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PubMed1997

N-acetylcysteine attenuates endotoxin-induced leukocyte-endothelial cell adhesion and macromolecular leakage in vivo.

OBJECTIVE: To determine the influence of N-acetylcysteine on endotoxin-induced leukocyte-endothelial cell adhesion, vascular leakage, and venular microhemodynamics. DESIGN: Randomized, blinded, controlled trial. SETTING: Experimental laboratory. SUBJECTS: Thirty male Wistar rats. INTERVENTIONS: After pretreatment with N-acetylcysteine (150 mg/kg; n = 40; group A) or 0.9% saline solution (n = 10; group B) animals were given an intravenous infusion of endotoxin (Escherichia coli lipopolysaccharide 026:B6; 2 mg/kg/hr) over 120 mins. Animals in the control group (n = 10; group C) received a volume-equivalent infusion of 0.9% saline solution. MEASUREMENTS AND MAIN RESULTS: Leukocyte adherence, red cell velocity (VRBC), vessel diameters, venular wall shear rate, and macromolecular leakage were determined in mesenteric postcapillary venules using in vivo videomicroscopy at baseline and at 30, 50, 90, and 120 mins after the start of the endotoxin challenge. Endotoxin exposure induced a marked increase in adherent leukocytes (group B: baseline, 391 +/- 24 cells/mm2; 120 mins, 1268 +/- 131 cells/mm2; p < .01). N-acetylcysteine pretreatment attenuated the adherence of leukocytes during endotoxemia (baseline, 366 +/- 28 cells/mm2; 120 mins, 636 +/- 49 cells/mm2; p < .01 vs. baseline; p < .01 vs. group B). Leukocyte adherence in control animals (group C) did not increase significantly. Administration of N-acetylcysteine did not influence the decrease in VRBC observed during endotoxemia. In group B1 VRBC decreased during the infusion of endotoxin from 2.0 +/- 0.2 mm/sec at baseline to 1.1 +/- 0.2 mm/ sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C), and in group A from 2.2 +/- 0.2 mm/sec to 1.1 +/- 0.1 mm/sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C). In group C, VRBC remained unchanged (baseline, 1.7 +/- 0.2 mm/sec; at 120 mins, 1.5 +/- 0.2 mm/sec). The venular diameters remained unchanged in all groups during the entire study period. After 120 mins, the venular wall shear rate decreased from 502 +/- 62 secs-1 at baseline to 272 +/- 46 sec-1 in group B (p < .01), and from 563 +/- 45 secs-1 at baseline to 283 +/- 31 secs-1 in group A (p < .01). No differences in venular wall shear rate were observed between these groups. In group C, the venular wall shear rate remained unchanged (baseline, 457 +/- 54 secs-1; at 120 mins, 409 +/- 51 secs-1). Macromolecular leakage, expressed as perivenular/intravenular fluorescence intensity after injection of fluorescence-labeled albumin, increased from 0.29 +/- 0.03 to 0.58 +/- 0.03 (p < .01) during the infusion of endotoxin in group B. In contrast, pretreatment with N-acetylcysteine diminished the extravasation of albumin (baseline, 0.27 +/- 0.01; at 120 mins, 0.37 +/- 0.02; p < .01 vs. baseline; p < .01 vs. group B). CONCLUSION: These results demonstrate that N-acetylcysteine attenuates endotoxin-induced alterations in leukocyte-endothelial cell adhesion and macromolecular leakage, suggesting N-acetylcysteine might be therapeutic in the prevention of endothelial damage in sepsis.

Acetylcysteine↗
PubMed1998

Soluble glucan protects against endotoxin shock in the rat: the role of the scavenger receptor.

Soluble carboxymethyl-b-1,3-glucan (CMG), a possible ligand for scavenger receptors, has macrophage-activating action but lacks the granulomatose inflammatory side effect: it is a promising immunomodulator that may mitigate the severity of sepsis. This motivated us to study in rats the effect of CMG (25 mg/kg), injected into the tail vein at 48 and 24 h prior to the administration of 5 mg/kg Escherichia coli 0127.B8 endotoxin on survival, hemodynamic condition, and, in vitro, on the chemiluminescence of PMNs and macrophages, and on macrophagal tumor necrosis factor (TNF) production. Acetylated low density lipoprotein (AcLDL) clearance in vivo and in vitro binding to macrophages was used to study scavenger receptor function. In the nonpretreated group 9 of 10 rats died during the first 24 h after endotoxin, but all CMG-pretreated rats survived. CMG-pretreatment prevented severe decreases in cardiac output and blood pressure after endotoxin. Chemiluminescence of macrophages and PMNs from CMG-pretreated rats was about two times less (p < .05) than that from nonpretreated ones; the endotoxin induced TNF production by macrophages also decreased. Pretreatment with CMG increased, but coinjection of CMG and AcLDL decreased the AcLDL clearance, while coinjection of endotoxin and AcLDL decreased the survival rate. In vitro AcLDL uptake by macrophages decreased after coinjection with CMG. Our results thus showed that CMG was protective in rat endotoxin shock, which seemed partly connected with enhancement of endotoxin clearance through scavenger receptors and to decreased TNF production.

Animals↗
PubMed1991

Domestic endotoxin exposure and clinical severity of asthma.

Endotoxins are potent pro-inflammatory substances present in several natural environments and in commercial house dust extracts. To investigate the possible effect of chronic endotoxin exposure on asthma, 28 patients with perennial chronic asthma (20 allergic to house dust mite and eight intrinsic asthmatics) were evaluated during a 4-month period (lung function, clinical and immunological criteria). At the same time, two house dust samples were collected from each patient's home to determine total house dust weight (mg/m2), endotoxin concentration and house dust mite antigen content (evaluated indirectly by guanine content with HPLC method). The mean (+/- s.d.) endotoxin concentration, as measured by quantitative Limulus assay was 2.59 (+/- 3.41) ng/mg house dust, ranging from 0.12 to 20 ng/mg. The mean guanine content was 0.13 (+/- 0.16) mg/100 mg house dust. There was no correlation between endotoxin and house dust mite concentrations. Patients were compared according to the low or high grade exposure to dust, endotoxins and guanine. Compared with patients with low grade (less than or equal to 5.6 ng/ml) exposure, subjects exposed to high endotoxin concentrations (greater than 5.6 ng/ml) showed a significant increase in dyspnea (median 2.6 vs 3.3; P less than 0.05) and treatment (median 14 vs 44.3; P less than 0.01) scores, oral corticosteroid (median 0.0 vs 13.5 mg/24 hr; P less than 0.01) and beta 2-mimetics (median four vs eight puffs/day; P less than 0.01) intake, and a significant decrease in FEV1/FVC (median 84.5 vs 67% of predicted value; P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2001

Comparison of endotoxin exposure assessment by bioaerosol impinger and filter-sampling methods.

Environmental assessment data collected in two prior occupational hygiene studies of swine barns and sawmills allowed the comparison of concurrent, triplicate, side-by-side endotoxin measurements using air sampling filters and bioaerosol impingers. Endotoxin concentrations in impinger solutions and filter eluates were assayed using the Limulus amebocyte lysate assay. In sawmills, impinger sampling yielded significantly higher endotoxin concentration measurements and lower variances than filter sampling with IOM inhalable dust samplers. Analysis of variance for repeated measures showed that this association remained after controlling for other factors such as replicate, sawmill, sawmill operation, wood type, and interaction terms. Endotoxin concentrations in the swine barns were 10-fold higher on average than in sawmills. These samples demonstrated comparable endotoxin concentration estimates for impinger and filter methods although the variability was lower using the impinger method. In both occupational settings, side-by-side replicates were more uniform for the impinger samples than for the filter samples. This study demonstrates that impinger sampling is an acceptable method for quantitation of area endotoxin concentrations. Further, when sampling is performed with impingers for airborne microorganism quantitation, these same impinger solutions can yield valid endotoxin exposure estimates, negating the need for additional filter sampling.

Air Pollutants, Occupational↗
PubMed1989

Regulation of serum tumor necrosis factor in glucocorticoid-sensitive and -resistant rodent endotoxin shock models.

Bolus injection of lethal or sublethal doses of endotoxin or lipopolysaccharide (LPS) results in the rapid and transient rise in tumor necrosis factor (TNF) levels in serum in mammals. TNF levels peak between 1 and 2 h after LPS injection in mice and guinea pigs and approach basal levels by 6 h. Although the kinetics of TNF in serum appear similar between these two species, guinea pigs respond to a lethal dose of LPS of 20 mg/kg by producing approximately 10-fold more TNF than mice do. These two endotoxin shock models also differ in their sensitivity to glucocorticoids. TNF levels in serum are not reduced in the lethal endotoxin shock model in guinea pigs after treatment with dexamethasone at 25 mg/kg. In contrast, TNF levels in mouse serum are inhibited by more than 90% after treatment with dexamethasone at 3 mg/kg. Coincident with the TNF peak in serum is a leukopenia which approaches control levels by 6 h in dexamethasone-treated mice, while remaining depressed in dexamethasone-treated guinea pigs. Treatment with dexamethasone at 25 mg/kg did not save guinea pigs from endotoxin lethality, whereas long-term survival of mice under identical conditions was apparent. These results suggest that the relative glucocorticoid resistance observed in guinea pigs is also apparent in a lethal endotoxin shock model in which dexamethasone does not modulate TNF levels or result in increased survival as occurs in mice. The lack of clear efficacy for steroid therapy in human clinical septic shock trials would suggest that the guinea pig endotoxin model may be a more predictive system than the mouse model for the identification of novel agents useful in the treatment of endotoxin shock.

Animals↗
PubMed1999

Neutralization of endotoxin in vitro and in vivo by a human lactoferrin-derived peptide.

Endotoxin (lipopolysaccharide [LPS]) is the major pathogenic factor of gram-negative septic shock, and endotoxin-induced death is associated with the host overproduction of tumor necrosis factor alpha (TNF-alpha). In the search for new antiendotoxin molecules, we studied the endotoxin-neutralizing capacity of a human lactoferrin-derived 33-mer synthetic peptide (GRRRRSVQWCAVSQPEATKCFQWQRNMRKVRGP; designated LF-33) representing the minimal sequence for lactoferrin binding to glycosaminoglycans. LF-33 inhibited the coagulation of the Limulus amebocyte lysate and the secretion of TNF-alpha by RAW 264.7 cells induced by lipid A and four different endotoxins with a potency comparable to that of polymyxin B. The first six residues at the N terminus of LF-33 were critical for its antiendotoxin activity. The endotoxin-neutralizing capacity of LF-33 and polymyxin B was attenuated by human serum. Coinjection of Escherichia coli LPS (125 ng) with LF-33 (2.5 microg) dramatically reduced the lethality of LPS in the galactosamine-sensitized mouse model. Significant protection of the mice against the lethal LPS challenge was also observed when LF-33 (100 microg) was given intravenously after intraperitoneal injection of LPS. Protection was correlated with a reduction in TNF-alpha levels in the mouse serum. These results demonstrate the endotoxin-neutralizing capability of LF-33 in vitro and in vivo and its potential use for the treatment of endotoxin-induced septic shock.

Amino Acid Sequence↗
PubMed1998

Induction of Mn SOD in human monocytes without inflammatory cytokine production by a mutant endotoxin.

Endotoxin selectively induces monocyte Mn superoxide dismutase (SOD) without affecting levels of Cu,Zn SOD, catalase, or glutathione peroxidase. However, little is known about the structure-activity relationship and the mechanism by which endotoxin induces Mn SOD. In this study we demonstrated that a mutant Escherichia coli endotoxin lacking myristoyl fatty acid at the 3' R-3-hydroxymyristate position of the lipid A moiety retained its full capacity to coagulate Limulus amoebocyte lysate compared with the wild-type E. coli endotoxin and markedly stimulated the activation of human monocyte nuclear factor-kappaB and the induction of Mn SOD mRNA and enzyme activity. However, in contrast to the wild-type endotoxin, it failed to induce significant production of tumor necrosis factor-alpha and macrophage inflammatory protein-1alpha by monocytes and did not induce the phosphorylation and nuclear translocation of mitogen-activated protein kinase. These results suggest that 1) lipid A myristoyl fatty acid, although it is important for the induction of inflammatory cytokine production by human monocytes, is not necessary for the induction of Mn SOD, 2) endotoxin-mediated induction of Mn SOD and inflammatory cytokines are regulated, at least in part, through different signal transduction pathways, and 3) failure of the mutant endotoxin to induce tumor necrosis factor-alpha production is, at least in part, due to its inability to activate mitogen-activated protein kinase.

Chemokine CCL4↗
PubMed1988

Regional lactate production in early canine endotoxin shock.

High serum lactate may not reflect the severity of endotoxin shock: the lactate load could even be formed immediately after the endotoxin challenge. During the first 30 min after endotoxin injection (Escherichia coli; 1.5 mg/kg iv) into anesthetized dogs (4 mg.kg-1.h-1 etomidate, n = 19) we studied arterial lactate concentration; contributions of portal and splanchnic (n = 6), renal and pulmonary (n = 7), and femoral (n = 6) vascular beds to the early lactate rise; and regional O2 extraction and blood flow (microspheres). In control dogs (n = 5, no endotoxin), we found no significant hemodynamic and biochemical changes. Endotoxin caused an immediate decrease in blood pressure, cardiac output, and organ perfusion, followed by recovery after approximately 5 min to approximately 75% of preshock values at t = 30 min (except for renal blood flow, which remained low). Arterial lactate concentration started to increase almost immediately after endotoxin and increased rapidly until t = 15 min (to 300%) and then leveled off, but in spite of the hemodynamic recovery it remained elevated. A major part of the early increase in lactate concentration can be explained by splanchnic lactate production. The total splanchnic bed released more lactate than the portal bed, indicating that the liver produces lactate. We conclude that the lactate concentration later in canine endotoxin shock depends on events that occur during early shock in which the liver may play a crucial role.

Animals↗
PubMed2003

Subchronic endotoxin inhalation causes persistent airway disease.

The endotoxin component of organic dusts causes acute reversible airflow obstruction and airway inflammation. To test the hypothesis that endotoxin alone causes airway remodeling, we have compared the response of two inbred mouse strains to subchronic endotoxin exposure. Physiological and biological parameters were evaluated after 1 day, 5 days, or 8 wk of exposure to endotoxin [lipopolysaccharide (LPS)] in endotoxin-sensitive (C3HeB/FeJ) and endotoxin-resistant (C3H/HeJ) mice. After 5 days or 8 wk of LPS exposure, only C3HeB/FeJ had elevated airway hyperreactivity to inhaled methacholine. Only the C3HeB/FeJ mice had significant inflammation of the lower respiratory tract after 1 day, 5 days, or 8 wk of LPS exposure. Stereological measurements of small, medium, and large airways indicated that an 8-wk exposure to LPS resulted in expansion of the submucosal area only in the C3HeB/FeJ mice. Cell proliferation as measured by bromodeoxyuridine incorporation contributed to the expansion of the submucosa and was only significantly elevated in C3HeB/FeJ mice actively exposed to LPS. C3HeB/FeJ mice had significantly elevated levels of interleukin-1beta protein in whole lung lavage after 1 day and 5 days of LPS exposure and significantly elevated protein levels of total and active transforming growth factor-beta1 in whole lung lavage fluid after 5 days of LPS exposure. Our findings demonstrate that subchronic inhalation of LPS results in the development of persistent airway disease in endotoxin-responsive mice.

Administration, Inhalation↗
PubMed2000

Free radical-mediated transgene inactivation of macrophages by endotoxin.

Endotoxin, the lipopolysaccharide component of gram-negative bacteria, is a common contaminant of plasmid DNA preparations. The present study investigated the effect of endotoxin on gene transfection efficiency and the role of reactive oxygen species (ROS) in this process. Gene transfection studies were performed in various cell types with cytomegalovirus-luciferase as a reporter plasmid and cationic liposome as a transfecting agent. The presence of endotoxin in plasmid DNA preparations severely limited transgene expression in macrophages but had little or no effect in other cell types tested. This decreased transfection was dependent on ROS-mediated cellular toxicity induced by endotoxin. Neutralizing the endotoxin by the addition of polymyxin B effectively increased transfection efficiency and reduced toxicity. Electron spin resonance studies confirmed the formation of ROS in endotoxin-treated cells and their inhibition by free radical scavengers. The ROS scavenger N-t-butyl-alpha-phenylnitrone, the H(2)O(2) scavenger catalase, and the.OH scavenger sodium formate effectively inhibited endotoxin-induced effects, whereas the O(2)(-) scavenger superoxide dismutase had lesser effects. These results indicate that multiple oxidative species are involved in the transfection inactivation process and that.OH formed by H(2)O(2)-dependent, metal-catalyzed Fenton reaction play a major role in this process.

Animals↗
PubMed1986

Mechanisms of endotoxin-induced impairment in Na+-Ca2+ exchange in canine myocardium.

Effects of endotoxin administration on the Na+-Ca2+ exchange in canine cardiac sarcolemma were characterized. In addition, roles of phospholipase A2 and phosphorylation on the endotoxin-induced impairment in Na+-Ca2+ exchange were investigated. The results show that intravesicular sodium (Nai+)-dependent 45Ca2+ uptake was decreased by 39-66% (P less than 0.05) and extravesicular sodium (Nao+)-induced 45Ca2+ efflux was decreased by 36-52% (P less than 0.05) at 2 h following endotoxin administration. Ca2+o-induced 45Ca2+ efflux in the absence of Ko+ was not affected, but Ca2+o-induced 45Ca2+ efflux in the presence of Ko+ was significantly reduced by endotoxin administration. The stoichiometry of Na+-Ca2+ exchange was altered from 3 Na+ for 1 Ca2+ for the control to 2 Na+ for 1 Ca2+ for the endotoxin-treated dogs. The ATP-dependent 22Na+ uptake and Na+-Ca2+ exchange in inside-out vesicles remained unchanged after endotoxin injection. Digestion of control heart sarcolemmal vesicles with exogenous phospholipase A2 (0.02-0.06 unit/500 micrograms protein) inhibited Na+-Ca2+ exchange activity measured as Nai+-dependent 45Ca2+ uptake, and the inhibition was concentration dependent. Lysophosphatidylcholine addition to the control cardiac sarcolemma had no effect on Na+-Ca2+ exchange. The inhibition of Na+-Ca2+ exchange caused by phospholipase A2 digestion in the control heart sarcolemma was completely reversible by the addition of phosphatidylcholine (0.1 mM). The inhibition of Na+-Ca2+ exchange caused by the in vivo administration of endotoxin was completely reversible by the addition of phosphatidylcholine (0.1-0.15 mM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphatases↗
PubMed2003

Circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response produced by peripheral E. coli challenge.

Peripheral administration of a variety of inflammatory stimuli, such as endotoxin or cytokines, induces an orchestrated set of brain-mediated events referred to as the sickness response. The mechanism for how immune products signal the brain is not clear, but accumulating evidence supports the existence of neural as well as blood-borne pathways. Although endotoxin or cytokine administration results in sickness responses, few data exist regarding the role of circulating endotoxin or cytokines in the induction of sickness during a real bacterial infection. Thus the present studies examined whether subcutaneously administered Escherichia coli can activate sickness responses and whether circulating endotoxin and/or proinflammatory cytokines are a prerequisite for these responses. Male Sprague-Dawley rats were injected subcutaneously with one of three doses (2.5 x 10(7), 2.5 x 10(8), 2.5 x 10(9) colony-forming units) of replicating E. coli, a ubiquitous bacterial strain, or vehicle. Core body temperature (Tc) and activity were measured for 3 days after the injection. A second set of groups of animals were killed 3, 6, 12, 18, 24, and 48 h after the injection, and blood samples and brains were collected. Injections dose dependently and consistently increased Tc and decreased activity, with increases in Tc beginning 4 h after the injection. In addition, E. coli significantly increased serum interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha and brain IL-1beta levels beginning at the 6-h time point. Corticosterone and endotoxin were first elevated in the circulation at 3 and 18 h after the injection, respectively. Because fever onset preceded brain cytokine induction, we also examined cytokine levels in the serum, brain, and inflammation site 2 and 4 h after injection. Cytokines were elevated at the inflammation site but were not detectable in the serum or brain at 2 and 4 h. We conclude that subcutaneous injection of replicating E. coli induces a consistent and naturalistic infection that includes features of the sickness response as well as increases in circulating, brain, and inflammation site tissue cytokines. In addition, injection of replicating E. coli produces a robust fever and corticosterone response at a time when there are no detectable increases in circulating cytokines or endotoxin. These results suggest that elevated levels of circulating cytokines and endotoxin are not necessary for the activation of the sickness or corticosterone response. Therefore, fever, activity reduction, and corticosterone elevation induced by E. coli infection may have been evoked by a neural, rather than a humoral, pathway from the periphery to the brain.

Animals↗
PubMed2002

Prolonged apneas and hypoxia mediated by nicotine and endotoxin in piglets.

OBJECTIVE: Infections and maternal smoking are risk factors for SIDS, and toxins from common bacteria have been proposed as a causative link between infections and SIDS. Nicotine can be transferred in significant amounts postnatally to the infant through environmental tobacco smoke or maternal smoking before nursing. We investigated the acute effects of nicotine and endotoxin on repeated apnea by laryngeal reflex stimulation and the following autoresuscitation. DESIGN: Thirty-four 1-week-old (+/- 1 day) piglets were sedated and randomized to 1 of 4 pretreatment groups: (1) 1 microg endotoxin i.v./kg; (2) 5 microg nicotine i.v./kg; (3) 1 microg endotoxin i.v./kg and 5 microg nicotine i.v./kg, and (4) placebo. Apnea was induced by insufflation of 0.1 ml of acidified saline (pH 2) in the subglottic space of the trachea three times with intervals of 2 min. RESULTS: Pretreatment with endotoxin caused a significant increase in plasma TNF-alpha in the endotoxin groups (mean value +/- SEM 953 +/- 246 and 980 +/- 226 pg/ml, respectively) but no significant change in plasma IL-1 beta. Blood pressure, respiratory rate or S(a)O(2) was not significantly affected before induced apnea. Both pretreatment with nicotine and endotoxin caused prolonged apneas by 35-45%, a complete loss of normal hyperventilation during autoresuscitation, and prolonged hypoxia after apnea. CONCLUSIONS: Nicotine and endotoxin interferes with autoresuscitation after apnea. This experimental model on piglets may shed light over important mechanisms involved in the causation of SIDS.

Animals↗
PubMed1997

Changes in mononuclear phagocyte microtubules after endotoxin stimulation. II. Changes in microtubule composition.

Microtubules are integral components of the cytoskeleton of human cells and are composed of alpha- and beta-tubulin as well as a variable number of microtubule-associated proteins. In monocytes and macrophages, microtubules bind endotoxin and partly regulate endotoxin-induced inflammatory events such as cytokine production. Endotoxin causes a rapid alteration in monocyte microtubule stability. To characterize the effect of endotoxin on mononuclear phagocyte microtubule composition, Western blots and flow cytometry were performed on human monocytes and the monocyte/macrophage-like cell line THP-1. Compared to unstimulated monocytes, monocytes stimulated with endotoxin for 18 h had increased quantities of alpha-, beta-, and tyrosinated alpha-tubulin as well as microtubule-associated protein-2. PMA-differentiated THP-1 cells had increased levels of alpha-tubulin, beta-tubulin, microtubule-associated protein-5, microtubule-associated protein-2, and tau after endotoxin stimulation. These results indicate that endotoxin can alter mononuclear phagocyte microtubules by causing an increase in certain microtubule component proteins.

Blotting, Western↗
PubMed1974

Stimulation of heme oxygenase in macrophages and liver by endotoxin.

In rat peritoneal macrophages, engaged in erythrophagocytosis in vitro, endotoxin stimulated heme oxygenase (HO) activity, which was additive to the substrate-mediated enzyme induction produced by the ingested erythrocyte hemoglobin. Endotoxin neither appeared to injure the erythrocytes, nor did it enhance the rate of erythrophagocytosis. In intact rats, HO activity in both parenchymal and sinusoidal cells of the liver was increased after treatment with endotoxin. It is likely that endotoxin directly stimulates HO activity, a process which may account for the reported rise in bilirubin formation in endotoxin-treated animals. The effect of endotoxin on HO may represent part of the general activation of phagocytic cells by endotoxin.

Animals↗
PubMed2006

Increment of plasma soluble CD14 level in carrageenan-primed endotoxin shock model mice.

CD14 is membrane-associating or free soluble glycoprotein which recognizes lipopolysaccharide (LPS) and is assumed to be involved in the onset of endotoxin shock. There are some reports suggesting the relationship between increased expression of CD14 in infectious or inflammatory diseases. However, little has been reported concerning the soluble CD14 (sCD14) level, especially in mice. In this study, we measured the plasma level of sCD14, TNF-alpha and IL-6 in the iota-carrageenan (CAR)-primed endotoxin shock model in addition to the D-galactosamine (D-galN)-primed endotoxin shock model mice. It was confirmed that all mice were dead within 12 h after a higher dose of LPS-treatment in both animal models. The level of TNF-alpha, IL-6 and sCD14 significantly increased in the CAR-primed endotoxin shock model mice. However, the D-galN-primed endotoxin shock model mice showed only a slight increment of TNF-alpha and IL-6 level, and sCD14 was below the detectable level. In the examination using several doses of LPS in CAR-primed model mice, IL-6 and sCD14 were increased dependent on the LPS dose, but TNF-alpha remained at an almost equal level at any dose of LPS in this study condition. In conclusion, the production of TNF-alpha, IL-6 and sCD14 was significantly enhanced in the CAR-primed model mice, compared to the D-galN-primed model mice. Therefore, these data indicate the possibility that the sCD14 level did not increase consistently, even under a fatal condition in endotoxin shock. Also, CAR-primed endotoxin shock would be an important experimental model to examine the elevation mechanisms for sCD14 and IL-6 production.

Animals↗
PubMed2001

Comparison of heartworm extract-induced shock and endotoxin-induced shock in dogs by determination of serum tumor necrosis factor concentrations.

OBJECTIVE: To compare the mechanisms of heartworm (HW) extract-induced shock and endotoxin-induced shock in dogs by determination of serum tumor necrosis factor (TNF) concentrations. ANIMALS: 11 mixed-breed dogs (7 without and 4 with HW infections). PROCEDURE: Eight dogs were treated with 2 ml of HW extract IV, and 3 dogs were given endotoxin (Escherichia coli lipopolysaccharide [LPS]) at 40 or 400 microg/kg of body weight, IV. Changes in clinical and hematologic findings and serum TNF concentrations were examined from before treatment to 120 minutes after treatment in dogs given HW extract or from before treatment to 180 minutes after treatment in dogs given LPS. Tumor necrosis factor concentration was determined by cytotoxic assay, using WEHI-164 murine sarcoma cells, and plasma endotoxin concentration was determined in 2 dogs treated with HW extract, using the endotoxin-specific chromogenic test. RESULTS: Eight dogs developed shock 3 to 16 minutes after HW extract treatment. Rectal temperature did not change during examination. Serum TNF concentration was detected at a low concentration only 60 and 120 minutes after HW extract treatment, and plasma endotoxin was not detected during examination. In dogs treated with LPS, rectal temperature increased to > 40 C in 2 of 3 dogs, and serum TNF concentration began to increase 30 minutes after LPS treatment, reaching a maximum concentration by 60 minutes. CONCLUSIONS: The cause and mechanism of HW extract-induced shock may be different from those of endotoxin-induced shock, because TNF, which was a pivotal mediator in endotoxin-induced shock, increased minimally in serum of dogs treated with HW extract.

Animals↗
PubMed2002

The role of endotoxin, TNF-alpha, and IL-6 in inducing the state of growth hormone insensitivity.

AIM: Critical illnesses such as sepsis, trauma, and burns cause a growth hormone insensitivity, which leads to an increased negative nitrogen balance. Endotoxin is generously released into blood under these conditions and stimulates the production of proinflammatory cytokines such as TNF-alpha, IL-6, and IL-1, which may play a very important role in inducing the growth hormone insensitivity. The objective of this current study was to investigate the role of endotoxin, TNF-alpha and IL-6 in inducing the growth hormone insensitivity at the receptor and post-receptor levels. METHODS: Spague-Dawley rats were injected with endotoxin, TNF-alpha, and IL-6, respectively and part of rats injected with endotoxin was treated with exogenous somatotropin simultaneously. All rats were killed at different time points. The expression of IGF-I, GHR, SOCS-3 and beta-actin mRNA in the liver was detected by RT-PCR and the GH levels were measured by radioimmunoassay, the levels of TNF-alpha and IL-6 were detected by ELISA. RESULTS: There was no significant difference in serous GH levels between experimental group and control rats after endotoxin injection, however, liver IGF-I mRNA expression had been obviously down-regulated in endotoxemic rats. Liver GHR mRNA expression also had a predominant down-regulation after endotoxin injection. The lowest regulation of liver IGF-I mRNA expression occurred at 12h after LPS injection, being decreased by 53% compared with control rats. For GHR mRNA expression, the lowest expression occurred at 8h and had a 81% decrease. Although SOCS-3 mRNA was weakly expressed in control rats, it was strongly up-regulated after LPS injection and had a 7.84 times increase compared with control rats. Exogenous GH could enhance IGF-I mRNA expression in control rats, but it did fail to prevent the decline in IGF-I mRNA expression in endotoxemic rats. Endotoxin stimulated the production of TNF-alpha and IL-6, and the elevated IL-6 levels was shown a positive correlation with increased SOCS-3 mRNA expression. The liver GHR mRNA expression was obviously down-regulated after TNF-alpha iv injection and had a 40% decrease at 8h, but the liver SOCS-3 mRNA expression was the 4.94 times up-regulation occurred at 40 min after IL-6 injection. CONCLUSION: The growth hormone insensitivity could be induced by LPS injection, which was associated with down-regulated GHR mRNA expression at receptor level and with up-regulated SOCS-3 mRNA expression at post-receptor level. The in vivo biological activities of LPS were mediated by TNF-alpha and IL-6 indirectly, and TNF-alpha and IL-6 may exert their effects on the receptor and post-receptor levels respectively.

Animals↗