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PubMed1987

Glucose kinetics and development of endotoxin tolerance during long-term continuous endotoxin infusion.

Alterations in glucose metabolism are seen following the acute administration of lethal doses (LD) and nonlethal doses of endotoxin, but relatively little information is available concerning glucose kinetics during long-term continuous endotoxin infusion. A nonlethal dose of endotoxin was administered intravenously to catheterized rats for up to 54 hours via a subcutaneously implanted osmotic pump; time-matched control animals were saline-infused. Glucose kinetics were assessed in vivo after 6, 30, and 54 hours of endotoxin by the constant infusion of [6-3H, U-14C]-glucose. The endotoxemic animals were hemodynamically stable throughout the experimental protocol and exhibited a febrile response at six and 30 hours of endotoxin infusion. Elevations in glucose turnover (50% and 42%) and recycling (140% to 150%) were seen after six and 30 hours of endotoxin infusion, but had returned to control values by 54 hours. A major portion (53% to 62%) of the increased glucose turnover in endotoxemic rats was accounted for by the elevated rate of recycling. The increased turnover appeared to be almost entirely due to enhanced gluconeogenesis and is consistent with the 160% to 170% elevation in plasma glucagon and increased lactate availability. After 54 hours, the plasma concentrations of glucose and lactate, glucose kinetics, and body temperature were not different between endotoxemic and control animals. In separate groups of rats, a bolus injection of endotoxin (LD 100) was administered to determine the presence of endotoxin tolerance. Endotoxin-infused animals showed improved survival after 30 and 54 hours (LD 20 and LD 0).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1956

The role of epinephrine in the reactions produced by the endotoxins of gram-negative bacteria. I. Hemorrhagic necrosis produced by epinephrine in the skin of endotoxin-treated rabbits.

Extensive lesions of dermal hemorrhagic necrosis occurred in rabbits when epinephrine (or norepinephrine) was injected into the skin within 4 hours after an intravenous injection of endotoxin. As little as 5 microg. of intradermal epinephrine, and 1 microg. of intravenous endotoxin, were sufficient to produce lesions. Similar lesions, but smaller in size and surrounded by a zone of acute inflammation, were produced by intradermal injection of a mixture of comparable amounts of endotoxin and epinephrine. No lesions were produced by combinations of endotoxin with serotonin, pitressin, or ephedrine. Both types of epinephrine-endotoxin lesion were prevented by pretreatment with cortisone, dibenzyline, and chlorpromazine. They were not prevented by heparin or nitrogen mustard. The lesions produced by intradermal mixtures of epinephrine and endotoxin were greatly enhanced in size and severity in animals treated with nitrogen mustard. Both types of lesion were prevented in rabbits rendered "tolerant" by repeated injections of sublethal amounts of endotoxin. It is concluded that endotoxin has the property of altering the reactivity of blood vessels to epinephrine in such a way that this hormone becomes a potent necrotizing agent. The possibility that this effect may represent a basic mechanism in the various intoxicating actions of endotoxin, and certain implications of this hypothesis, are discussed.

Animals↗
PubMed1956

The role of epinephrine in the reactions produced by the endotoxins of gram-negative bacteria. II. The changes produced by endotoxin in the vascular reactivity to epinephrine, in the rat mesoappendix and the isolated, perfused rabbit ear.

The effects of endotoxin on the epinephrine reactivity of blood vessels in the rat mesoappendix have been studied. Following intravenous injection of a relatively small, sublethal dose of endotoxin, the terminal arterioles and venules exhibited greatly augmented and prolonged vasoconstrictor responses to epinephrine and norepinephrine. Hyperreactivity became evident within 30 minutes after injection of endotoxin, and persisted for as long as 6 hours. After larger doses of endotoxin, sufficient to cause illness or death, the vascular hyperreactivity to epinephrine was of briefer duration, and was followed by a stage of increasing hyporeactivity reaching levels much below normal. With lethal doses, the terminal arterioles and venules became completely refractory to epinephrine, while heightened reactivity persisted in the larger arteries and veins. The end result was pooling of stagnant blood in distended capillaries and venules, accompanied by the appearance of petechiae. Topical applications of epinephrine during this stage were followed promptly by an increase in petechial hemorrhage at the site of testing. Rats which were rendered tolerant to the lethal effect of endotoxin, by repeated daily injections of small doses, developed resistance to the effects of endotoxin on epinephrine reactivity. Neither hyperreactivity nor hyporeactivity to epinephrine were demonstrable in these animals, nor were spontaneous abnormalities of blood flow or petechial hemorrhages observed in the mesoappendix. Analogous results were obtained in perfusion studies of the vessels of the isolated rabbit ear. Perfusion of small amounts of endotoxin was followed within a few minutes by potentiation of epinephrine reactivity. Larger doses caused complete reversal of this effect, to such an extent that epinephrine now produced marked degrees of vasodilation. The possible meaning of these observations in the interpretation of the endotoxin-epinephrine skin lesions described in the preceding paper is discussed. It is suggested that abnormal reactions to epinephrine or norepinephrine in the tissues of intact animals may represent a basic mechanism in the intoxicating and tissue-damaging properties of endotoxin.

Animals↗
PubMed1962

Studies on the biologic relationship of endotoxin and other toxic proteins. II. Enhancement of susceptibility to snake venom by endotoxin.

1. Injections of sublethal quantities of Agkistrodon piscivorus venom into endotoxin-treated rabbits produces a consistent early death. 2. The endotoxin-induced hypersusceptibility state (EIHS) to venom is produced by intravenous, intradermal, and intraperitoneal administration of endotoxin. The latency and duration of the EIHS vary with the route of administration. 3. EIHS is induced by as little as 1 gamma of endotoxin administered intravenously. Although the degree of susceptibility was no greater with a 100 gamma dose than with 1 gamma, 1 mg of endotoxin made the rabbits susceptible to smaller venom doses. 4. EIHS was demonstrated with intravenous, intradermal and intraperitoneal injection of Agkistrodon piscivorus venom. Endotoxin-pretreated animals were not as susceptible to venom given intramuscularly. 5. Normal rabbits are very resistant to venom given intradermally and intraperitoneally. 6. Enhanced susceptibility to intravenous endotoxin was demonstrated in animals pretreated with sublethal doses of moccasin venom. It differed from EIHS in its short duration and its outcome: a late, slowly progressive death. 7. EIHS was demonstrated with other venoms: Crotalus adamanteus and Vipera russellii, and in a modified form (resulting in late death) with Notechis scutatus. Endotoxin pretreatment had no effect on susceptibility to Naja flava, Bungarus candidus, or Crotalus durissus terrificus venoms. 8. Major hypotheses regarding the nature of endotoxin-induced alterations in non-specific resistance were considered in relation to EIHS to venom.

Animals↗
PubMed1993

Association between gastric intramucosal pH and splanchnic endotoxin, antibody to endotoxin, and tumor necrosis factor-alpha concentrations in patients undergoing cardiopulmonary bypass.

OBJECTIVES: To determine the association between gastric intramucosal pH, a minimally invasive marker reflecting the adequacy of oxygen delivery to the gastrointestinal tract, and splanchnic endotoxin, antibody to endotoxin, and tumor necrosis factor (TNF)-alpha concentrations in patients undergoing cardiopulmonary bypass. DESIGN: Single-arm, prospective study. SETTING: University hospital. PATIENTS: Adults (n = 10) free of hepatic, pulmonary, and renal disease undergoing nonemergent coronary artery bypass surgery. INTERVENTIONS: After induction of general anesthesia and endotracheal intubation, a tonometer nasogastric tube was positioned in the stomach, and triple-lumen fiberoptic catheters were inserted into the hepatic vein and pulmonary artery. Hepatic venous and mixed venous blood samples were analyzed for endotoxin, antibody to endotoxin, and TNF-alpha at six times: 30 mins after induction of anesthesia (time 1); during vena caval cannulation (time 2); after 15 mins of hypothermic cardiopulmonary bypass (time 3); during spontaneous left ventricular ejection after release of the aortic cross-clamp, but before termination of cardiopulmonary bypass (time 4); 15 mins after termination of cardiopulmonary bypass (time 5); and 1 hr after termination of cardiopulmonary bypass (time 6). Gastric intramucosal pH, systemic oxygen delivery (DO2), mixed venous oxygen saturation, hepatic venous oxygen saturation, and hepatic venous lactate concentrations were recorded at these same times. Data for each variable were compared with baseline values (time 1) for statistical significance. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary bypass was associated with an increase (p < .05) in systemic endotoxin concentrations from ventricular ejection until the end of the study. Virtually identical changes in the splanchnic circulation at this time approached, but did not reach, statistical significance, because hepatic venous endotoxin concentrations were higher than the mixed venous endotoxin concentrations at baseline (41.6 +/- 11.2 vs. 16.9 +/- 4.9 pg/mL). Gastric intramucosal pH was abnormal (< 7.35) at 15 mins (p > .05) and at 1 hr after termination of cardiopulmonary bypass (p > .05). The relationship between endotoxin and gastric intramucosal pH was not statistically significant (p = .15). The decrease in endotoxin antibody was small and statistically insignificant. TNF-alpha was not detected in any patient. Systemic DO2 decreased (p < .05) after 15 mins of hypothermic cardiopulmonary bypass, but returned to baseline values thereafter. There were no significant changes in mixed venous and hepatic venous oxygen saturation values. Splanchnic lactate concentrations increased at cannulation (p < .05), after 15 mins of hypothermic cardiopulmonary bypass (p < .05), and 15 mins after termination of cardiopulmonary bypass (p < .05). CONCLUSIONS: These observations are consistent with the hypothesis that impaired gut-barrier function is responsible for endotoxemia occurring during cardiopulmonary bypass. It is unclear whether increased mucosal permeability and mucosal acidosis are causally related phenomena or simply independent markers of damage to gut epithelium.

Adult↗
PubMed1992

Endotoxin concentration in neutropenic patients with suspected gram-negative sepsis: correlation with clinical outcome and determination of anti-endotoxin core antibodies during therapy with polyclonal immunoglobulin M-enriched immunoglobulins.

We carried out a study in patients with severe neutropenia from hematologic malignancy and suspected gram-negative sepsis to evaluate the clinical significance of endotoxin concentrations in plasma before and during a therapeutic intervention with a human polyclonal immunoglobulin M (IgM)-enriched immunoglobulin preparation (Pentaglobin; Biotest, Dreieich, Germany). Twenty-one patients with acute leukemia or non-Hodgkin's lymphoma entered the study upon the development of clinical signs of gram-negative sepsis and received the IgM-enriched immunoglobulin preparation every 6 h for 3 days (total dose, 1.3 liter with 7.8 g of IgM, 7.8 g of IgA, and 49.4 g of IgG), in addition to standardized antibiotic treatment. Concentrations of endotoxin and IgM and IgG antibodies against lipid A and Re lipopolysaccharide (LPS) in plasma were determined by a modified chromogenic Limulus amebocyte lysate test and semiquantitative enzyme linked immunosorbent assay, respectively, before each immunoglobulin infusion and during the following 25 days. Seventeen patients were endotoxin positive; in five of these patients, gram-negative infection was confirmed by microbiologic findings. Prior to therapy, endotoxemia correlated significantly with the occurrence of fever, and a quantitative correlation between the endotoxin concentration and body temperature was found during the individual course of infection in 8 of the 17 patients. Overall mortality from endotoxin-positive sepsis was 41% (7 of 17) and 64% (7 of 11) in patients with symptoms of septic shock. Nonsurvivors had significantly higher maximum concentration of endotoxin in plasma compared with those of survivors at the first study day (median of 126 versus 34 pg/ml; P < 0.05) and during the whole septic episode (median of 126 versus 61 pg/ml; P < 0.05). In survivors, immunoglobulin therapy resulted in a significant decrease in endotoxin levels in plasma within the initial 18-h treatment period, from a pretreatment median value of 28 pg/ml to a value of 8 pg/ml (P< 0.05). In the seven patients who died from uncontrollable infection, no effect of therapy on endotoxin levels in plasma was observed. IgM and IgG antibodies against lipid A and Re LPS increased significantly under immunoglobulin treatment, with significant correlations between antibodies against lipid A and Re LPS. These data strongly suggest a prognostic significance of the endotoxin levels in plasma and a potential effect of treatment with a polyclonal IgM-enriched immunoglobulin preparation. Further studies are needed to substantiate these findings and to assess the impact on the clinical course by way of a prospective placebo-controlled clinical trial.

Adult↗
PubMed1992

[Plasma endotoxin measured by the combination of new perchloric acid pretreatment method and endotoxin specific assay in liver cirrhosis].

Using with the newly modified perchloric acid pretreatment method and endotoxin specific assay (Endospecy), the plasma endotoxin in the patients with liver cirrhosis was investigated. The mean value of plasma endotoxin in control (n = 20) was below 9.8 pg/ml. The plasma endotoxin level in liver cirrhosis was 5.7 +/- 5.3 pg/ml (n = 70, mean +/- SD), and 20% of the patients (15 cases) showed above 9.8 pg/ml. Endotoxin level significantly correlated with the severity of liver function based on the Child-Turcotte classification (p less than 0.01). Plasma endotoxin positively correlated with total bilirubin (r = 0.417) and ICG clearance test (r = 0.298) and negatively correlated with prothrombin time (%) (r = 0.497) and HDL-cholesterol (r = 0.578) in the patients with liver cirrhosis. There was no correlation between esophageal varices and plasma endotoxin level. Plasma endotoxin was slightly detected in the patients with decompensated cirrhosis, and these data suggest that plasma endotoxin level in cirrhosis is not so elevated.

Bilirubin↗
PubMed1982

Binding of 125I-labeled endotoxin to bovine, canine, and equine platelets and endotoxin-induced agglutination of canine platelets.

Endotoxin from Escherichia coli O127:B8, Salmonella abortus-equi and S minnesota induced clumping of some canine platelets (PLT) at a final endotoxin concentration of 1 microgram/ml. Endotoxin-induced clumping of canine PLT was independent of PLT energy-requiring processes, because clumping was observed with canine PLT incubated with 2-deoxy-D-glucose and antimycin A. The PLT responded to adenosine diphosphate before, but not after, incubation with the metabolic inhibitors. Endotoxin induced a slight and inconsistant clumping of bovine and equine PLT at high (mg/ml) endotoxin concentration. High-affinity binding sites could not be demonstrated on canine, bovine, and equine PLT, using 125I-labeled E coli O127:B8 endotoxin. Nonspecific binding was observed and appeared to be due primarily to an extraneous coat on the PLT surface that was removed by gel filtration. The endotoxin that was bound to PLT did not appear to modify PLT function. An attempt to identify plasma proteins that bound physiologically relevant amounts of endotoxin was not successful. The significance of the endotoxin-induced clumping or lack of it on the pathophysiology of endotoxemia is discussed.

Agglutination↗
PubMed1994

Macrophage endotoxin tolerance: effect of TNF or endotoxin pretreatment.

Macrophages pretreated with low-dose endotoxin [lipopolysaccharide (LPS1)] have an altered response to subsequent endotoxin (LPS2) stimulation, a process known as endotoxin tolerance. In this study we investigated whether the LPS1 pretreatment effects were mediated primarily via tumor necrosis factor (TNF alpha). Murine peritoneal macrophages were pretreated in vitro with either TNF alpha or LPS1 and the effects on mediator production in response to a second endotoxin exposure, LPS2, were compared. Mediators in macrophage supernatant were measured using specific bioassays [TNF, interleukin-1 (IL-1), and IL-6] or enzymatic immunoassays [prostaglandin E2 (PGE2) and TNF]. Macrophage production of all mediators was stimulated by endotoxin in the absence of LPS1 pretreatment. Pretreatment with LPS1 completely inhibited LPS2-triggered TNF release whereas preexposure to TNF alpha had no effect. In contrast, LPS1 pretreatment significantly augmented IL-1 and PGE2 release in response to LPS2, whereas pretreatment using either high- or low dose TNF alpha did not. TNF, stimulated by an initial exposure to endotoxin, LPS1, is not solely responsible for the observed alterations in macrophage mediator release following a subsequent endotoxin stimulus (LPS2). Thus, the data suggest that endotoxin tolerance is mediated primarily by factors other than TNF.

Animals↗
PubMed1984

Are the decreases in hepatic cytochrome P-450 and other drug-metabolising enzymes caused by indomethacin in vivo mediated by intestinal bacterial endotoxins? 16,16-Dimethylprostaglandin F2 alpha prevents decreases in hepatic drug-metabolising enzymes due to exogenous endotoxin.

Administration of either indomethacin (8.5 mg/kg) or E. coli endotoxin (3.5 mg/kg) to rats caused significant decreases in a variety of drug-metabolising enzyme activities. Either agent markedly decreased biphenyl 4-hydroxylase by 72-80% and caused lesser decreases (21-64%) in cyt. P-450, aminopyrine N-demethylase, ethoxyresorufin O-deethylase (EROD), benzyloxyphenoxazone O-debenzylase (BPOD), cyt. b5, NADPH-cyt. c reductase, NADH-cyt. b5 reductase, epoxide hydrolase (EH) and glucuronyl transferase (GT). The decreases in GT (21-22%) were significantly less than in cyt. P-450 (45-57%). Sulphotransferase was not affected by either indomethacin or endotoxin. The overall pattern of relative decreases in the different enzymes was similar for either indomethacin or endotoxin. Four activities, however, were affected to a significantly greater extent by indomethacin than by endotoxin at 2-6 mg/kg: EROD, BPOD, cyt. b5 and EH. Additionally, hepatic glutathione was decreased by indomethacin but not by endotoxin. Indomethacin or endotoxin caused similar but not identical decreases in selected protein bands in the "cyt. P-450 region" of microsomal SDS-polyacrylamide gel electrophoretograms. Concomitant administration of 16,16-dimethylprostaglandin F2 alpha afforded significant (50-100%) protection against all the above-mentioned effects of indomethacin or endotoxin. The effects of indomethacin on cyt. P-450 were lessened by concomitant administration of a mixture of neomycin, polymyxin B and bacitracin. Throughout the study there was a close correlation between the extent of decrease in hepatic cyt. P-450 and the degree of intestinal ulceration caused by indomethacin. It was concluded that bacterial endotoxins liberated into the portal blood as a result of indomethacin-induced ulceration of the small intestine probably only partially mediated the effects of indomethacin on hepatic drug-metabolising enzymes. The protection afforded by 16,16-dimethylprostaglandin F2 alpha could have been due to both the prevention of ulceration and to a direct cytoprotective effect on the liver.

Animals↗
PubMedDate not supplied

High in vitro endotoxin responsiveness of macrophages from an endotoxin-resistant wild rodent species, Sigmodon hispidus.

It has been reported that macrophages primarily mediate endotoxin shock and cell death by synthesizing and releasing cytokines, largely tumor necrosis factor (TNF) and interleukin-1 (IL-1). However, macrophages from some laboratory mouse strains such as C3h/HeN are unresponsive to endotoxin both in vivo and in vitro. We found members of a wild rodent species, Sigmodon hispidus, to also be extremely resistant to bacterial endotoxin challenge. Intravenous administration of up to 100,000 micrograms/kg body mass of Escherichia coli O26:B6 endotoxin did not cause lethality in adult S. hispidus. In contrast to the endotoxin-resistant mouse strain, peritoneal macrophages derived from S. hispidus were responsive to in vitro endotoxin challenge as measured by high levels of TNF and IL-1 activity in supernatants of macrophage cultures. Thus, in vitro macrophage responsiveness to endotoxin does not always indicate high host sensitivity to endotoxin challenge.

Animals↗
PubMed2004

Evaluation of the bacterial endotoxin test for quantification of endotoxin contamination of porcine vaccines.

We investigated the application of the bacterial endotoxin test for the quantification of the endotoxin contamination of various commercial porcine vaccines. In endotoxin-spiked samples, Freund's complete adjuvant and aluminum hydroxide gel adjuvant failed to interfere with the results of the endotoxin test, and both recovery ratios were within the permissible range mentioned in the Japanese Pharmacopoeia. At the various dilutions tested, none of the adjuvants in commercial porcine vaccines caused noteworthy interference in the test. In addition, none of the 39 samples of porcine vaccines approved in Japan induced an interfering effect in the endotoxin test. Our findings suggest that the bacterial endotoxin test using endotoxin-specific Limulus amoebocyte lysate (LAL) can detect endotoxin contamination in commercial porcine vaccines containing either oil or aluminum adjuvants.

Aluminum Hydroxide↗
PubMed2006

The presence of endotoxin in powdered infant formula milk and the influence of endotoxin and Enterobacter sakazakii on bacterial translocation in the infant rat.

Lipopolysaccharide (LPS) is a heat stable endotoxin that persists during the processing of powdered infant formula milk (IFM). Upon ingestion it may increase the permeability of the neonatal intestinal epithelium and consequently bacterial translocation from the gut. To determine the level of endotoxin present in IFM, 75 samples were collected from seven countries (representing 31 brands) and analysed for endotoxin using the kinetic colorimetric Limulus amoebocyte lysate (LAL) assay. The endotoxin levels ranged from 40 to 5.5 x 10(4) endotoxin units (EU) per gram and did not correlate with the number of viable bacteria. The neonate rat model was used to address the risk of endotoxin-induced bacterial translocation from the gut. Purified Escherichia coli LPS was administered to rat pups followed by inoculation with Enterobacter sakazakii ATCC 12868. Bacteria were isolated from the mesentery, spleen, blood and cerebral spinal fluid (CSF) of endotoxin-treated rats due to enhanced gut and blood brain barrier penetration. Histological analysis of the colon showed marked distension of the mucosal and muscular layers. It is plausible that the risk of neonatal bacteraemia and endotoxemia, especially in neonates with immature innate immune systems, may be raised due to ingestion of IFM with high endotoxin levels.

Animals↗
PubMed2001

Endotoxin release and endotoxin neutralizing capacity during colonoscopy.

In 38 patients who underwent elective colonoscopy, endotoxin and endotoxin neutralizing capacity (ENC) were determined by use of the limulus--amebocyte--lysate test. A control group of 10 patients, prepared for colonoscopy, were sampled in the same manner as the study group prior to endoscopy. Elevated endotoxin plasma levels were only found when comparing the plasma levels before endoscopy with the highest levels available during endoscopy. The timed endotoxin plasma levels did not change significantly by use of the conventional limulus amebocyte test. However, ENC was found to decrease significantly 5 min after the onset of endoscopy. Maximal values were reached at the end of colonoscopy which recovered completely 24 h later. These results, obtained in a population which did not receive any infusions, demonstrate that the half life of endotoxin in the circulation seems to be very short and therefore endotoxin cannot itself be detected. On the other hand, small amounts of endotoxin reaching the blood stream are able to reduce ENC which can be analyzed by a modified limulus--amebocyte--lysate test. With the use of ENC and plasma endotoxin determinations, we are able to show significant endotoxemia during a minimal invasive procedure such as colonoscopy.

Adult↗
PubMedDate not supplied

Differentiation between endotoxin and non-endotoxin pyrogens in human albumin solutions using an ex vivo whole blood culture assay.

Purified E.coli endotoxin, Gram negative bacteria and Gram positive bacteria induce IL-6 secretion by whole blood cultures (WBC's). Polymyxin B at concentrations greater than 2 U/ml completely inhibits IL-6 secretion caused by 10 EU/ml of endotoxin. Polymyxin B has no effect on IL-6 secretion by WBC's in the absence of endotoxin. The inhibition of endotoxin induced IL-6 secretion is Polymyxin B concentration dependent at concentrations less than 1 U/ml. IL-6 induction caused by E.coli is only partially inactivated by 8 U/ml Polymyxin B. Polymyxin B has no effect on IL-6 secretion caused by B.subtilis. Two pyrogenic batches of human serum albumin (HSA), as tested by the rabbit assay for pyrogens, were also investigated. Polymyxin B at 4 U/ml inhibits less than 40 % of IL-6 secretion caused by these pyrogenic HSA batches. All the endotoxin activity in HSA samples spiked with purified endotoxin is inhibited by Polymyxin B indicating that HSA does not protect endotoxin against Polymyxin B inhibition. These results indicate that the pyrogenicity of these HSA batches are caused by Polymyxin B inhibitable and non-inhibitable fractions. This study shows that pyrogenic substances other than endotoxin can contaminate batches of pharmaceutical products and that results obtained using the Limulus Amoebocyte Lysate (LAL) assay does not necessarily indicate the pyrogenic status of pharmaceutical products. The WBC assay for pyrogens, having a broader sensitivity range than the LAL assay, is a better indicator of the pyrogenic status of pharmaceutical products.

Animals↗
PubMed1961

Biological properties of parent endotoxins and lipoid fractions, with a kinetic study of acid-hydrolyzed endotoxin.

The biological potencies of a number of lipid fractions separated from endotoxins by acid hydrolysis, including the material known as lipid A, were determined in parallel with those of their parent endotoxins, employing bio-assays based on the following dose-related host responses: fever, resistance to infection, tumor damage, primary inflammation of skin, and lethality. Without exception, lipid fractions dispersed by detergents exerted less than 1 per cent of the biological activity of the potent endotoxins from which they were derived. A study was made of the rate at which biologic activities diminished in relation to the release of bound lipid during progressive hydrolysis of Salmonella enteritidis endotoxin with dilute acid. Each of the five assays for endotoxin revealed that biological activity had been reduced to negligible proportions prior to any significant liberation from the endotoxin of water-insoluble firmly bound lipid. The major pharmacological activity of endotoxins, therefore, is acid-labile and cannot be accounted for in isolated lipids. This conclusion is also supported by the finding that lipids with activity similar to that of lipid A could be obtained by non-hydrolytic methods without diminishing the potency of the parent endotoxins.

Antitoxins↗