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PubMed1990

Direct effects of endotoxin on the function of the isolated perfused rat kidney.

When the endotoxin-lipopolysaccharide (LPS) derived from the cell wall of gram-negative bacteria is given to the rat in vivo, there are prompt, marked decreases in glomerular filtration rate (GFR), renal blood flow (RBF) and % Na+ reabsorption (%T-Na+). However, it has not been determined whether the endotoxin itself has a direct effect on these renal functions. To test whether endotoxin has a direct renal effect, isolated rat kidneys (N = 8) were perfused for 160 minutes with a Krebs-Ringer-HCO3- solution containing substrate-free albumin (40 g/liter), glucose (5 mM) and L(+) lactate (7.5 mM). After control observations (20 to 80 min) were made, purified LPS from E. coli was added (N = 4) to the perfusate to achieve [endotoxin] of 0.01 micrograms/ml (80 to 120 min) and 0.1 micrograms/ml (120 to 160 min). Endotoxin had no effect on GFR, Na+ reabsorption or tissue K+ content when compared to timed-control perfusions (N = 4). There was a small (approximately 10%) but significant decrease in mean perfusion flow rate (PFR) at the highest [endotoxin] when compared to the low [endotoxin]p but no change in GFR occurred. When the same LPS was given to four rats in vivo at a dose which achieved an [endotoxin] of approximately 0.08 micrograms/ml plasma, there were prompt decreases in GFR and %T-Na+ and an increase in body temperature when compared with timed-controls; there also was a large loss of K+ from the kidney tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1990

Reactive oxygen metabolites in endotoxin-induced acute renal failure in rats.

Based on recent reports that reactive oxygen metabolites may play a role in endotoxin-induced injury in other tissues, we postulated that reactive oxygen metabolites may be important mediators of endotoxin-induced acute renal failure. Superoxide dismutase, a scavenger of superoxide, or catalase, which destroys hydrogen peroxide, did not protect against endotoxin-induced renal failure. Similarly, neither the hydroxyl radical scavenger dimethylthiourea nor the iron chelator deferoxamine (which presumably would act by preventing the generation of hydroxyl radical via the iron-catalyzed Haber-Weiss reaction) prevented the endotoxin-induced fall in renal function. In separate experiments, we found no increase in renal cortical lipid peroxidation (a marker of reactive oxygen metabolite-mediated tissue injury) in endotoxin-treated rats, providing further evidence against a role for reactive oxygen metabolites in endotoxin-induced renal injury. Finally, using the aminotriazole-induced inhibition of catalase (a measure of in vivo changes in the hydrogen peroxide generation) we found no evidence of enhanced hydrogen peroxide generation in the renal cortex in endotoxin-treated rats. Taken together, the data from these three separate experimental approaches suggest that reactive oxygen metabolites are not important mediators of endotoxin-induced acute renal failure.

Acute Kidney Injury↗
PubMed2001

Inhibition of DNA synthesis in cultured hepatocytes by endotoxin-conditioned medium of activated stellate cells is transforming growth factor-beta and nitric oxide-independent.

Activated hepatic stellate cells play a major role in the pathophysiology of chronic liver disease. They can influence the metabolism of hepatocytes by producing a variety of cytokines and growth factors. Upon stimulation with endotoxin, stellate cells also synthesize nitric oxide (NO), a potent mediator of growth of several cell types including hepatocytes. We investigated the effect of serum-free medium conditioned by activated stellate cells in the absence and presence of endotoxin on NO and DNA synthesis in hepatocytes. Stellate cells and hepatocytes were isolated by enzymatic digestion of the liver. Stellate cells were cultured for 10 days after which the majority exhibited alpha-smooth muscle actin (a marker for activated cells); hepatocytes were used after overnight culture. While the medium conditioned by stellate cells in the absence of endotoxin stimulated DNA synthesis in hepatocytes, medium conditioned in its presence inhibited this process in an endotoxin concentration-dependent manner (10 - 1000 ng ml(-1)). Endotoxin-conditioned stellate cell medium also stimulated NO synthesis in hepatocytes; the effect was consistent with increased protein and mRNA expression of inducible NO synthase (iNOS). However, inhibition of DNA synthesis in hepatocytes caused by endotoxin-conditioned stellate cell medium was unaffected by the NOS inhibitor, L-N(G)-monomethylarginine (L-NMMA), guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and neutralizing antibodies for TGF-beta, IL-1beta, IL-6 and TNF-alpha. These results indicate that factors other than these cytokines produced by activated stellate cells upon stimulation with endotoxin or by hepatocytes challenged with endotoxin-conditioned stellate cell medium inhibit DNA synthesis in hepatocytes.

Animals↗
PubMed2004

Exposure to wood dust and endotoxin in small-scale wood industries in Tanzania.

Workers in small-scale wood industries (SSWI) have increased risks of developing asthma and other respiratory diseases. Wood dust and microbial agents have both been suggested to play a role, but few studies have measured endotoxin exposure in SSWI in Africa. We assessed inhalable dust levels in 281 samples from 115 workers and bacterial endotoxins levels in 157 samples from 136 workers from SSWI in Dar es Salaam, Tanzania. The overall geometric mean of personal exposure was 3.3 mg/m(3); geometric standard deviation (GSD) 2.5; range 0.45-67.0 mg/m(3)) and 91 EU/m(3) (GSD 3.7; range 9-4914.8 EU/m(3)) for wood dust and endotoxins, respectively. Dust and endotoxin levels were weakly correlated (r = 0.44, n = 157, P < 0.0001). Between- and within-worker variances and percentages explained by the differences among job titles and seasons were 0.31 (9%) and 0.35 (30%), respectively, for wood dust exposure, and 0.35 (0%) and 0.35 (38%) for endotoxin exposure. Higher dust and endotoxin exposure levels were observed in the dry compared to the wet season, after correcting for differences in exposure between jobs. Carving and manual cleaning were associated with the highest dust exposures. Sewing seat covers and manual cleaning were associated with the highest endotoxin exposures. Dust and endotoxin exposure levels in SSWI are high and appropriate control measures are necessary.

Air Pollution↗
PubMed1999

Kupffer cell blockade, tumour necrosis factor secretion and survival following endotoxin challenge in experimental biliary obstruction.

BACKGROUND: Gram-negative sepsis and its sequelae frequently complicate invasive procedures in patients with obstructive jaundice. In response to endotoxin, Kupffer cells secrete tumour necrosis factor (TNF), a pivotal early mediator of sepsis. An investigation was carried out into the specific role of Kupffer cell TNF secretion following endotoxin challenge in obstructive jaundice. METHODS: Survival following intraperitoneal administration of endotoxin (2.0, 0.02 and 0.0002 mg per 100 g) was determined in rats following bile duct ligation (BDL) or sham operation. Plasma TNF concentration was quantified following endotoxin administration (0.0002 mg per 100 g) at 1, 2 and 6 h. Subsequently, the effect of Kupffer cell blockade by gadolinium chloride on survival and plasma TNF concentration was assessed. RESULTS: Jaundiced animals showed a significantly increased mortality rate following intraperitoneal injection of endotoxin 2.0 mg per 100 g (BDL 100 per cent versus sham 0 per cent) and 0.02 mg per 100 g (BDL 70 per cent versus sham 0 per cent; P = 0. 002, Fisher's exact test). Median plasma TNF concentration was significantly greater in jaundiced animals 1 h after endotoxin administration (BDL 943 (interquartile range (i.q.r.) 211-3900) pg/ml versus sham 64 (i.q.r. 47-127) pg/ml; P = 0.002, Mann-Whitney U test). Kupffer cell blockade with gadolinium chloride increased the survival rate following endotoxin administration in BDL animals (BDL-GdCl3 100 per cent versus BDL-saline 40 per cent; P = 0.0003, Fisher's exact test) and decreased median plasma levels of TNF (BDL-GdCl3 88 (i.q.r. 0-1065) pg/ml versus BDL-saline 16 550 (1255-29 360) pg/ml; P = 0.002, Mann-Whitney U test). CONCLUSION: Kupffer cell blockade improved survival and suppressed systemic TNF activity after endotoxin challenge. In obstructive jaundice, hypersecretion of TNF by Kupffer cells may supplement systemic cytokine production and be responsible for significant complications.

Animals↗
PubMed2000

Preventive effect of preoperative portal vein ligation on endotoxin-induced hepatic failure in hepatectomized rats is associated with reduced tumour necrosis factor alpha production.

BACKGROUND: Preoperative portal vein embolization successfully reduces the incidence of postoperative hepatic failure in which endotoxin is postulated to be involved. To identify the mechanism of this preventive effect, the relationship of endotoxin-induced liver injury with tumour necrosis factor (TNF) alpha and nitric oxide production in the peripheral blood, liver and spleen of rats subjected to preoperative portal vein branch ligation (PVL) was compared with that in rats undergoing sham operation. METHODS: Rats with PVL and those that underwent sham operation were subjected to resection of ligated liver lobes (PVL-Hx rats) and two-thirds hepatectomy (noPVL-Hx rats) respectively at day 5, followed by intravenous administration of endotoxin 200 microgram/kg body-weight at day 7. At various time intervals after endotoxin injection, the peripheral blood, liver and spleen tissues were harvested and analysed for TNF-alpha and nitric oxide production. RESULTS: The survival rates of noPVL-Hx and PVL-Hx rats at 48 h after endotoxin administration were 40 and 100 per cent respectively. The former rats showed more extensive liver injury as represented by higher serum aminotransferase and hyaluronate levels than the latter. Plasma concentrations of TNF-alpha at 1.5 h after endotoxin treatment were significantly higher in noPVL-Hx rats (mean(s.e.m.) 22 125(2175) pg/ml; n = 6) than PVL-Hx rats (8344(4076) pg/ml; n = 6) (P < 0.01). Consistent with this, expression of TNF-alpha messenger RNA in the liver and spleen was suppressed in PVL-Hx rats. In two-thirds hepatectomized rats, plasma TNF-alpha concentrations after endotoxin administration at 1, 2 and 3 days (14 350(2186), 26 375(2478) and 23 000(3745) pg/ml respectively; n = 6 each) were significantly higher than that before operation (9067(1559) pg/ml; n = 6) (P < 0.05), whereas those at 5 and 7 days (10 102(3616) and 8580(1427) pg/ml respectively; n = 6 each) showed no significant increase. Furthermore, nitric oxide production in peripheral blood and liver was suppressed by preoperative PVL. CONCLUSION: Prevention of endotoxin-induced liver failure by preoperative PVL is associated with reduced production of TNF-alpha in the later phase of liver regeneration.

Animals↗
PubMed2003

Early endotoxin exposure and atopy development in infants: results of a birth cohort study.

BACKGROUND: Exposure to endotoxin in childhood is currently discussed to protect from the development of allergic diseases. OBJECTIVE: To study the effect of early endotoxin exposure on incidence of atopic sensitization, atopic dermatitis and wheezing until the age of 2 years in infants with different risk status in terms of parental atopy. METHODS: Data of 1942 infants of an ongoing birth cohort study were analysed by logistic regression. Endotoxin was measured in settled dust of the mothers' mattresses at infants' age of 3 months. Data on allergic symptoms and physicians' diagnoses were gathered by questionnaire. Sensitization to common food and inhalant allergens was assessed by specific serum IgE. RESULTS: High endotoxin levels increased the risk of repeated wheeze [adjusted odds ratio (OR) for 4th exposure quartile (Q4) 1.52, 95% confidence interval (CI) 1.08-2.14], but were associated with neither sensitization to food allergens nor atopic dermatitis. Stratification by parental atopy showed that there was an association of endotoxin exposure with incidence of repeated wheeze as well as with sensitization to inhalant allergens (P for trend = 0.008 and 0.044, respectively) only in infants with parental atopy, with the highest risk in the 4th exposure quartile (repeated wheeze: ORQ4 1.77, 95% CI 1.14-2.73; sensitization to inhalant allergens: ORQ4 1.69, 95% CI 0.70-4.11). CONCLUSION: Early endotoxin exposure in terms of mattress dust endotoxin levels seemed to increase the risk of atopic reactions to inhalant allergens at the age of 2 years, especially in infants at risk due to parental atopy. Our data disagree with an early protective effect of endotoxin on atopy development until the age of 2 years.

Bedding and Linens↗
PubMedDate not supplied

Effects in humans of intravenously administered endotoxin on soluble cell-adhesion molecule and inflammatory markers: a model of human diseases.

1. Endotoxin, a component of the cell wall of Gram-negative bacteria, could be a predisposing mediator of many pathological disorders. The present study was undertaken to determine the effects and time-course of acute endotoxin challenge on inflammatory and cell-adhesion molecule markers shedding in the plasma as potential surrogates. 2. Six normal male subjects per group (age range 21-35 years) were injected with 4 ng/kg, i.v., reference standard Escherichia coli (0113:h10:k) endotoxin or physiological saline. 3. Plasma inflammatory markers (tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and TNF-receptor I (RI)) and cell-adhesion molecule markers (soluble L-selectin, soluble P-selectin, soluble vascular cell adhesion molecule (VCAM)-1) were determined using sensitive and specific ELISA. 4. Tumour necrosis factor-alpha increased from a basal level of 2.8 pg/mL to approximately 800 pg/mL at 90 min after endotoxin. Similarly, IL-6 peaked 2-3 h after endotoxin injection, with a rapid decline by 6-8 h, and levels returned to basal values by 24 h. 5. In contrast, TNF-RI peaked at 2 h (increasing from basal levels of 900-3300 pg/mL) with a much slower decline and without return to basal levels at 24 h (1400 pg/mL). 6. Endotoxin resulted in a rapid rise in soluble L-selectin within 1 h, which increased from a basal of 150-425 ng/mL. This rapid rise in soluble L-selectin was sustained for up to 2.5 h and then rapidly declined to basal levels by 3.5 h. 7. In contrast, plasma soluble P-selectin levels showed a delayed and progressive increase up to 8 h (increasing from a basal level of 50-95 ng/mL), with a partial decline at 24 h (80 ng/mL). 8. Similarly, soluble VCAM-1 levels showed a progressive rise up to 24 h (increasing from basal values of 600-1000 ng/mL). 9. This acute human model of endotoxin exposure demonstrated an upregulation of inflammatory stimuli leading to a short-term hyperactivation of leucocytes and a more sustained activation of platelets and endothelium. 10. This model provides a non-invasive method for studying the complex effects of endotoxin-like pathogens on different cellular events using soluble plasma surrogate markers.

Adult↗
PubMed2001

Endotoxin treatment causes an upregulation of the endothelin system in the liver: amelioration of increased portal resistance by endothelin receptor antagonism.

BACKGROUND: Mechanisms underlying hepatic microcirculatory failure during endotoxemia are incompletely understood. Because endothelin-1 (ET-1) has been implicated in endotoxin-induced liver injury, we investigated the hepatic ET-1 system in endotoxin-treated rats. METHODS: Rats were treated with endotoxin (Escherichia coli lipopolysaccharide; 3 mg/kg, i.p.), and various determinations were made 24 h later. RESULTS: Endotoxin treatment caused 11.2 +/- 1.6% weight loss, a decrease in mean arterial pressure (MAP; 96 +/- 5 mmHg vs 108 +/- 3 mmHg; P < 0.05) and an increase in portal pressure (11.6 +/- 1.3 mmHg vs 7.4 +/- 1 mmHg; P < 0.02). No significant changes in the serum levels of liver enzymes or hepatocellular necrosis were observed. Endotoxin caused increases in hepatic ET-1 (from 345 +/- 31 to 565 +/- 38 pg/g; P < 0.01), ET-1 receptor density (from 179 +/- 16 to 340 +/- 26 fmol/mg; P < 0.02), and mRNA expression of preproendothelin-1, and ET(A) and ET(B) receptors. While the serum nitric oxide (nitrite +/- nitrate) concentration was increased in endotoxin-treated rats, that of ET-1 remained unchanged. A mixed ET(A)/ET(B) receptor antagonist, TAK-044 (10 mg/kg, i.v.), reduced the weight loss from 11.2 +/- 1.6% to 5.9 +/- 2.9% (P < 0.05) and the portal pressure from 11.6 +/- 1.3 mmHg to 8.6 +/- 0.7 mmHg (P < 0.05) in endotoxin-treated rats. The mixed ET(A)/ET(B) receptor antagonist also caused an increase in serum ET-1 concentration, but did not affect serum nitric oxide and MAP in endotoxin-treated rats. CONCLUSIONS: These results suggest that the upregulated hepatic ET-1 system is an important mechanism of increased portal resistance and related complications of endotoxemia.

Animals↗
PubMed2002

Endotoxin removal by direct hemoperfusion with an adsorbent column using polymyxin B-immobilized fiber ameliorates systemic circulatory disturbance in patients with septic shock.

Direct hemoperfusion (DHP) with an adsorbent column using polymyxin B-immobilized fiber (PMX-F) has been shown to improve the state of shock in patients with septic shock. However, no evidence has been presented for a direct link between endotoxin removal by DHP with PMX-F and improvement in septic shock. We retrospectively analyzed clinical profiles of 24 patients with septic shock (16 patients, gram-negative; 8 patients, non-gram-negative septic shock) who underwent DHP with PMX-F. Patients with gram-negative septic shock were characterized by hyperdynamic circulation. DHP with PMX-F reduced blood endotoxin concentrations and ameliorated shock, with an improvement in hyperdynamic circulation in patients with gram-negative septic shock. Mean arterial pressure also was elevated after therapy in patients with non-gram-negative septic shock, but systemic hemodynamics were unaffected. Regardless of the causative microorganism, patients with endotoxemia (blood endotoxin level > 10 pg/mL) showed hyperdynamic shock, and DHP with PMX-F reduced blood endotoxin levels and ameliorated hyperdynamic circulation, whereas patients without endotoxemia showed features of shock without hyperdynamic circulation, and DHP with PMX-F ameliorated shock without affecting cardiac performance. In patients with gram-negative septic shock, blood endotoxin concentration correlated positively with cardiac output and negatively with systemic vascular resistance before DHP therapy. Reduction in blood endotoxin concentration by DHP therapy positively correlated with the reduction in cardiac output. Our findings indicate that the improvement in hyperdynamic circulation was related directly to endotoxin removal by the PMX-F column, and endotoxin has an important role in the development of hyperdynamic circulation in patients with gram-negative septic shock.

Adsorption↗
PubMedDate not supplied

Dexamethasone inhibits endotoxin-induced changes in calcium and contractility in rat isolated papillary muscle.

This study investigates whether endotoxin-induced contractile dysfunction is associated with a defect in the modulation of calcium homeostasis and the potential mechanisms involved. Treatment of rats in vivo with endotoxin significantly decreased the magnitude of contractile transients in electrically stimulated left ventricular papillary muscle isolated after an equilibration period of 6 hours. Although no significant difference was found in the peak intracellular calcium concentration ([Ca2+]i) between the endotoxin-treated and control groups, resting [Ca2+]i) was significantly elevated in the endotoxin-treated group, producing a smaller Ca2+ transient (basal-peak difference) in this group. Pretreatment of rats with dexamethasone prevented the endotoxin-induced decrease in peak tension and inhibited the elevation in resting [Ca2+]i, with a resultant maintenance of Ca2+ transient magnitude. Similar observations were made during stimulation of the muscles by the beta-adrenoceptor agonist, isoprenaline. These results show that endotoxin-induced reduction of cardiac contractile performance is mediated, at least in part, by elevating resting [Ca2+]i, and a glucocorticoid protected from these negative effects. While endotoxin reduces the magnitude of the Ca2+ transient it does not alter peak [Ca2+]i availability. Further investigation is required to determine whether endotoxin decreases contractile performance by reducing the sensitivity of cardiac myofilaments to calcium.

Adrenergic beta-Agonists↗
PubMed1988

Lipoxygenase and cyclooxygenase blockade by BW755C prevents endotoxin-induced hypotension but not changes in glucose metabolism.

Arachidonic acid metabolites are mediators of various pathophysiologic events following endotoxin administration. However, their role in the endotoxin-induced increase in glucose metabolism has not been examined. Rats were administered either saline or BW755C (an inhibitor of both the cyclooxygenase and lipoxygenase pathways) 30 min prior to injection of E. coli endotoxin and whole body glucose kinetics assessed using a constant iv infusion of [6-3H] glucose. Treatment with BW755C prevented the endotoxin-induced hypotension and tachycardia. Endotoxin produced characteristic increases in the plasma glucose (23-70%) and lactate (2- to 9-fold) concentrations, as well as elevations in the rate of glucose appearance (34-63%) and metabolic clearance (40-92%). In contrast to the amelioration in hemodynamics, pretreatment with BW755C did not prevent these alterations in glucose metabolism normally seen after endotoxin. BW755C markedly reduced the endotoxin-induced increase in plasma catecholamine concentrations, but levels were still elevated 2- to 4-fold compared to control values. The results suggest that arachidonic acid metabolites mediate the early hypotensive response following endotoxin, but are not by themselves responsible for the elevated rates of glucose production and utilization.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗
PubMed1989

The cardiovascular response of normal humans to the administration of endotoxin.

Marked abnormalities in cardiovascular function accompany septic shock, and bacterial endotoxin is believed to be one of the principal mediators of these abnormalities. To evaluate the cardiovascular effects of endotoxemia in humans, we measured hemodynamic variables in nine normal subjects given an intravenous bolus dose of endotoxin (Escherichia coli, 4 ng per kilogram of body weight) and in six normal subjects given a bolus dose of saline, before and three hours after administration. All the subjects then underwent volume loading with normal saline (mean, 2217 ml) during the fourth and fifth hours after administration of the bolus, and the measurements were repeated. Three hours after the administration of endotoxin and before volume loading, the cardiac index had increased by 53 percent and the heart rate by 36 percent (both changes were significant; P less than or equal to 0.008), and the systemic vascular-resistance index had decreased by 46 percent (P = 0.004). After volume loading (five hours after the administration of endotoxin), the left ventricular ejection fraction decreased by 1 percent of the base-line value in the subjects given endotoxin, but increased by 14 percent in the controls (P = 0.008). The left ventricular end-diastolic and end-systolic volume indexes increased by 18 percent (P = 0.07) and 24 percent (P = 0.042), respectively. Left ventricular performance, as measured by the ratio of the peak systolic pressure to the end-systolic volume index, was depressed (a decrease of 0.90 in the subjects given endotoxin vs. an increase of 0.76 in the controls; P = 0.024). We conclude that the administration of endotoxin to normal subjects causes a depression of left ventricular function that is independent of changes in left ventricular volume or vascular resistance. The changes in function are similar to those observed in septic shock and suggest that endotoxin is a major mediator of the cardiovascular dysfunction in this condition.

Adult↗
PubMed2001

The abnormal lipid spectrum in malignant obstructive jaundice in relation to endotoxin sensitivity and the result of preoperative biliary drainage.

BACKGROUND: Biliary obstruction changes the spectrum of lipoproteins, which are now known to bind and neutralize endotoxin. Postoperative septic complications related to an increased susceptibility to endotoxin occur frequently in patients with obstructive jaundice. The effect of preoperative biliary drainage on changes in the lipoprotein spectrum and its relation to endotoxin sensitivity was studied. METHODS: Abnormalities in the lipoprotein spectrum were assessed in 15 patients with malignant obstructive jaundice before and 3 weeks after endoscopic biliary drainage. Changes in endotoxin responsiveness were assessed by using endotoxin-neutralizing reagents (anti-CD14 monoclonal antibody, polymyxin B, and recombinant bactericidal permeability increasing protein) to block cytokine production in whole blood cell cultures that were stimulated by cholestatic plasma taken before and after drainage. RESULTS: Drainage normalized very-low-density, low-density, and high-density lipoprotein cholesterol fractions from, respectively, 43% to 19%, 50% to 65%, and 6% to 16% (P <.01). Ex vivo stimulation of whole blood with predrainage cholestatic plasma was 20-fold higher (P <.001) than with postdrainage plasma. Blocking the endotoxin response during the stimulation with predrainage cholestatic plasma with anti-CD14 monoclonal antibody, polymyxin B or recombinant bactericidal permeability increasing protein resulted in attenuation of the inflammatory response, reducing tumor necrosis factor-alpha levels at least 5-fold. CONCLUSIONS: Preoperative biliary drainage normalizes the changed lipid profile and the endotoxin-stimulating capacity of cholestatic plasma, and this signifies a change in sensitivity to endotoxin.

Bile Ducts↗
PubMed1975

An endotoxin-induced serum factor that causes necrosis of tumors.

In studying "hemorrhagic necrosis" of tumors produced by endotoxin, it was found that the serum of bacillus Calmette--Guerin (BCG)-infected mice treated with endotoxin contains a substance (tumor necrosis factor; TNF) which mimics the tumor necrotic action of endotoxin itself. TNF-positive serum is as effective as endotoxin itself in causing necrosis of the sarcoma Meth A and other transplanted tumors. A variety of tests indicate that TNF is not residual endotoxin, but a factor released from host cells, probably macrophages, by endotoxin. Corynebacteria and Zymosan, which like BCG induce hyperplasia of the reticulo-endothelial system, can substitute for BCG in priming mice for release of TNF by endotoxin. TNF is toxic in vitro for two neoplastic cell lines; it is not toxic for mouse embryo cultures. We propose that TNF mediates endotoxin-induced tumor necrosis, and that it may be responsible for the suppression of transformed cells by activated macrophages.

Adjuvants, Immunologic↗
PubMedDate not supplied

Worker exposures to particulates, endotoxins, and bioaerosols in two refuse-derived fuel plants.

Exposures of refuse-derived fuel (RDF) production workers to total particulates, endotoxin, and total (viable plus nonviable) bioaerosols were characterized at two RDF production plants. Full-shift personal air monitoring for 35 workers was conducted for total particulates, analyzed by gravimetric analysis; endotoxin, analyzed by chromogenic endpoint assay; and total bioaerosols, analyzed by fluorescent microscopy (FM). Geometric mean values of personal air samples were 0.50 mg/m3 for total dust, 29.0 EU/m3 (2.9 ng/m3) for endotoxin, and 6.8 x 10(5) organisms/m3 for bioaerosols. Significant differences were observed between the two plants only for total endotoxin exposures. The mean concentrations for total particulates, total FM bioaerosols, and endotoxins did not differ among the day, evening, or night shifts. Interjob differences were found for exposures to total dust, total endotoxin, and FM bioaerosols. Individual comparisons for total particulates and endotoxin exposures were significant for comparisons between job categories as a result of the greater exposures for personnel cleaning the plants. Significant correlations were detected between total particulates and total endotoxin measurements and between inhalable and total particulates.

Aerosols↗
PubMed1992

Effects of endotoxin in mice bearing solid metastasizing tumors and treated with lysozyme hydrochloride.

The effects of the i.v. administration of endotoxin (6.25-50 micrograms/mouse on day 13 after tumor implantation) in mice treated orally with lysozyme hydrochloride (100 mg/kg on days 5-12 from tumor implantation) were examined using Lewis lung carcinoma in the C57Bl mouse and MCa mammary carcinoma of CBA mice. On primary tumor growth, endotoxin alone causes a dose-dependent and statistically significant reduction with a nadir on day +2 from endotoxin treatment. Combined with lysozyme, endotoxin causes an effect independent of the dose used, corresponding to the effect caused by endotoxin alone at the dose of 25 micrograms/mouse. No tumor regression was recorded in any of the treated groups. Endotoxin is virtually devoid of effects at the metastatic level. In the same conditions, lysozyme causes a reduction of primary tumor growth and a more pronounced inhibition of lung metastasis formation as expected from its already reported effects. The antitumor activity of endotoxin, unlike lysozyme, can be ascribed to tumor hemorrhagic necrosis due to tumor necrosis factor (TNF) production, as determined in tumor homogenates. Endotoxin does not increase the antitumor effects in mice treated with lysozyme, as expected from the data obtained with the more immunogenic SA1 sarcoma, although lysozyme increased the mitogenic response to ConA of ex vivo isolated splenocytes, in vitro cultured in the presence of IL-2.

Administration, Oral↗
PubMed1960

On the collapse of bacterial endotoxin resistance following hemorrhage.

Unanesthetized immature albino rabbits exposed to 2 hours of severe but reversible hemorrhagic shock induced with aseptic precautions by multiple cardiac bleedings exhibited no increase in susceptibility to single intravenous injections of 200 microg./kg. E. coli endotoxin administered 4 hours post retransfusion, a quantity of endotoxin that was found to be the largest dose uniformly non-lethal to normal rabbits. Paired and randomly selected rabbits treated identically except for the additional procedure of a femoral arterial cutdown and ligation (without aseptic precautions) exhibited increases in susceptibility to the same endotoxin of several hundredfold. This effect could not be attributed to the femoral cutdown and arterial ligation alone since such trauma when coupled with sham cardiac bleedings failed to increase susceptibility to 200 microg./kg. of endotoxin. These data appear valid since sham cardiac bleedings produced no detectable impairment of myocardial contractility, while 2 hours of hemorrhagic shock at 50 mm. Hg with the Lamson reservoir technique caused an increase in endotoxin susceptibility comparable to that seen when cardiac bleedings were combined with a non-sterile femoral arterial cutdown and ligation. The mechanisms increasing the susceptibility to E. coli endotoxin were investigated. It was found that (a) rabbit femoral skeletal muscle is normally contaminated with clostridia, (b) the use of aseptic femoral wounding precautions exerted some suggestive protective influence, (c) the use of aseptic wounding precautions combined with immediate topical sulfanilamide and wound closure exerted a significant protective influence, and (d) prophylactic polyvalent gas gangrene antitoxin protected in a manner not demonstrable when diphtheria antitoxin was employed as a control. These observations suggest that clostridial wound infection is one mechanism whereby a femoral arterial cutdown lowers endotoxin resistance of the rabbit following hemorrhagic shock. It is, however, not the only mechanism since the ligation of a femoral artery during hemorrhagic shock led to edema following retransfusion equivalent to a mean of approximately 30 per cent of the original circulating plasma volume. The intensification of shock caused by this transudation presumably intensified reticulo-endothelial injury, and thus further lowered the resistance of the rabbit to an intravenous injection of endotoxin 4 hours following retransfusion.

Animals↗