesis of intestinal damage caused by bolus intravenous injection of endotoxin (ETX; 3 mg/kg) was investigated. Administration of ETX to rats induced reddish discoloration suggestive of bleeding, increased hemoglobin amounts, and leakage of plasma protein in the intestine. However, light microscopic examination of the intestine demonstrated blood congestion of the microvessels. Plasma accumulation was partially inhibited by combined pretreatment with a histamine H1 antagonist and a serotonin (5-HT) antagonist. Neither a 5-lipoxygenase inhibitor, a soybean trypsin inhibitor, nor atropine was observed to inhibit plasma accumulation. Both the intestinal leakage of plasma and the accumulation of hemoglobin were completely inhibited by indomethacin, a selective thromboxane A synthetase inhibitor (OKY 1581), and a stable PGI2 analogue (beraprost). Intravital microscopic observation of the microvessels of the small intestinal villi demonstrated microthrombus formation within several minutes after the injection of ETX, and pretreatment with OKY 1581 attenuated the formation of microthrombus. Platelet counts decreased significantly 10 min after ETX administration, and the decrease was not inhibited by pretreatment with either OKY 1581 or beraprost. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were not prolonged. These observations thus suggest that microcirculatory disturbances by platelet thrombus, which are mediated by thromboxane A2 at least in part, play an important role in ETX-induced intestinal damage.

The local Schwartzman phenomenon and human dentin permeability to endotoxin

The local Schwartzman phenomenon is a thrombotic hemorrhagic reaction that develops in response to local preparatory administration followed by intravenous provoking injection of endotoxin. This study investigated permeability of coronal dentin to endotoxin. Cavities were prepared in human dentin discs and received either 10 μg or 100 μg Salmonella enteritidis endotoxin or pyrogen-free water over the cavity floor. The cavities were then restored with a glass ionomer cement. The discs were implanted in rabbits' abdominal skin. The rabbits also received intradermal injections of 10 μg and 100 μg endotoxin and pyrogen-free water. 18 h after implantation/injection, a provoking intravenous injection of endotoxin was administered and the animals were terminated 6 h later. Intradermal injection of both doses of endotoxin elicited LSP in all rabbits. In the majority of specimens, endotoxin at 10 μg and 100 μg dosage did not permeate dentin to elicit LSP.

A diet containing glycine improves survival in endotoxin shock in the rat.

In this study, we investigated the effects of a glycine-containing diet (5%) on mortality and liver injury due to intravenous injection of endotoxin [Escherichia coli lipopolysaccharide (LPS)] in Sprague-Dawley rats in vivo. Fifty percent of the rats fed control diet died within 24 h after an intravenous injection of LPS (10 mg/kg), whereas feeding the rats glycine totally prevented mortality and markedly reduced an LPS-induced elevation of serum transaminase levels, hepatic necrosis, and lung injury. The elevation in serum tumor necrosis factor-alpha (TNF-alpha) due to LPS was also blunted and delayed significantly by glycine feeding. In a two-hit model (hepatic ischemia-reperfusion and injection of sublethal LPS), all rats fed control diet died, whereas 83% of glycine-fed animals survived with a significant reduction in transaminases and improved liver and lung histology. LPS elevated intracellular Ca2+ concentration ([Ca2+]i) in cultured Kupffer cells, an effect blocked almost completely by glycine. Glycine most likely reduces injury and mortality by preventing the LPS-induced elevation of [Ca2+]i in Kupffer cells, thereby minimizing toxic eicosanoid and cytokine production.

Role of Kupffer cells and the spleen in modulation of endotoxin-induced liver injury after partial hepatectomy

The hypothesis that both activated Kupffer cells and the spleen may be responsible for endotoxin-induced liver injury following partial hepatectomy was investigated. Male rats were divided into a sham group receiving laparotomy alone and three groups receiving a two-thirds hepatectomy; one group was given normal saline (NS) solution as a vehicle control, one group received intravenous gadolinium chloride (GC group) (7 mg/kg body weight) for 2 days before intravenous injection of endotoxin to inhibit Kupffer cell phagocytosis, and the third group simultaneously underwent splenectomy and partial hepatectomy (SH group). As endotoxin, lipopolysaccharide (LPS) (1 mg/kg body weight) was administered intravenously 2 days after surgery. In the GC and SH groups, phagocytic activity was reduced to approximately 40% of that in the sham group. The highest plasma tumor necrosis factor alpha (TNF-alpha) level (8,544 ± 1,223 pg/mL) was observed in the NS group at 1 hour after LPS administration, and the level was significantly reduced by GdCl3 or splenectomy (P < 0.05). Inhibition of Kupffer cell function and splenectomy attenuated functional and structural liver damage associated with the decreased hepatic infiltration of polymorphonuclear leukocytes (PMNs) and reduced priming of circulating PMNs in the early stage of endotoxemia following partial hepatectomy. Consequently, the 24-hour survival rate of the SH and GC groups was significantly improved to 50% and 80%, respectively (P < .05), while that of the NS group was 12.5%. These findings indicate that the modification of inflammatory mediator generation by splenectomy or inhibition of Kupffer cell function may be beneficial for the prevention of endotoxin-induced liver injury after partial hepatectomy. (Hepatology 1996 Jul;24(1):219-25)

Role of Kupffer Cells and the Spleen in Modulation of Endotoxin–Induced Liver Injury After Partial Hepatectomy

The hypothesis that both activated Kupffer cells and the spleen may be responsible for endotoxin–induced liver injury following partial hepatectomy was investigated. Male rats were divided into a sham group receiving laparotomy alone and three groups receiving a two–thirds hepatectomy; one group was given normal saline (NS) solution as a vehicle control, one group received intravenous gadolinium chloride (GC group) (7 mg/kg body weight) for 2 days before intravenous injection of endotoxin to inhibit Kupffer cell phagocytosis, and the third group simultaneously underwent splenectomy and partial hepatectomy (SH group). As endotoxin, lipopolysaccharide (LPS) (1 mg/kg body weight) was administered intravenously 2 days after surgery. In the GC and SH groups, phagocytic activity was reduced to approximately 40% of that in the sham group. The highest plasma tumor necrosis factor alpha (TNF–alpha) level (8,544 ± 1,223 pg/mL) was observed in the NS group at 1 hour after LPS administration, and the level was significantly reduced by GdCl3 or splenectomy ( P &lt; 0.05). Inhibition of Kupffer cell function and splenectomy attenuated functional and structural liver damage associated with the decreased hepatic infiltration of polymorphonuclear leukocytes (PMNs) and reduced priming of circulating PMNs in the early stage of endotoxemia following partial hepatectomy. Consequently, the 24–hour survival rate of the SH and GC groups was significantly improved to 50% and 80%, respectively ( P &lt; .05), while that of the NS group was 12.5%. These findings indicate that the modification of inflammatory mediator generation by splenectomy or inhibition of Kupffer cell function may be beneficial for the prevention of endotoxin–induced liver injury after partial hepatectomy.

Synthetic Protease Inhibitor Prevents Impaired Hepatic Secretion of Lysosomal Enzymes into Bile and Hepatic Lysosomal Fragility Induced by Endotoxin in Rats

This study was designed to examine the effect of sepsis on the hepatic functions, particularly from the view point of hepatic lysosomal functions. Endotoxemia was produced in rats by intravenous injection of endotoxin (1 mg/kg), and at 6 h after the injection of endotoxin, we studied (1) the hepatic secretion of lysosomal enzymes (β-glucuronidase, β-galactosidase and N-acetyl-β-glucosaminidase) into bile in the isolated perfused rat liver model; (2) the aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) and lysosomal enzyme levels in the effluent in the isolated liver model; (3) hepatic lysosomal fragility in an in vitro incubation study; (4) protective effect of a new synthetic protease inhibitor, sepinostat mesilate (FUT-187) against hepatic injuries induced by endotoxin. Decreased hepatic secretion of lysosomal enzymes into bile and accelerated hepatic lysosomal fragility were observed in endotoxemia. FUT-187 showed significant protective effects against these hepatic injuries induced by endotoxin. These results indicate that impaired hepatic functions, depressed hepatic secretion of lysosomal enzymes into bile, and increased hepatic lysosomal fragility, seem to be closely related to the hepatic injuries induced by endotoxin. These results also indicate that some unknown protease activities, which are susceptible to inhibition by FUT-187, seem to play an important role in the development of hepatic injuries induced by endotoxin.

Endotoxin-induced changes in intrarenal pO 2, measured by in vivo electron paramagnetic resonance oximetry and magnetic resonance imaging

Electron Paramagnetic Resonance (EPR) oximetry was used to measure tissue oxygen tension (pO 2—partial pressure of oxygen) simultaneously in the kidney cortex and outer medulla in vivo in mice. pO 2 in the cortex region was higher compared to that in the outer medulla. An intravenous injection of endotoxin resulted in a sharp drop in pO 2 in the cortex and an increase in the medulla region, resulting in a transient period of equal pO 2 in both regions. In control kidneys, functional Magnetic Resonance (MR) images showed the cortex region to have high signal intensity (T 2 ∗-weighted images), indicating that this region was well supplied with oxygenated hemoglobin, whereas the outer medulla showed low signal intensity. After administration of endotoxin, we observed an immediate increase in signal intensity in the outer medulla region, reflecting an increased level of oxygenated blood in this region. Pretreatment of mice with N O-monomethyl- l-arginine prevented both the changes in tissue pO 2 and distribution of oxygenated hemoglobin, suggesting that localized production of nitric oxide has a critical role to play in renal medullary hemodynamics. In combining in vivo EPR with MR images of kidneys, we demonstrate the usefulness of these techniques for monitoring renal pO 2 and changes in the distribution of oxygen.

Fat Emulsion Infusion Potentiates Coagulation Activation during Human Endotoxemia

Intravenous fat emulsions are frequently given to malnourished patients who are prone to suffer from infectious complications. As injection of low dose endotoxin represents a model to study the human response to acute infection, we sought to determine the effect of lipid emulsion infusion on endotoxin-induced activation of the hemostatic mechanism in man. Ten healthy men received a bolus intravenous injection of endotoxin (lot EC-5; 20 U/kg) midway through a 4-h infusion (125 ml/h) of either dextrose 5% (n = 5) or Intralipid 20% (n = 5). Lipid infusion potentiated endotoxin-induced coagulation activation, as indicated by higher plasma levels of the prothrombin fragment F1 + 2 and of thrombin-antithrombin III complexes (both p < 0.05 for the difference between groups). However, lipid infusion did not influence the fibrinolytic response to intravenous endotoxin, as reflected by similar increases in the levels of tissue-type plasminogen activator and plasmin-alpha 2-antiplasmin complexes in both groups. Endotoxin-induced appearance of plasminogen activator inhibitor type I was enhanced by lipid infusion (p < 0.05). These data suggest that fat emulsion infusion may enhance the tendency towards thrombotic complications in patients with infections.

Endotoxin induces downregulation of tumor necrosis factor receptors on circulating monocytes and granulocytes in humans

Leukocytes rapidly lose their surface receptors for tumor necrosis factor (TNF) after exposure to various stimuli in vitro. To assess the effect of endotoxin on cellular TNF receptors in humans in vivo, binding of biotinylated TNF to circulating monocytes and granulocytes was determined by fluorescence-activated cell sorter analysis in six healthy subjects after intravenous injection of endotoxin (lot EC-5, 20 U/kg). Endotoxin administration was associated with a transient decrease in monocyte TNF receptors, reaching a nadir after 2 hours (P < .0001), and a more sustained decrease in granulocyte TNF receptors (P < .001). Although the decrease in cellular TNF receptors coincided with increases in soluble TNF receptors types I and II, no correlations were observed between trough monocyte or granulocyte TNF receptors and peak plasma concentrations of soluble TNF receptors. Stimulation of human whole blood with endotoxin resulted in reduced expression of both type I and type II TNF receptors on monocytes and granulocytes. Endotoxin induces downmodulation of monocyte and granulocyte TNF surface receptors in humans in vivo, which may represent a mechanism to reduce excessive activity of TNF during systemic infection.

Endotoxin Induces Downregulation of Tumor Necrosis Factor Receptors on Circulating Monocytes and Granulocytes in Humans

Abstract Leukocytes rapidly lose their surface receptors for tumor necrosis factor (TNF) after exposure to various stimuli in vitro. To assess the effect of endotoxin on cellular TNF receptors in humans in vivo, binding of biotinylated TNF to circulating monocytes and granulocytes was determined by fluorescence-activated cell sorter analysis in six healthy subjects after intravenous injection of endotoxin (lot EC-5, 20 U/kg). Endotoxin administration was associated with a transient decrease in monocyte TNF receptors, reaching a nadir after 2 hours (P &lt; .0001), and a more sustained decrease in granulocyte TNF receptors (P &lt; .001). Although the decrease in cellular TNF receptors coincided with increases in soluble TNF receptors types I and II, no correlations were observed between trough monocyte or granulocyte TNF receptors and peak plasma concentrations of soluble TNF receptors. Stimulation of human whole blood with endotoxin resulted in reduced expression of both type I and type II TNF receptors on monocytes and granulocytes. Endotoxin induces downmodulation of monocyte and granulocyte TNF surface receptors in humans in vivo, which may represent a mechanism to reduce excessive activity of TNF during systemic infection.

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.

Effects of arterial hypoxia and β‐adrenoceptor blockade on cerebral blood flow and oxygen uptake following E. coli endotoxin in dogs

Earlier studies in normoxia have shown that an endotoxin injection in dogs leads to an increase in cerebral metabolic rate of oxygen (CMRo2), a decrease in cerebral blood flow (CBF) and increased concentrations of monoamines in blood and cerebrospinal fluid (CSF). In animals pretreated with propranolol (PPL) the CMRo2 increase was abolished and thus beta-adrenoceptor mediated. Arterial hypoxia normally increases CBF without any influence on CMRo2. The aim of this study was to investigate the effects of moderate arterial hypoxia on CBF, CMRo2 and catecholamine concentrations in blood and CSF after endotoxin with and without pretreatment with PPL. Three groups of dogs were studied. Group 1: Six animals were subjected to arterial hypoxia without any other intervention. Group 2: Six animals were given an endotoxin injection (E. coli lipopolysaccharide O 111: B 4), before the induction of hypoxia. Group 3: Eight animals were pretreated with PPL per os, 12.5 mg.kg-1 twice a day for one week before the experiments, and the effects of arterial hypoxia were studied both before and after an intravenous injection of endotoxin. Two levels of hypoxia were studied; oxygen saturation in arterial blood aiming at 75 and 50%. Endotoxin was given intravenously in a dose of 1 mg.kg-1 bodyweight over a 5 minute period. After an endotoxin injection, the response to arterial hypoxia was an increase in CMRo2, in contrast to the unchanged CMRo2 without endotoxin. After pretreatment with PPL the increase in CMRo2 after endotoxin was prevented. The CBF reaction to hypoxia was uniformly an increase.(ABSTRACT TRUNCATED AT 250 WORDS)