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PubMed1994

Effect of lidocaine pretreatment on endotoxin-induced lung injury in rabbits.

BACKGROUND: It is well known that endotoxin causes acute lung injury resulting in adult respiratory distress syndrome. Numerous cellular and humoral factors such as macrophages, neutrophils, platelets, and inflammatory mediators (e.g., activated complements, cytokines, and arachidonic acid metabolites) are thought to play a pivotal role in the pathogenesis of endotoxin-induced lung injury. Furthermore, pulmonary edema in acute lung injury is associated with an increase in vascular permeability that may arise from a perturbation of the endothelial cell surface membrane. Lidocaine has been shown to inhibit function of these cells and stabilize cell membranes. The aim of the current study was to determine whether pretreatment with intravenous lidocaine could attenuate acute lung injury induced by endotoxin in rabbits. METHODS: Twenty-seven anesthetized male rabbits were randomly assigned to receive one of three treatments (n = 9 for each group); infusion of saline (as a control), infusion of Escherichia coli endotoxin (30 micrograms kg-1 over a 60-min period) without treatment with lidocaine, and infusion of endotoxin with treatment with lidocaine. A single dose of intravenous lidocaine 2 mg.kg-1 was administered 10 min before infusion of endotoxin and thereafter infused at a rate of 2 mg.kg-1.h-1 until 6 h after the start of endotoxin administration, when the animals were killed. The lungs of the rabbits were ventilated with 40% oxygen. Hemodynamics, peripheral leukocytes counts, and arterial oxygen tension were recorded during the ventilation period. After the observation, lung mechanics, cell fraction of bronchoalveolar lavage fluid (BALF), activated complements, cytokines, and arachidonic acid metabolites concentrations in BALF were measured and analyzed. The lung wet-to-dry-weight ratio and albumin concentrations in BALF were analyzed as an indices of pulmonary edema. The cypridina luciferin analog-dependent chemiluminescence (representing superoxide production) by neutrophils isolated from the pulmonary artery and light microscopic findings were compared among the three groups. RESULTS: Endotoxin caused decreases in peripheral leukocyte counts, lung compliance, and arterial oxygen tension, and increases in the lung wet-to dry-weight ratio, polymorphonuclear cell counts in BALF, and albumin, C3a, C5a, tumor necrosis factor alpha, interleukin-1 beta, and thromboxane B2 concentrations in BALF. Lidocaine pretreatment attenuated these changes. The cypridina luciferin analog--dependent chemiluminescence was greater in rabbits receiving endotoxin than in the control. Lidocaine pretreatment attenuated the increase in chemiluminescence. Endotoxin caused extensive morphologic lung damage, which was lessened by lidocaine. CONCLUSIONS: These results suggest that intravenous lidocaine pretreatment has a prophylactic effect on endotoxin-induced lung injury in rabbits. However, further studies are required to investigate the therapeutic (as an early posttreatment) effect of the drug given after lung injury because rabbits in the current study received lidocaine before endotoxemia.

Animals↗
PubMed1999

Prednisolone inhibits endotoxin-induced disseminated intravascular coagulation and improves mortality in rats: importance of inflammatory cytokine suppression.

In order to determine whether prednisolone has a protective effect against the development of disseminated intravascular coagulation (DIC), we measured the effect of prednisolone on changes in hemostatic parameters and plasma levels of inflammatory cytokines in endotoxin-treated rats. Decreases in platelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products and levels of thrombin-antithrombin III (TAT) complex following the administration of endotoxin, all of which are associated with DIC, were significantly suppressed by the administration of prednisolone. Heparin administration significantly suppressed changes in all these parameters except for the decrease in platelet count. The combination of prednisolone and heparin was more effective than either treatment alone. In order to determine whether these effects of prednisolone are correlated with the suppression of inflammatory cytokine production, we examined the relationship between changes in plasma levels of cytokine, the hemostatic parameters listed above, and mortality using a number of intervention regimens designed to alter events of the experimentally induced DIC. Changes in hemostatic parameters associated with DIC following 30 mg/kg per 4 h of endotoxin infusion were significantly suppressed by treatment with 1 mg/kg prednisolone 30 min before beginning endotoxin infusion, followed by administration of 250 U/kg heparin 2 h after the start of endotoxin infusion (prednisolone-endotoxin-heparin regimen). The heparin and prednisolone were administrated subcutaneously. The administration of prednisolone and heparin in the reverse order (i.e. heparin first and prednisolone second: heparin-endotoxin-prednisolone regimen) also suppressed changes in hemostatic parameters, albeit to a smaller degree. Cytokine production was also significantly suppressed by the first treatment, but was not affected by the regimen in which heparin was administered first. Administration of prednisolone alone or heparin alone 30 min before endotoxin significantly reduced the number of renal glomeruli with fibrin thrombi. Plasma levels of creatinine and alanine transferase were reduced only by prednisolone. Increased plasma levels of interleukin-1beta, tissue necrosis factor-alpha and interleukin-6 were suppressed by prednisolone but not by heparin, and there were significant correlations between plasma levels of TAT and cytokines. Prednisolone was more effective than heparin in reducing mortality at 24 h after 100 mg/kg over 4 h of endotoxin infusion (four of 20 versus 15 of 20 deaths for prednisolone and heparin, respectively). These findings suggest that prednisolone inhibits the development of endotoxin-induced DIC and reduces mortality by a different mechanism than heparin, possibly through suppressing the production of inflammatory cytokines. Prednisolone may be efficacious in preventing DIC and multiple organ dysfunction caused by endotoxin.

Animals↗
PubMed1996

High-dose recombinant endotoxin neutralizing protein improves survival in rabbits, with Escherichia coli sepsis.

OBJECTIVE: To assess the benefit of a recombinant endotoxin neutralizing protein from Limulus polyphemus in treating Gram-negative bacterial sepsis in rabbits. DESIGN: Prospective, blinded, controlled, laboratory trial. SETTING: Animal research laboratory. SUBJECTS: New Zealand White rabbits. INTERVENTIONS: We established a rabbit model of Escherichia coli peritonitis and bacteremia, with high mortality rate, despite treatment with gentamicin and ceftriaxone. Twenty-five pairs of male New Zealand White rabbits were challenged intraperitoneally with E. coli O18ac K1 in 5% porcine mucin (mean 7 x 10(1) colony-forming units). All animals were treated with intravenous gentamicin (2.5 mg/kg) and ceftriaxone (100 mg/kg), and with either intravenous endotoxin neutralizing protein (50 mg/kg) or saline 1 hr after E. coli challenge. MEASUREMENTS AND MAIN RESULTS: All animals were bacteremic 1 hr after challenge (mean 3.6 x 10(5) colony-forming units/mL). Animals in both groups developed tachycardia, hypotension, and acidosis (NS). Geometric mean serum endotoxin and tumor necrosis factor (TNF) concentrations were significantly ( p < .001) higher 1 hr after challenge compared with baseline prechallenge concentrations in both groups. From 1 to 2 hrs after challenge, endotoxin concentrations increased 2.5-fold in control animals (95% confidence interval = 13.1 to 32.9 endotoxin units/mL, p = .024), whereas endotoxin concentrations increased only 1.2-fold in endotoxin neutralizing protein-treated animals (95% confidence interval = 20.4 to 23.6 endotoxin units/mL, NS). TNF concentrations increased significantly (p < .001) in both groups from 1 to 2 hrs after challenge. Eighteen (72%) of 25 endotoxin neutralizing protein-treated animals vs. 11 (44%) of 25 controls survived 24 hrs (p = .032). CONCLUSIONS: Treatment with endotoxin neutralizing protein had the following effects: a) the increase in serum endotoxin was blunted, but not TNF concentrations measured 1 hr after antibiotic treatment; and b) survival in rabbits with E. Coli sepsis was improved.

Animals↗
PubMed1998

Aminoguanidine attenuates endotoxin-induced acute lung injury in rabbits.

OBJECTIVE: To assess the effect of aminoguanidine, a selective inducible nitric oxide synthase inhibitor, on endotoxin-induced acute lung injury in rabbits. DESIGN: Prospective, blinded, controlled laboratory study. SETTING: University research laboratory. SUBJECTS: Twenty-eight male rabbits. INTERVENTIONS: The animals were randomly assigned to receive one of four treatments (n = 7 for each group): infusion of saline only (S-S group), infusion of saline and aminoguanidine (S-AG group), infusion of Escherichia coli endotoxin (5 mg/kg over 60 mins) (E-S group), and infusion of endotoxin and aminoguanidine (E-AG group). Fifteen minutes before infusion of endotoxin (E-S and E-AG groups) or saline (S-S and S-AG groups), the animals received an intravenous injection of 1 mg/kg of aminoguanidine (S-AG and E-AG groups) or saline (S-S and E-S groups). The same dose of aminoguanidine or saline was given 1 hr after the end of endotoxin or saline infusion. The lungs of the rabbits were ventilated with 40% oxygen. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, peripheral leukocyte counts, and PaO2 were recorded during the ventilation period (6 hrs). After these observations were made, lung mechanics, cell fraction of bronchoalveolar lavage fluid, and concentrations of thromboxane A2 and prostacyclin metabolites in bronchoalveolar lavage fluid were determined. The wet weight/dry weight ratio of the lung and albumin concentrations in bronchoalveolar lavage fluid were analyzed as indices of pulmonary edema. Endotoxin decreased the lung compliance and PaO2 and increased the wet weight/dry weight ratio, neutrophil counts, and albumin concentrations in bronchoalveolar lavage fluid. The bronchoalveolar lavage fluid concentrations of thromboxane B2 in bronchoalveolar lavage fluid were increased by infusion of endotoxin. Aminoguanidine attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by aminoguanidine. CONCLUSIONS: Aminoguanidine given intravenously before and after endotoxin attenuated endotoxin-induced lung injury in rabbits. These findings suggest that inducible nitric oxide synthase inhibition may be useful in the treatment of endotoxin-induced lung injury. However, further studies are required to determine the optimal dosage of aminoguanidine, when the inhibitor is given alone as therapy after lung injury.

Animals↗
PubMed1999

Effect of endotoxin shock on the clearance of lidocaine and indocyanine green in the perfused rat liver.

Endotoxin administration and cecal ligation and puncture produce significant hepatocellular dysfunction when studied in vivo. Specific factors that are present in vivo after endotoxin administration and cecal ligation and puncture, such as alterations in liver blood flow, circulating mediators, and hypoxia, can alter hepatic function. In this study, we used an isolated perfused liver to evaluate the effects of in vivo administration of endotoxin on hepatic function using indocyanine green (ICG) as a global marker of function and lidocaine and its metabolite, MEGX, as specific markers of the CYP450 enzyme system. Endotoxin (Escherichia coli; 45 mg/kg i.p.) was administered to rats followed by a 6-h monitoring before preparation of the isolated in situ perfused liver. Livers from control and endotoxin groups received either ICG (control, n = 6; endotoxin, n = 5) or lidocaine (control, n = 8; endotoxin, n = 8). A separate group of rats (n = 6) received cimetidine (an inhibitor of the CYP450 enzyme system) at a dose of 80 mg/kg daily for 3 days. Livers were perfused via the portal vein by using a single-pass system with a balanced salt solution 6 h after receiving either endotoxin or saline or 24 h after receiving the last dose of cimetidine. After a 40-min stabilization period, ICG or lidocaine was infused via the portal vein until steady-state concentrations were reached in the venous outflow. The total hepatic clearance and intrinsic hepatic clearance for ICG and lidocaine were unchanged in the livers obtained from endotoxin-treated rats. This model could adequately detect CYP450 inhibition because cimetidine-treated rats had significantly lower initial MEGX concentrations (0.63 +/- 0.03 mg/L) compared with control (0.77 +/- 0.03 mg/L) and endotoxin-treated (0.74 +/- 0.04 mg/L) rats. Septic livers had significantly higher initial hepatic oxygen consumption (HVO2) than did control livers (45 +/- 3 microL/min/g vs 82 +/- 9 microL/min/g). The HVO2 remained higher in the septic livers and significantly increased throughout the study, which demonstrated that the livers remained viable and functional. These data indicate that there is no detectable hepatocellular dysfunction after endotoxin shock using ICG, lidocaine, and MEGX in the isolated perfused liver; therefore the dysfunction reported from in vivo studies may be reversible when the liver is removed from the shocked environment.

Anesthetics, Local↗
PubMed1976

Tolerance and other biological properties of Vibrio parahaemolyticus endotoxins.

Biological properties of endotoxins prepared from three strains of Vibrio parahaemolyticus were compared with reference to commercially prepared Salmonella typhi endotoxin. Endotoxin assays performed in rabbits included dermal Shwartzman reactivity, pyrogenicity, heat stability, and ability to induce tolerance as well as cross-tolerance. Mice were used for endotoxin LD50 determinations. Results showed V. parahaemolyticus endotoxins were similar to that of S. typhi strain O901. Induction of tolerance to V. parahaemolyticus strain 11590 endotoxin resulted in complete cross-tolerance to S. typhi endotoxin, and vice versa. Partial cross-tolerance to S. typhi endotoxin was demonstrated with rabbits rendered tolerant to endotoxin from V. parahaemolyticus strains Sak-3 and FC1011. Absorption spectra, nitrogen, phosphorus and carbohydrate analyses revealed additional similarities between endotoxins from V. parahaemolyticus and endotoxin from a member of the Enterbacteriaceae.

Animals↗
PubMed1984

Calcium behavior in endotoxin-poisoned mice: especially calcium accumulation in mitochondria.

A possible role of intracellular Ca2+ and participation of calmodulin in cellular metabolism in endotoxin-poisoned mice were investigated. The levels of calcium in liver cytosol and liver mitochondria fractions in poisoned mice were markedly higher 18-48 hr after endotoxin injection than in the control mice. On the other hand, the levels of serum calcium in the poisoned mice were about 20% lower at 18 hr than in the controls. The serum calcium levels in mice injected with 50 and 100 micrograms of endotoxin showed no dose-response effect, but a dose-response effect was observed at a dose of 200-400 micrograms. The serum Ca2+ levels in endotoxin-tolerant mice were similar to those in the control mice. The levels in mice injected with glucocorticoid-antagonizing factor mice were about 14% lower at 3 hr than in the controls. The mice fed a vitamin D3- and calcium-free diet showed a higher mortality rate in the early stage (12-18 hr) of endotoxication than that of the mice fed a normal diet. The lipid peroxide levels and Ca2+-ATPase activity in the liver mitochondria fraction in endotoxin-poisoned mice showed a higher level than those of the control mice. There was little or no difference in the levels of serum glucose between the mice injected with calmodulin antagonist (trifluoperazine, TFP) plus endotoxin and those given endotoxin alone. However, the liver glycogen levels in TFP plus endotoxin-treated mice were markedly higher than that in mice given endotoxin alone. Furthermore, calcium antagonist (verapamil) plus endotoxin-treated mice had about a 40% higher survival rate after 72 hr than those given endotoxin alone. The findings suggest that there is a possibility of participation of the Ca2+-calmodulin system in carbohydrate metabolic disorders during endotoxemia and that the changes in intracellular Ca2+ may result in various metabolic disorders.

Animals↗
PubMed2004

Determinants of endotoxin levels in living environments of farmers' children and their peers from rural areas.

BACKGROUND: Lower frequencies of asthma and hayfever have been observed in children with contact to livestock. At school age, the amount of endotoxin measured in the dust of children's mattresses is inversely related to the occurrence of atopic asthma, hayfever and atopic sensitization both in children from farming and non-farming households. OBJECTIVE: The aim of the present study was to investigate which home and lifestyle characteristics of farm and non-farm families contribute to endotoxin levels measured in different indoor home environments. METHODS: In the framework of the Allergy and Endotoxin (ALEX) Study, endotoxin was measured in dust samples from the living room floor and the child's mattress of 319 farmers' families and 493 non-farming families, and in settled dust from stables. Endotoxin content of all dust samples was determined by a kinetic Limulus assay (Limulus-Amebocyte-Lysate test). Information about the child's activities on farms, home characteristics and cleaning behaviours was obtained from parental questionnaires. RESULTS: Endotoxin levels in stables did not predict the amount of endotoxin measured in floors or mattresses. However, a dose-dependent association between the child's activity on the farm and indoor home endotoxin levels was observed, both in farm and non-farm children. In non-farm children pet keeping and the frequency of floor cleaning were additionally associated with endotoxin levels, whereas in farm children parental farm activities, study area, time since last cleaning, the mattress type as well as younger age of the children contributed to increased microbial exposure. CONCLUSION: These results demonstrate that regular contact to farm animals increases indoor home endotoxin concentrations, both in farm and non-farm children, and might thus explain the protective effect of contact to livestock on atopic outcomes. To assess children's individual exposure to a microbial environment, measures of mattress dust exposure are needed as stable endotoxin concentrations were not associated with indoor home levels.

Agriculture↗
PubMed2005

Mapping the areas sensitive to long-term endotoxin tolerance in the rat brain: a c-fos mRNA study.

We have recently found that a single endotoxin administration to rats reduced the hypothalamic-pituitary-adrenal response to another endotoxin administration 4 weeks later, which may be an example of the well-known phenomenon of endotoxin tolerance. However, the time elapsed between the two doses of endotoxin was long enough to consider the above results as an example of late tolerance, whose mechanisms are poorly characterized. To know if the brain plays a role in this phenomenon and to characterize the putative areas involved, we compared the c-fos mRNA response after a final dose of endotoxin in animals given vehicle or endotoxin 4 weeks before. Endotoxin caused a widespread induction of c-fos mRNA in the brain, similar to that previously reported by other laboratories. Whereas most of the brain areas were not sensitive to the previous experience with endotoxin, a few showed a reduced response in endotoxin-pretreated rats: the parvocellular and magnocellular regions of the paraventricular hypothalamic nucleus, the central amygdala, the lateral division of the bed nucleus and the locus coeruleus. We hypothesize that late tolerance to endotoxin may involve plastic changes in the brain, likely to be located in the central amygdala. The reduced activation of the central amygdala in rats previously treated with endotoxin may, in turn, reduce the activation of other brain areas, including the hypothalamic paraventicular nucleus.

Animals↗
PubMed1973

Further observations on mesenteric vasoconstriction, survival and the clotting defect after endotoxin administration.

1. The initial response after endotoxin administration (3 mg/kg) in cats involved pulmonary vasoconstriction. This was not seen when endotoxin was given by slow infusion and it could be prevented after a bolus injection of endotoxin by pretreatment of the cats with aspirin (10 mg/kg). Intense mesenteric vasoconstriction occurred in all the cats.2. The mesenteric vasoconstriction was a specific response of the mesenteric blood vessels. At the time the mesenteric bed constricted, the renal bed dilated, the hepatic arterial bed remained unchanged and the smooth muscle of the intestinal wall relaxed.3. Arterial blood from cats with a fully developed mesenteric vasoconstriction after endotoxin administration was perfused through a normal intestine. No immediate vasoconstriction developed but the perfused intestine constricted slowly over 60 minutes. This suggests that mesenteric constriction was not due to circulating vasoconstrictor factors or the intestinal innervation, but involved a slow local mechanism within the intestine. It could not be prevented or reversed by a variety of pharmacological agents.4. These observations suggest that endotoxin caused a unique type of mesenteric vasoconstriction in cats by a local mechanism which took up to 60 min to develop, was sufficiently potent to reduce mesenteric flow to <30% control, and was maintained until death of the cats. Blood from these animals did not clot when placed in a glass tube.5. The mesenteric constriction and the clotting defect could be prevented by repeated administration of aminophylline and dextran solution before and after a bolus intravenous injection of endotoxin. Arterial pressure and mesenteric flow were maintained for at least 10 h in these experiments. Inadequate treatment intensified rather than reduced the intestinal mucosal damage.6. Cats were treated with aspirin, endotoxin and the optimal regimen for prevention of the mesenteric constriction and allowed to recover from the anaesthetic agent. In this series, 63% survived indefinitely compared to 25% after aspirin and endotoxin treatment and 0% after endotoxin alone.7. The possible mechanisms of action of aspirin and aminophylline-dextran solution are discussed. Our failure to obtain 100% survival is probably due to pulmonary damage which develops 10-24 h after endotoxin administration. This delayed pulmonary action of endotoxin is not prevented by aspirin treatment and it seems unlikely that aspirin will be of any value in the treatment of the pulmonary lesion in man.

Aminophylline↗
PubMed1995

Influence of various dust sampling and extraction methods on the measurement of airborne endotoxin.

The influence of various filter types and extraction conditions on the quantitation of airborne endotoxin with the Limulus amebocyte lysate test was studied by using airborne dusts sampled in a potato processing plant. Samples were collected with an apparatus designed to provide parallel samples. Data from the parallel-sampling experiment were statistically evaluated by using analysis of variance. In addition, the influence of storage conditions on the detectable endotoxin concentration was investigated by using commercially available lipopolysaccharides (LPS) and endotoxin-containing house dust extracts. The endotoxin extraction efficiency of 0.05% Tween 20 in pyrogen-free water was seven times higher than that of pyrogen-free water only. Two-times-greater amounts of endotoxin were extracted from glass fiber, Teflon, and polycarbonate filters than from cellulose ester filters. The temperature and shaking intensity during extraction were not related to the extraction efficiency. Repeated freeze (-20 degrees C)-and-thaw cycles with commercial LPS reconstituted in pyrogen-free water had a dramatic effect on the detectable endotoxin level. A 25% loss in endotoxin activity per freeze-thaw cycle was observed. Storage of LPS samples for a period of 1 year at 7 degrees C had no effect on the endotoxin level. House dust extracts showed a decrease of about 20% in the endotoxin level after they had been frozen and thawed for a second time. The use of different container materials (borosilicate glass, "soft" glass, and polypropylene) did not result in different endotoxin levels. This study indicates that the assessment of endotoxin exposure may differ considerably between groups when different sampling, extraction, and storage procedures are employed.

Air Pollutants↗
PubMed1974

Disaggregation of endotoxin by isolated rat liver plasma membranes and lack of product binding.

The interaction of bacterial endotoxin with isolated rat liver cell membranes was studied to determine the extent and nature of any binding. Serratia marcescens endotoxin was incubated with isolated rat liver plasma membranes for varying periods of time at 37 C, and this mixture was then centrifuged through a discontinous sucrose density gradient. The membranes banded primarily at the 35 to 45% sucrose interface, whether or not they had been incubated with endotoxin. The endotoxin distributed itself throughout the gradient except when incubated with membranes, in which case it failed to sediment. This membrane-induced alteration in sedimentation could be prevented by heat inactivation of the membranes, and was found to be pH, time, temperature, and concentration dependent. There was neither associated degradation of the endotoxin, as measured by molecular sieve chromatography, nor loss in toxicity, as determined in lead-sensitized rats. These observations are consistent with an enzymatic disaggregation of the endotoxin by membranes and could represent a step in the uptake of the endotoxin by the reticuloendothelial system. No significant binding of this disaggregated endotoxin to the membranes could be detected, either after gradient separation or after repeated washing. This finding strongly suggests that, at least in cells that are active in the uptake of endotoxin, membrane-endotoxin interactions may be relatively transitory in nature, and that firm adherence to such membranes may not be a central feature of endotoxin toxicity.

Animals↗
PubMed1965

Hypoferremia in mice and its application to the bioassay of endotoxin.

Baker, Phillip J. (University of Wisconsin, Madison), and J. B. Wilson. Hypoferremia in mice and its application to the bioassay of endotoxin. J. Bacteriol. 90:903-910. 1965.-The ability of endotoxin to induce hypoferremia in mice was used for the bioassay of endotoxin. A marked depression in the serum-iron levels of mice occurred 12 hr after the intraperitoneal injection of 0.01 to 100 mug of Escherichia coli endotoxin; similar results were obtained with 1.0 to 100 mug of Brucella abortus endotoxin. This biological response to endotoxin appeared to be specific, reproducible, and dose-dependent. As heat-killed cells of B. abortus and E. coli were also able to induce hypoferremia, this bioassay could be employed for the determination of the endotoxin content of killed-cell preparations. Treatment of endotoxin by acid hydrolysis, acetylation, or pyridine-formic acid greatly diminished the hypoferremic response as well as its lethality for mice. Pretreatment of mice with Thorotrast had little effect upon the ability of endotoxin to induce hypoferremia; however, a stimulation of the activity of the reticuloendothelial system (RES) by treatment of mice with triolein markedly reduced the ability of endotoxin to induce hypoferremia. The relationship between the hypoferremic response to endotoxin and alterations in the activity of the RES are discussed.

Animals↗
PubMed1968

Role of tryptophan pyrrolase in endotoxin poisoning.

Using substrate induction as a tool, we attempted to determine the role of tryptophan pyrrolase in the response to endotoxin in mice. Previous results have shown that the administration of the ld(50) of endotoxin lowers tryptophan pyrrolase activity. alpha-Methyltryptophan was found to maintain tryptophan pyrrolase activity above control levels in endotoxin-poisoned mice without increasing survival. 5-Hydroxytryptophan, by contrast, lowered tryptophan pyrrolase activity but did not sensitize mice to endotoxin. These results suggest that tryptophan pyrrolase per se does not play a unique role in survival of mice poisoned with endotoxin. This enzyme, however, may reflect the fate of other liver enzymes inducible by adrenocorticoids. In mice given concurrent injections of tryptophan and endotoxin, tryptophan pyrrolase activity was elevated to a level intermediate between that of normal mice and that of mice given tryptophan alone. The mice injected with tryptophan and endotoxin also had about the same mortality as mice given endotoxin alone. Mice treated with tryptophan 4 hr after endotoxin, at a time when the substrate did not fully elevate tryptophan pyrrolase activity, died convulsively and in larger numbers than those given endotoxin alone. This effect was reversed by prior treatment with cyproheptadine, an antiserotonin drug. These results indicate that the depression of tryptophan pyrrolase activity previously observed in vitro after injection of endotoxin reflects an actual decrease in the in vivo activity of the enzyme.

Animals↗
PubMed1994

In vitro endotoxin exposure induces contractile dysfunction in adult rat cardiac myocytes.

In vivo endotoxin treatment causes a nitric oxide-mediated hypocontractility in cardiac myocytes. The objective of this study was to assess whether in vitro endotoxin exposure confers similar contractile defects in adult rat cardiac cells. We found that incubation of cardiac myocytes for 6 h with 10-100 ng/ml endotoxin resulted in progressive time- and protein synthesis-dependent decreases in electrically stimulated twitch magnitudes and increased contraction and relaxation times. Serum was not required for the endotoxin-induced hypocontractility. The endotoxin-induced defect in contractility was reversed over time, since myocytes continuously incubated with endotoxin for 24 h exhibited normal contractility; in contrast, control cells incubated for 18 h were suppressed by a subsequent 6-h exposure to endotoxin. Nitric oxide synthase activity was increased after a 6-h endotoxin treatment as evidenced by a dose-dependent enhanced conversion of [3H]arginine to [3H]citrulline and by elevated guanosine 3',5'-cyclic monophosphate levels. Superfusion of endotoxin-incubated cells with N omega-nitro-L-arginine methyl ester restored contractile function, whereas superfusion with L-arginine reimposed abnormal contractility. Naive myocytes superfused with 8-bromoguanosine 3',5'-cyclic monophosphate expressed contractile defects similar to those induced by endotoxin. These findings demonstrate that endotoxin has direct negative effects on cardiac cell contractile function and that induction of NO synthase activity is a primary intracellular mediator of the diminished contractility.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Differential effects of caspase inhibitors on endotoxin-induced myocardial dysfunction and heart apoptosis.

Endotoxin is one of the major factors causing myocardial depression and death during sepsis in humans. Recently, it was reported that endotoxin may induce cardiomyocyte apoptosis. Also, multiple caspase activation has been implicated in endotoxin-induced apoptosis in several organ systems. In this study, we investigated whether endotoxin would increase myocardial caspase activities and evaluated the effects of in vivo administration (3 mg/kg) of the broad-spectrum caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone(z-VAD.fmk), the caspase-3-like inhibitor benzyloxycarbonyl-Asp-Glu-Val-Asp-chloromethylketone (z-DEVD.cmk), and the caspase-1-like inhibitor acetyl-Tyr-Val-Ala-Asp-chloromethylketone (Ac-YVAD. fmk), on endotoxin-induced myocardial dysfunction and apoptosis. Endotoxin administration (10 mg/kg iv) induced myocardial contractile dysfunction that was associated with caspase activity increases and nuclear apoptosis. Broad-spectrum z-VAD.fmk and z-DEVD.cmk improved endotoxin-induced myocardial dysfunction and reduced caspase activation and nuclear apoptosis when given immediately and 2 h after endotoxin. In contrast, no effects of Ac-YVAD.fmk were observed on myocardial function and caspase-induced apoptosis. Administration of caspase inhibitors 4 h after endotoxin treatment was not able to protect the rat heart from myocardial dysfunction and nuclear apoptosis. These observations provide evidence that in our model, caspase activation plays a role in endotoxin-induced myocardial apoptosis. Caspase inhibition strategy may represent a therapeutic approach to endotoxin-induced myocardial dysfunction.

Amino Acid Chloromethyl Ketones↗
PubMed1986

Dexamethasone protects against high-dose endotoxin without loss of tolerance to oxygen.

Endotoxin (500 micrograms/kg)-treated rats are very tolerant to hyperoxia (greater than 95% O2, 1 ATA). We have now attempted to determine if dexamethasone given to rats 1 h before a usually lethal dose of endotoxin would diminish endotoxin's lethality without substantially abrogating its capacity to confer tolerance to hyperoxia. Endotoxin (20 mg/kg) given alone killed 70-80% of air- or O2-breathing rats within 24 h; dexamethasone (0.6 mg) given 1 h before endotoxin decreased mortality at 24 h to 10-15%. About 90% of the rats that were alive 24 h after receiving dexamethasone plus endotoxin (20 mg/kg) survived 72 h of hyperoxia. Dexamethasone plus endotoxin (10 mg/kg) provided as much protection against pulmonary edema resulting from 72 h of hyperoxia as did 500 micrograms/kg endotoxin alone. Tolerance to hyperoxia produced by dexamethasone plus high-dose endotoxin was accompanied by a rise in the activity in the lung of antioxidant enzymes. We conclude that dexamethasone protects rats against the lethal effects of high doses of endotoxin without interfering with endotoxin's capacity to engender tolerance to hyperoxia.

Animals↗
PubMed2006

Caspase activation contributes to endotoxin-induced diaphragm weakness.

Infections produce significant respiratory muscle weakness, but the mechanisms by which inflammation reduces muscle force remain incompletely understood. Recent work suggests that caspase 3 releases actin and myosin from the contractile protein lattice, so we postulated that infections may reduce skeletal muscle force by activating caspase 3. The present experiments were designed to test this hypothesis by determining 1) diaphragm caspase 3 activation in the diaphragm after endotoxin and 2) the effect of a broad-spectrum caspase inhibitor, Z-Val-Ala-Asp(OCH3)-fluoromethylketone (zVAD-fmk), and a selective caspase 3 inhibitor, N-acetyl-Asp-Glu-Val-Asp-al (DEVD-CHO), on endotoxin-induced diaphragm weakness. Caspase 3 activation was assessed by measuring caspase protein levels and by measuring cleavage of a fluorogenic substrate. Diaphragm force was measured in response to electrical stimulation (1-150 Hz). Caspase-mediated spectrin degradation was assessed by Western blotting. Parameters were compared in mice given saline, endotoxin (12 mg/kg ip), endotoxin plus zVAD-fmk (3 mg/kg iv), zVAD-fmk alone, or endotoxin plus DEVD-CHO (3 mg/kg iv). Endotoxin increased diaphragm active caspase 3 protein (P<0.003), increased caspase 3 activity (P<0.002), increased diaphragm spectrin degradation (P<0.001), and reduced diaphragm force (P<0.001). Administration of zVAD-fmk or DEVD-CHO prevented endotoxin-induced weakness (e.g., force in response to 150-Hz stimulation was 23.8+/-1.4, 12.1+/-1.3, 23.5+/-0.8, 22.7+/-1.3, and 24.4+/-0.8 N/cm2, respectively, for control, endotoxin, endotoxin plus zVAD-fmk, endotoxin plus DEVD-CHO, and zVAD-fmk alone treated groups, P<0.001). Caspase inhibitors also prevented spectrin degradation. In conclusion, endotoxin administration elicits significant diaphragm caspase 3 activation and caspase-mediated diaphragmatic weakness.

Actins↗