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PubMed1997

Contrasting effects of growth hormone and insulin-like growth factor I on the biological activities of endotoxin in the rat.

We previously demonstrated that GH potentiates the biological activities of endotoxin in the rat. In the present study, we wanted to determine if the potentiating effects of GH on the biological activities of endotoxin could be reproduced by insulin-like growth factor I (IGF-I). Endotoxin (5 mg/kg BW) was injected in rats primed with or without GH or IGF-I for 3 days. As expected, endotoxin administration markedly increased circulating tumor necrosis factor (TNF) and interferon-gamma (IFN gamma) and induced organ injury, hypoglycemia, and hyperlipidemia. In GH-primed rats, endotoxin induced a further increase of serum IFN gamma (but not TNF); and five out of six of those rats died within 15 h after giving endotoxin. However, little difference between endotoxin-treated rats with and without IGF-I priming could be seen. Furthermore, IGF-I infusion altered blood glucose, urea, and circulating ICF-I levels more than GH infusion. Therefore, IGF-I does not enhance the biological activities of endotoxin in the rat, suggesting that the enhancement of endotoxin effects by GH is via an IGF-I-independent pathway. Priming rats by GH (but not by IGF-I) induced a further increased response of serum IFN gamma but not TNF to subsequent endotoxin challenge, suggesting that IFN gamma rather than TNF is likely to be involved in this process.

Animals↗
PubMed1990

Early burn excision attenuates the postburn lung and systemic response to endotoxin.

The lung and systemic physiologic response to endotoxin is markedly accentuated in the presence of a body burn. Our purpose was to determine whether early burn excision and closure would decrease this response. We compared the endotoxin (2 micrograms/kg)-induced response in 10 adult sheep with lung and soft-tissue lymph fistulas 3 days after a 15% total-body surface full-thickness burn that was excised immediately with that of sheep without burn excision and nonburned sheep. No infection was present in the burn wound. Early excision prevented the ongoing postburn lipid peroxidation and lung inflammation seen 3 days after burn before endotoxemia in animals with 15% total body surface burn wound not excised. Sheep that underwent excision demonstrated significantly less pulmonary hypertension and hypoxia after endotoxin than did either endotoxin-treated and intact burned sheep or endotoxin-treated nonburned sheep. Lung inflammatory changes as determined by neutrophil content of lung tissue and the increase in lung tissue malondialdehyde in the group that underwent burn excision after endotoxin were comparable to those seen with endotoxin alone, as was the lung lymph-flow response. Also, the systemic response was nearly identical to that seen with endotoxin alone with no increase in soft-tissue permeability as measured by lymph flow. Oxygen consumption (VO2) remained unchanged from baseline. In contrast, VO2 doubled in burn-intact animals initially after endotoxin, after which VO2 decreased to levels below baseline. An increase in soft-tissue vascular permeability was also noted. We can conclude that early burn excision and closure prevent the accentuated response to endotoxin that is seen when the burn wound is left intact, even if it is uninfected.

Animals↗
PubMed1983

Arachidonic acid metabolism in endotoxin tolerance.

The arachidonic acid metabolites thromboxane A2, a potent platelet aggregator, and prostacyclin, a potent vasodilator, are released early in endotoxin shock and may contribute to its pathologic sequelae. Plasma levels of thromboxane (Tx) A2 and prostacyclin were measured via radioimmunoassay of their stable metabolites immunoreactive (i) TxB2 and i6-keto-PGF1 alpha in tolerant and nontolerant rats after endotoxin. Long-Evans rats were made tolerant to endotoxin by four daily IV injections of S enteritidis (endotoxin) (0.1, 0.5, 1, and 5 mg/kg). In normal rats (N = 15) given LPS (IV, 15 mg/kg), only 11% survived at 24 h; in contrast, tolerant rats (N = 13) all survived even at a dose of 50 mg/kg. At 1 h, after endotoxin (15 mg/kg) IV, plasma i6-keto-PGF1 alpha in nontolerant rats was 1,005 +/- 149 pg/ml (N = 14) and continued to rise to 4,209 +/- 757 pg/ml (N = 5) (P less than 0.001) after 4 h. In tolerant rats, given endotoxin (15 mg/kg), plasma i6-keto-PGF1 alpha at 1 h was 800 +/- 203 pg/ml (N = 5) and was not significantly different (734 +/- 254 pg/ml) at 4 h. Plasma iTxB2 at both 1 and 4 h was significantly (P less than 0.01) lower in tolerant than nontolerant rats. Both iTxB2 and i6-keto-PGF1 alpha were significantly (P less than 0.01) lower in tolerant rats given 50 mg/kg IV endotoxin than nontolerant rats. Endotoxin-induced elevation in fibrin degradation products was significantly decreased (P less than 0.05) during endotoxin tolerance although there was no difference in the severity of thrombocytopenia. These composite observations demonstrate that endotoxin tolerance in the rat is associated with altered arachidonic acid metabolism.

Acid Phosphatase↗
PubMed1964

EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM. VII. ENZYME INDUCTION AND CORTISONE PROTECTION.

Cortisone acetate administered to mice at the same time as either the LD(50) or 2 x LD(50) of endotoxin significantly protected against lethality. Delaying the injection of cortisone to 1, 2, or 4 hours after that of endotoxin resulted in loss of protection with the possible exception of a 1 hour delay with the LD(50) of endotoxin. Associated with this loss of protection was the failure of the hormone to induce liver tryptophan pyrrolase. Normal mice given only cortisone showed an increase in enzyme activity nearly three times that of control values when assays were carried out either 4 or 17 hours after the hormone was given. Endotoxin-poisoned mice showed normal levels of enzyme activity with concurrent injection of cortisone but depressed levels of enzyme when the cortisone injection was delayed for only 1 hour or more. Apparently, therefore, enzyme induction (or maintenance) is related to survival in endotoxin poisoning. In line with this hypothesis was the observation that inhibitors of enzyme (protein) synthesis were found to potentiate the lethal action of endotoxin and to prevent the protective effect of cortisone. The inhibitors employed were actinomycin D, ethionine, 2-thiouracil, and 8-azaguanine. Activity of liver tryptophan pyrrolase was lowered by endotoxin and elevated by cortisone. When the two were given concurrently, normal enzyme activity was maintained. Chloramphenicol, an active inhibitor of protein synthesis in microorganisms but with limited effect in mammals, was without observable influence in these respects. Mice 18 hours postinfection with Salmonella typhimurium, strain SR-11, given at a level that caused first deaths on the 3rd day, had a lower than normal activity of liver tryptophan pyrrolase and responded to cortisone induction with a smaller increase in enzyme level than that found in control mice. Each is characteristic of endotoxin poisoning. Animals 42 hours postinfection were free of these signs of endointoxication, an observation in agreement with earlier experiments where other measures of endotoxin were employed.

Animals↗
PubMed1965

LYSOSOMAL ACID HYDROLASES AND HYPERREACTIVITY TO ENDOTOXIN IN MICE INFECTED WITH BCG.

Experiments are reported dealing with the correlation between activities of lysosomal acid hydrolases and hyperreactivity to endotoxin induced by BCG infection. Acid hydrolases were determined quantitatively in peritoneal MP, liver homogenate, and plasma of normal and hyperreactive mice. Mice infected with BCG not only exhibited a hyperreactive state to lethal effect of endotoxin, but also responded to endotoxin by rapid increase of acid hydrolases, especially of beta-glucuronidase, in the plasma; whereas control mice responded to endotoxin by almost no change in plasma acid hydrolases. The extent of increase of beta-glucuronidase in plasma of hyperreactive mice was shown to correlate fairly well with the degree of hyperreactivity to the lethal effect of endotoxin. Desensitization of such animals with endotoxin was found to cause a decreased response of plasma beta-glucuronidase parallel with decreased mortality. A large amount of PPD exerted the similar effect to that of endotoxin in hyperreactive mice. Furthermore, the effect of PPD was decreased by desensitization of such animals with endotoxin, a fact which suggests contamination of PPD with endotoxin.

Acid Phosphatase↗
PubMed1989

Endotoxin tolerance is associated with reduced secretion of tumor necrosis factor.

Bacterial endotoxin effects are partially mediated by tumor necrosis factor (TNF). It is known that sublethal doses of endotoxin induce transient refractoriness (tolerance) to some of its effects. We studied the role of TNF in endotoxin tolerance in rats. Weight loss, lethality, and TNF production were measured after an initial dose of endotoxin and after subsequent doses. Weight loss reached its peak 72 hours after the initial endotoxin challenge, followed by recovery even under continued administration of endotoxin. While tolerant, rats could survive a dose of endotoxin that was lethal for 100% of naive rats. The high serum levels of TNF, observed 90 minutes after the first dose of endotoxin, markedly diminished when rechallenged during tolerance. Recovery of responsiveness to these effects followed the refractory phase by 3 weeks. We concluded that endotoxin tolerance is associated with a reduced secretion of TNF.

Animals↗
PubMed1989

Endotoxin-induced hypercoagulability: a possible aggravating factor of alcoholic liver disease.

The present experiments were designed to study the effect of chronic ethanol consumption on endotoxin toxicity. The intravenous injection of endotoxin produced a more pronounced increase of serum AST and ALT activities in chronic ethanol-fed rats, when compared to controls. The activities of hepatic mitochondrial enzymes, succinate dehydrogenase and cytochrome oxidase, were also distinctly decreased by endotoxin treatment in chronic ethanol-fed rats. Consistent with these biochemical alterations, light and electron microscopic examinations revealed severe liver injury after endotoxin injection in chronic ethanol-fed rats. Furthermore, the increase of blood BUN and creatinine levels accompanied by the degeneration of the renal tubulus and slight infiltration of neutrophils into the glomerule were produced by endotoxin treatment and were more conspicuous in chronic ethanol-fed rats than controls. Therefore, the biochemical and histological evidence indicates that endotoxin markedly potentiates organ injury after chronic ethanol consumption. In addition, a more pronounced decrease in blood antithrombin III activity accompanied by an increase in fibrin degradation product level in blood was recognized in chronic ethanol-fed rats receiving endotoxin, when compared to controls receiving endotoxin. This increase of blood fibrin degradation product level correlated well with the decrease of antithrombin III activity (r = -0.6116; p less than 0.005). These findings of blood antithrombin III activity and fibrin degradation product level indicate that the coagulation-fibrinolysis system is more activated by endotoxin treatment after chronic ethanol consumption. Furthermore, the activation of the coagulation-fibrinolysis system was well correlated with biochemical and histological alterations representing hepatorenal involvement.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed2000

Endotoxin induces structure-function alterations of rat liver peroxisomes: Kupffer cells released factors as possible modulators.

We report that endotoxin treatment results in decreased amounts of peroxisomes as well as changes in structure and function of peroxisomal membranes. Peroxisomes isolated from the liver of control and treated animals showed a marked decrease in total protein, but no significant alteration in the sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) protein profile. However, the Western blot study of the peroxisomal beta-oxidation enzymes and catalase showed an increase in those enzymes in the peroxisomal peak of normal density in endotoxin-treated rats. Disintegration of peroxisomal membranes by carbonate treatment from endotoxin-treated liver and change in the fluidity of peroxisomal membranes suggests alterations in peroxisomal membrane structure. No such alterations were found in mitochondrial or microsomal membranes of endotoxin-treated livers. The lipid analysis of these organelles showed that the only organelle affected was the peroxisome, with a significant decrease in the phospholipid and cholesterol concentrations. To understand the mechanism of endotoxin-mediated alterations in peroxisomes, we studied the possible role of Kupffer cell secreted soluble factors (tumor necrosis factor alpha [TNF-alpha]) on the peroxisomal structure/function. Inactivation/elimination of Kupffer cells by gadolinium chloride before endotoxin treatment did not normalize the overall peroxisomal protein amount and the lipid composition of isolated peroxisomes. However, the levels of individual protein amount in remaining peroxisomes were normalized. Endotoxin also decreased peroxisomal beta-oxidation, and this was partially restored with gadolinium treatment. These results clearly show that peroxisomes are severely affected by endotoxin treatment and suggest that the damage to this organelle may contribute, at least in part, to endotoxin-induced hepatic cytotoxicity.

Animals↗
PubMed1989

In vitro effects of endotoxin on bovine and sheep lung microvascular and pulmonary artery endothelial cells.

A single infusion of Escherichia coli endotoxin into sheep results in structural evidence of pulmonary endothelial injury, increases in both prostacyclin and prostaglandin E2 (PGE2) in lung lymph, and an increase in pulmonary microvascular permeability. Endotoxin-induced lung endothelial damage can also be induced in vitro, but to date these studies have utilized endothelium from large pulmonary vessels. In the present study, we have grown endothelial cells from peripheral lung vessels of cows and sheep and exposed these microvascular endothelial cells to endotoxin. Controls included lung microvascular endothelium without endotoxin and endothelial cells from bovine and sheep main pulmonary artery with and without addition of endotoxin. We found that endotoxin caused significant increases in release of prostacyclin and PGE2 from both bovine and sheep lung microvascular and pulmonary artery endothelium. Normal bovine and sheep pulmonary artery and bovine lung microvascular endothelium released greater levels of prostacyclin than PGE2 (ng/ng); release of PGE2 from the microvascular cells was greater than from the pulmonary artery endothelium in both species. Exposure of endothelial cells from cow and sheep main pulmonary artery to endotoxin results in endothelial cell retraction and pyknosis, a loss of barrier function, increased release of prostacyclin and PGE2 and eventual cell lysis. In lung microvascular cells, the increases in prostanoids were accompanied by changes in cell shape but occurred in the absence of either detectable alterations in barrier function or cytolysis. Thus, while endotoxin causes alterations to endothelial cells from both large and small pulmonary vessels, the effects are not identical suggesting site specific phenotypic expression of endothelial cells even within a single vessel. To determine whether the response of either the large or small pulmonary vessel endothelial cells in culture mimics most closely the in vivo response of the lung to endotoxin requires further study.

Animals↗
PubMed1999

Measurement and removal of adherent endotoxin from titanium particles and implant surfaces.

Aseptic loosening is thought to be due primarily to osteolysis induced by cytokines and prostaglandins that are produced in response to implant-derived wear particles. Because endotoxin has many of the same effects as have been reported for wear particles, we hypothesized that adherent endotoxin may be responsible for the biological responses induced by wear particles. We demonstrated the presence of significant levels of adherent endotoxin on commonly used preparations of titanium particles as well as on titanium and titanium-alloy implant surfaces. In contrast, supernatants obtained by centrifugation of particle suspensions contained approximately 1% as much endotoxin as did the particles. Therefore, it is erroneous to assume that particles do not contain endotoxin on the basis of data that it cannot be detected in their supernatants or filtrates. These results emphasize the importance of considering the potential role of adherent endotoxin when examining the in vitro effects of wear particles and the in vivo performance of orthopaedic implants. We also developed a protocol that removed more than 99.94% of the adherent endotoxin from the titanium particles without detectably affecting their size or shape. The removal of adherent endotoxin will allow comparison of the biological responses induced by particles with or without adherent endotoxin.

Endotoxins↗
PubMed1993

Endotoxin protects the gastric mucosa against ulcerogenic stimuli.

It is well-documented that large amounts of endotoxin produce hemorrhagic mucosal lesions in the stomach. To determine whether endotoxin, when injected at small doses, similarly exerts ulcerogenic actions, endotoxin (0.4-40 micrograms/kg) was injected into 24 hr-fasted rats. These small doses of endotoxin did not affect the integrity of the gastric mucosa. Unexpectedly, however, pretreatment with these minute amounts of endotoxin protected the gastric mucosa against various ulcerogenic stimuli such as stress, nonsteroidal anti-inflammatory drugs and ethanol. The anti-ulcer actions of endotoxin were not observed in endotoxin-insensitive animals (C3H/HeJ mice), thereby suggesting that endogenous cytokines such as interleukin-1 may mediate these protective actions. These findings stand in contrast to the toxic effect of endotoxin as an ulcerogen and indicate that endotoxin, albeit its term "toxin," may have a beneficial effect for the host.

Animals↗
PubMed1993

Assay of pertussis vaccine reactivity factors by measurement of the paw swelling response, endotoxin and histamine-sensitizing factor.

Bordetella pertussis is composed of a series of active components: (1) a heat-labile or dermonecrotic toxin (HLT); (2) a lipopolysaccharide endotoxin (LPS); (3) pertussis toxin; (4) filamentous hemagglutinin (FHA); (5) agglutinogens; (6) outer membrane proteins; (7) adenylate cyclase; and (8) tracheal cytotoxin. Pertussis toxin (PT), also called lymphocytosis-promoting factor (LPF), encompasses a series of biological activities including: (1) histamine-sensitization (HSF); (2) leukocytosis-promoting activity (LPF); (3) LPF-hemagglutinin (LPF-HA); and (4) pancreatic islet-activating protein (IAP). The heat-labile toxin is inactivated during vaccine production. Pertussis toxin is inactivated when heated to 80 degrees C for 30 min and endotoxin at a temperature greater than 120 degrees C for 30 min. The effect of pre- and post-heat treatment on DTP vaccine, Bordetella pertussis endotoxin, pertussis toxin and a pertussis toxin/endotoxin combination, was determined as related to: (1) paw swelling response; (2) LAL activity (endotoxin); and (3) HSF activity. With the exception of DTP and B. pertussis endotoxin, the average paw swelling response after injection of non-treated and heat-treated test samples was similar to the saline control at all measured time intervals. Contrary to anticipated results, heat treatment enhanced the paw-swelling response of DTP vaccine and B. pertussis endotoxin. Endotoxin levels, as measured by LAL, were significantly lower after heat-treatment, with the exception of B. pertussis endotoxin and the E-1 control. The addition of pertussis toxin, B. pertussis endotoxin or pertussis toxin/endotoxin did not restore LAL values to the levels seen for non-treated DTP vaccine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylate Cyclase Toxin↗
PubMed1995

Participation of hepatic macrophages and plasma factors in endotoxin-induced liver injury.

The present study was designed to investigate the mechanism responsible for endotoxin-induced liver injury, based on the working hypothesis that hepatic macrophages activated by endotoxin play a key role in the development of this injury. At both the protein and the transcription levels, the intravenous administration of endotoxin was shown to have increased the capacity of hepatic macrophages to produce chemical mediators. To inhibit the function of hepatic macrophages, gadolinium chloride (GdCl3), a specific inhibitor of resident hepatic macrophages, was preadministered to rats before endotoxin injection. GdCl3 reduced the elevated glutamic oxaloacetic transamiase and lactate dehydrogenase serum levels produced by endotoxin treatment, suppressed the increased mRNA expression of tumor necrosis factor (TNF-alpha) produced in liver nonparenchymal cells by endotoxin, and then improved the survival rate of lipopolysaccharide-injected rats. These results indicated that hepatic macrophages played a crucial role in liver injury and that TNF-alpha was the most likely factor implicated in the development of endotoxin-induced liver injury. Furthermore, we found that liver injury did not progress during perfusion of endotoxin-pretreated extirpated liver with lactate Ringer's solution, whereas liver perfused with plasma developed remarkable hepatic impairment, which was inhibited almost completely by GdCl3-pretreatment; moreover, addition of heparin to the perfusate also prevented this deterioration. Thus, the present study showed that the activation of hepatic macrophages and factors in the plasma were two essential elements in the occurrence and development of endotoxin-induced liver injury.

Animals↗
PubMed2001

Interleukin-10 prevents loss of tone of rat skeletal muscle arterioles exposed to endotoxin.

BACKGROUND: The anti-inflammatory cytokine interleukin-10 (IL-10) is known to inhibit the development of septic shock in animal models. This study was conducted to investigate the effect of IL-10 on the loss of vascular tone during exposure to endotoxin. Unlike numerous proinflammatory cytokines, the effects of IL-10 at the level of the microvasculature have not been previously studied. MATERIALS AND METHODS: First-order rat cremasteric arterioles (n = 27) were placed in an isolated vessel preparation and allowed to achieve spontaneous tone. An opened segment of thoracic aorta was then placed upstream from the arteriole in the superfusion line. The resistance arteriole of this in-series model, in contrast to the isolated arteriole alone, demonstrates a significant loss of tone when exposed to endotoxin. Following 1 h of equilibration in the presence or absence of IL-10 (20 ng/ml), the aorta and arteriole were then superfused with 2.5 microg/ml endotoxin or physiologic buffer for 60 min and serial arteriolar diameter measurements were recorded. Group 1 was exposed to endotoxin only, Group 2 was a time control, and Group 3 was pretreated with IL-10 prior to endotoxin exposure, while Group 4 was a control pretreated with IL-10 only. RESULTS: After the 60-min equilibration period there were no differences among the four groups in arteriolar tone. At t = 120 min, the percentage of tone in the control group was 43.6 +/- 3% (mean +/- SEM) and this was not changed by treatment with IL-10 (47.0 +/- 7% tone). Endotoxin alone caused arteriolar tone to fall to 31.4 +/- 3% (P < 0.05). However, endotoxin applied to arterioles pretreated with IL-10 was without effect (47.5 +/- 2%). CONCLUSIONS: Resistance arterioles pretreated with IL-10 maintain vascular tone during endotoxin exposure. We conclude that IL-10 pretreatment prevents loss of vascular tone of isolated arterioles exposed to endotoxin.

Acetylcholine↗
PubMed2001

Possible role of nitric oxide and mast cells in endotoxin-induced cardioprotection.

The present study is designed to investigate the role of nitric oxide (NO) and cardiac mast cells in the cardioprotective effect of endotoxin in isolated rat heart subjected to 30 min of global ischaemia and 30 min of reperfusion. Endotoxin (2.5 mg kg(-1); i.p.) was administered 8 h before subjecting the heart to global ischaemia. Endotoxin pretreatment markedly reduced the release of lactate dehydrogenase (LDH) and creatine kinase (CK), markers of cardiac injury, in coronary effluent and the percentage incidence of ventricular premature beats (VPBs) and ventricular tachycardia/fibrillation (VT/VF) during the reperfusion phase. Endotoxin pretreatment significantly increased the release of nitrite prior to and after global ischaemia. On the other hand, endotoxin pretreatment decreased the release of mast cell peroxidase (MPO) during the reperfusion phase. The cardioprotective and antiarrhythmic effect of endotoxin pretreatment was abolished by dexamethasone (3 mg kg(-1); i.p.) or l -canavanine (20 mg kg(-1); i.p.) given 1 h before the administration of endotoxin. It is proposed that the cardioprotective and antiarrhythmic effect of the endotoxin may be ascribed to the induction of nitric oxide synthase (NOS) and subsequent increase in the release of NO. NO may stabilize cardiac mast cells and consequently decrease the release of cytotoxic mediators from these cells. Prevention of degranulation of cardiac mast cells may be responsible for the cardioprotective and antiarrhythmic effects of the endotoxin.

Animals↗
PubMed1987

Synergistic action of human recombinant tumor necrosis factor with endotoxins or nontoxic poly A:U against solid Meth A tumors in mice.

Antitumor effects of i.v. injected human recombinant tumor necrosis factor (rTNF) against solid Meth A tumors in mice appeared to be critically dependent on the dose and were limited by its toxicity. Extensive necrosis and complete cures were only induced by doses having untoward effects, such as diarrhea, hypothermia, ruffled fur, and lethargy. Murine tumor necrosis serum (TNS, 0.5 ml) had about the same antitumor potential and induced all side effects except diarrhea. More extensive necrosis and approximate doubling of the incidence of complete regression in the absence of gross side effects were observed upon administration of a low dose of rTNF combined with detoxified endotoxin, nontoxic poly A:U, or submicrogram doses of toxic endotoxin. The separate constituents had little antitumor effects, if any at all. Increasing the dose of toxic endotoxin resulted in a further potentiation of necrosis, overt toxicity, but no cures. Muramyl dipeptide and interferon alpha/beta did not potentiate effects of rTNF. In vitro growth of Meth A cells was not inhibited by toxic endotoxin, rTNF or the combination, although TNS was highly inhibitory. Data show that therapeutic effects of rTNF and its synergy with endotoxin are not due to direct effects on the tumor cells and that the extent of prompt in vivo tumor necrosis does not predict the course of tumor growth. Therapeutic effects of both TNS and toxic endotoxin probably involve a synergy between low levels of TNF and other factors/effects induced by endotoxin. Detoxified endotoxin and poly A:U probably induce the latter effects and little or no TNF, so explaining the absence of side effects, their weak antitumor potential, and their powerful synergistic action with rTNF. A role for interferon alpha/beta as an induced synergistic factor is not likely. Muramyl dipeptide and TNF might share properties needed for synergy with endotoxins.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1984

The therapeutic significance of concomitant antitumor immunity. II. Passive transfer of concomitant immunity with Ly-1+2- T cells primes established tumors in T cell-deficient recipients for endotoxin-induced regression.

Intravenous injection of 50 micrograms bacterial endotoxin can cause complete regression of an established SA1 sarcoma, but not if the tumor ir growing in mice that are incapable of generating concomitant immunity because they have been made T cell-deficient by thymectomy and gamma-radiation (TXB mice). It also was shown that endotoxin fails to cause complete regression of a tumor that is either too large or too small. Only when administered on day 9 of tumor growth, at the time of peak concomitant immunity, did endotoxin cause the tumor to undergo complete regression. Direct evidence that the antitumor effect of endotoxin is dependent on concomitant immunity consisted in the demonstration that an SA1 sarcoma growing in TXB recipients can be primed for endotoxin-induced regression by IV infusion of splenic T cells from concomitantly immune donors bearing an endotoxin-susceptible 9-day tumor. Surprisingly, the donor T cells that primed the recipient tumor for endotoxin-induced regression were of the Ly-1+2- phenotype, as evidenced by their susceptibility to treatment with anti-Ly-1 antibody and complement, and their complete resistance to treatment with anti-Ly-2 antibody and complement. They were different, therefore, from the T cells that cause the regression of smaller tumors in gamma-irradiated recipients without the aid of endotoxin. It is suggested that the antitumor function of endotoxin depends on its ability to cause intratumor macrophages to acquire and express tumoricidal function, but only after the macrophages have been activated by Ly-1+2-tumor-sensitized T cells.

Animals↗
PubMed1982

Aspects of beneficial endotoxin-mediated effects.

The status of hyperreactivity and hyporeactivity following the administration of endotoxin in a susceptible host represents phenomena which are of interest in an attempt to understand the role of endotoxins in pathophysiological events in general. Two experimental approaches designed to examine these events are reported herein; i.v. injection with minute concentrations of endotoxin (10 ng of a BOIVIN endotoxin from E. coli 0111) induces tolerance against lethal doses of endotoxin (0.5 microgram or 5.0 microgram) within 24 h in hyperreactive NMRI mice that were infected 14 days before with BCG. Transfer of post-endotoxin serum from BCG infected mice, which contains a myriad of macrophage mediators and which induces nonspecific resistance to X-irradiation, renders a strain of mice (C3H/HeJ) that is hyporeactive to endotoxins, susceptible to the lethal effect of endotoxin. Studies of the role of the macrophage and its mediators in the experimental models described here may contribute to a further understanding of the mechanisms underlying endotoxin-induced biological activities.

Animals↗