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PubMed1997

The endothelin receptor antagonist, bosentan, in combination with the cyclooxygenase inhibitor, diclofenac, counteracts pulmonary hypertension in porcine endotoxin shock.

OBJECTIVE: To prevent endotoxin-induced pulmonary hypertension in the pig with a combination of a nonpeptide mixed endothelin receptor antagonist, bosentan, and a cyclooxygenase inhibitor, diclofenac. DESIGN: Prospective, controlled trial. SETTING: Animal laboratory at a large university medical center. SUBJECTS: Twelve domestic pigs, weighing 17.5 to 27 kg. INTERVENTIONS: Endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide endotoxin (15 micrograms/kg/hr). Six pigs receiving only endotoxin served as controls. Six pigs were pretreated with intravenous bolus injections of bosentan (5 mg/kg) and diclofenac (3 mg/kg) followed by a continuous bosentan infusion (2.5 mg/kg/hr). MEASUREMENTS AND MAIN RESULTS: Systemic hemodynamics and regional circulation were measured using ultrasonic flow probes. Arterial and mixed venous blood samples were collected regularty for determination of Big endothelin-1-like immunoreactivity, endothelin-1-like immunoreactivity, norepinephrine, and blood gases. The bosentan/diclofenac pretreatment per se significantly decreased mean pulmonary arterial pressure (p < .001), pulmonary vascular resistance index (p < .001), and mean arterial blood pressure (p < .001), but cardiac index did not change. Splenic blood flow increased (p < .01) while renal blood flow decreased (p < .001). In addition, intestinal blood flow decreased slightly (p < .05). In the control group, only three animals survived the 3 hrs of endotoxin infusion, while all pretreated animals survived. The biphasic increase in mean pulmonary arterial pressure and pulmonary vascular resistance index seen in control animals during endotoxemia was markedly attenuated in animals pretreated with the bosentan/diclofenac combination. The pretreated group generally showed a favorable hemodynamic course, with a relatively higher cardiac index, stroke volume index, and splenic and renal blood flow. In control animals, a pronounced metabolic acidosis developed during endotoxin infusion. A relatively higher arterial plasma concentration of endothelin-1-like immunoreactivity was reached in pretreated animals, while the Big endothelin-1-like immunoreactivity plasma increase was similar in both groups. Arterial concentrations of norepinephrine were significantly (p < .01) higher in control animals when compared with diclofenac/bosentan-treated animals. CONCLUSIONS: The combination of bosentan and diclofenac induced systemic and pulmonary vasodilation in the intrinsic state. During endotoxin shock, this drug combination efficiently counteracts pulmonary hypertension and improves cardiac performance and splenic and renal blood flow. These favorable circulatory effects may have resulted in a reduction of both sympathetic nervous system activation and metabolic acidosis. Thus, we conclude that the endothelin receptors participate in intrinsic regulation of vascular tone in the anesthetized pig. During endotoxin shock, blockade of these receptors, as well as inhibition of the cyclooxygenase enzymes, contributes to a less adverse effect on the systemic and pulmonary circulation.

Animals↗
PubMed1998

ONO-5046, an elastase inhibitor, attenuates liver mitochondrial dysfunction after endotoxin.

OBJECTIVE: To investigate the effect of ONO-5046, an elastase inhibitor, on liver mitochondrial dysfunction after endotoxin administration. DESIGN: Prospective, randomized, controlled animal study. SETTING: Research laboratory. SUBJECTS: Male Hartley guinea pigs. INTERVENTIONS: Endotoxin shock was induced by intravenous infusion of Escherichia coli lipopolysaccharide endotoxin (50 mg/kg). Six guinea pigs were treated with endotoxin and saline. Twenty-four guinea pigs received 5, 10, and 30 mg/kg/hr of ONO-5046 after endotoxin administration. Six guinea pigs received only saline. MEASUREMENTS AND MAIN RESULTS: We measured oxygen uptake in state 3 (substrate and adenosine 5'-diphosphate [ADP]) and state 4 (excess substrate, no ADP), as well as the respiratory control ratio (state 3/state 4), adenosine 5'-diphosphate/oxygen ratio (ADP/O), and arterial ketone body ratio. ONO-5046 was dose dependently effective in liver mitochondrial oxidative phosphorylation, such as oxygen uptake in stage 4, respiratory control ratio, adenosine triphosphate synthesis, ADP/O, and arterial ketone body ratio when ONO-5046 was started 30 mins after endotoxin. The administration of 30 mg/kg/hr of ONO-5046 improved mean blood pressure, which had decreased after endotoxin. CONCLUSION: ONO-5046 attenuates the endotoxin-induced liver mitochondrial dysfunctions that may be related to increased liver blood flow.

Adenosine Diphosphate↗
PubMed1996

Dibutyryl cAMP improves systemic vasoconstriction caused by endotoxin in dogs.

We studied whether dibutyryl cyclic adenosine monophosphate (DbcAMP), which freely penetrates into the cells, improves systemic vasoconstriction caused by endotoxin in dogs. Thirteen anesthetized dogs were randomized into three groups. The endotoxin (ETX) group (n = 5) received only Escherichia coli endotoxin (3 mg.kg-1, intravenously). The ETX + DbcAMP group (n =5) received DbcAMP (6 mg.kg-1, intravenously) 30 min before the administration of endotoxin. The DbcAMP group received the same dose of DbcAMP 30 min after administration of saline. In the ETX group, systemic blood pressure and cardiac index significantly decreased, and systemic vascular resistance significantly increased, while in the ETX + DbcAMP group, increases in systemic and pulmonary vascular resistances after the administration of endotoxin were attenuated. DbcAMP did not cause hemodynamic changes in normal dogs. Plasma concentrations in thromboxane B2 in the ETX group were higher than in the ETX + DbcAMP group. Also, the change in plasma cyclic AMP concentrations showed a good logarithmic correlation with the change in plasma thromboxane B2 concentrations after the administration of endotoxin (r = .908, log (delta T x B2) = -.002* (delta cAMP) + 3.786). We conclude that DbcAMP improves systemic vasoconstriction caused by endotoxin in dogs. The beneficial mechanism of DbcAMP on systemic vasoconstriction after the administration of endotoxin may be partially due to inhibition of thromboxane B2.

Animals↗
PubMed1998

Effect of liposome-encapsulated hemoglobin on the development of endotoxin-induced shock in the rat.

Liposome-encapsulated hemoglobin (LEH) is an experimental oxygen-carrying resuscitation fluid. Because LEH is cleared from the circulation primarily by the reticuloendothelial system, its effect on the development of sepsis remains a major concern. Thus, the present study aimed to evaluate whether LEH modifies consequences of endotoxemia in the conscious normovolemic rat. LEH infusion at 10% of estimated blood volume (n = 10) did not affect mortality (30%, p < .05) and serum tumor necrosis factor-alpha levels (6204 +/- 414, p < .05) induced by 3.6 mg/kg Escherichia coli endotoxin administered (intravenous bolus) 22 h later. In contrast, when a shorter LEH-endotoxin time interval (<12 h, n = 10) or a higher dose of endotoxin (14.4 mg/kg, n = 20) was tested, LEH enhanced endotoxin-induced mortality (90% and 100%, respectively, p < .05) and broadened serum tumor necrosis factor-alpha response without modifying its peak levels. LEH (n = 20) did not exacerbate the endotoxin-induced tachycardia, leukopenia, and thrombocytopenia. Therefore, in this model, the effect of LEH on endotoxin-induced responses was dependent on the time interval between LEH and endotoxin administration as well as the endotoxin dose. The clinical relevance of these results should be further investigated.

Animals↗
PubMed2006

Intravenous administration of choline or cdp-choline improves platelet count and platelet closure times in endotoxin-treated dogs.

This study was performed to assess the effects of intravenous choline chloride and cytidine-5'-diphosphate choline (CDP-choline) treatments on circulating platelet, white blood cell, and red blood cell counts and platelet functions in response to endotoxin. Saline (0.2 mL/kg), choline chloride (20 mg/kg), or CDP-choline (70 mg/kg) were given intravenously three times at 4-h intervals, and endotoxemia was induced by endotoxin (E. coli 055:B5, 20 microg/kg) infusion, 5 min after the first treatment. Blood samples were collected before and at multiple time points after the challenge, for a panel of hematologic parameters and platelet closure times measured by PFA-100. In saline-treated dogs, circulating platelet counts decreased by 85% (P < 0.001) at 0.5 h and remained low by 36%-80% (P < 0.5-0.001) 1-12 h after endotoxin. Circulating WBC counts decreased by 80%-90% (P < 0.001) at 0.5-2 h, and increased (P < 0.001) by 190% 12 h after the endotoxin. In response to endotoxin, RBCs increased by 10%-13% (P < 0.05) at 1-12 h. Endotoxin-induced decline in circulating platelets was attenuated at 0.5 h (P < 0.05-0.01) and reversed at 1-12 h (P < 0.05-0.001) by choline. Platelet closure times were shortened from 81 +/- 10 s and 135 +/- 10 s to 29 +/- 5 s (P < 0.001) and 60 +/- 3 s (P < 0.001) at 0.5 h, and prolonged (P < 0.001) at 1-8 h after endotoxin induction. Endotoxin-induced shortening in platelet closure times was attenuated (P < 0.05) and blocked (P < 0.01) by choline and CDP-choline, respectively. These results showed that choline and CDP-choline treatments improved circulating platelet counts and platelet function during endotoxemia in dogs.

Animals↗
PubMed2006

Protective effects of endotoxin in a rat model of chronic inflammation are accompanied by suppressed secretion of pro-inflammatory cytokines and biphasic alteration in hypothalamo-pituitary-adrenal axis activity.

We have previously demonstrated that Gram-negative bacterial endotoxin can exert long-term protective effects against the chronic inflammatory disease adjuvant arthritis in rats. The present study was designed to investigate the mechanisms and time-course of hypothalamo-pituitary-adrenocortical (HPA) axis activity and cytokine secretion underlying this phenomenon. Rats were injected with endotoxin (lipopolysaccharide) and blood was collected either 7 or 21 days later. Priming with endotoxin induced a biphasic alteration in secretion of adrenocorticotrophic hormone and corticosterone in response to a second injection of endotoxin, with decreased secretion observed after 7 days whereas robust secretion was observed at 21 days. Seven days following priming with endotoxin, plasma concentrations of pro-inflammatory cytokines interleukin (IL)-6 and interferon (IFN)-gamma were reduced by 90%, and tumour necrosis factor (TNF)-alpha by 70%, compared to saline-treated rats, whereas robust secretion of the anti-inflammatory cytokine IL-10 was maintained in both groups. A similar net change favouring an anti-inflammatory cytokine secretory milieu was also observed 21 days following priming with endotoxin. This study provides evidence that the long-term protective effects of endotoxin on inflammation are associated with a sustained reduction in secretion of pro-inflammatory cytokines. HPA axis hypoactivity at 7 days suggests that corticosterone is not involved in suppressing IL-6, IFN-gamma and TNF-alpha at this time point. Conversely, hypersecretion of corticosterone at 21 days may underlie synchronous suppression of IL-6 and IFN-gamma. These data provide novel insight into interactions between HPA axis activity and cytokine secretion following endotoxin priming prior to induction of inflammatory disease.

Adrenocorticotropic Hormone↗
PubMed1984

Failure of drugs that selectively inhibit thromboxane synthesis to modify endotoxin shock in conscious rats.

The effects of two thromboxane synthetase inhibitors ( dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat. Infusion of E. coli endotoxin (41.7 ng kg-1 min-1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia. The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin-treated 935 +/- 150 pg ml-1 at 1 h compared with pre-endotoxin values of 125 +/- 30 pg ml-1). The administration of either dazoxiben (30 mg kg-1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg-1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations. Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality. These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.

Animals↗
PubMedDate not supplied

Differential effects of one and repeated endotoxin treatment on pituitary- adrenocortical hormones in the mouse: role of interleukin-1 and tumor necrosis factor-alpha.

The role of endogenous interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in modulating the hypothalamic-pituitary-adrenal (HPA) axis response was examined in male C57BL/6 mice injected with endotoxin (lipopolysaccharide, LPS) or saline at 24-hour intervals for 4 or 8 consecutive days. The mice were divided into four groups: (1) LPS injections for 4 or 8 days and LPS injection on day 5 or 9, respectively (LPS-LPS); (2) LPS injections for 4 or 8 days and saline injection on day 5 or 9, respectively (LPS-saline); (3) saline injections for 4 or 8 days and LPS injection on day 5 or 9, respectively (saline-LPS), and (4) saline injections for 4 or 8 days and saline injection on day 5 or 9 (saline-saline). The mice were sacrificed by decapitation 2 h after the last injection and plasma levels of hormones and cytokines and tissue levels of IL-1beta were measured. Plasma adrenocorticotropin (ACTH) levels were significantly attenuated in the LPS-LPS group compared with the dramatic increases in the saline-LPS group following 4 or 8 days of endotoxin treatment. Plasma corticosterone concentrations were comparable in the LPS-LPS group after 4 days' treatment, but significantly lower following 8 days of treatment when compared with saline-LPS group. Repeated endotoxin treatment followed by a single saline injection (LPS-saline) did not alter the levels of IL-1beta in plasma or any of the tissues examined. IL-1beta levels in the hippocampus, hypothalamus, adrenal gland and plasma were elevated to comparable levels in the saline-LPS and LPS-LPS groups after 4 days of treatment. In contrast to the plasma IL-1beta response, TNFalpha levels were dramatically increased in the saline-LPS group but not in the LPS-LPS group following the 4-day treatment regimen. Increases in IL-1beta concentrations were seen in all tissues following one endotoxin challenge in the saline-LPS group following the 8-day treatment regimen, while increases were significantly attenuated in the hypothalamus, adrenal gland and plasma in LPS-LPS for 8 days. The sustained increases in tissue levels of IL-1beta following 4-day endotoxin treatment appears to have functional consequences since [125I]IL-1alpha binding was significantly decreased in the LPS-saline group compared with the saline-saline group. Furthermore, [125I]IL-1alpha binding was markedly reduced in the LPS-LPS group compared with the saline-LPS group. There was a significant positive correlation between plasma ACTH and IL-1beta after a single and repeated LPS treatment for 4 days, while a significant correlation was seen between plasma ACTH and TNFalpha following one but not repeated LPS treatment. These data demonstrate a differential regulation of IL-1beta and TNFalpha by repeated endotoxin treatment and suggest that while TNFalpha may be important modulating the attenuated pituitary adrenocortical response following the 4-day endotoxin treatment, IL-1beta appears to be the primary regulator of the response following the 8-day endotoxin treatment in the regulation of the HPA axis.

Adrenal Cortex Hormones↗
PubMed1987

Effect of endotoxin tolerance on drug hepatotoxicity: amelioration of taurolithocholate cholestasis in the perfused rat liver.

Induction of endotoxin tolerance may cause resistance not only to endotoxin itself but also to the hepatotoxic effects of other membrane-active agents. To further study this effect, we tested whether endotoxin tolerance could ameliorate the adverse effects of taurolithocholate (TLCA) which causes cholestasis by altering liver plasma membrane organization. Isolated perfused rat livers from endotoxin-tolerant rats had a lower basal bile flow than control livers. However, a bolus addition of TLCA at 3 X 10(-5) or 5 X 10(-5) M in the perfusate caused a marked and prolonged decrease of bile flow in controls, but only a transient and significantly less pronounced diminution of bile flow in endotoxin-tolerant livers. Likewise, TLCA caused a significantly lower alteration of hepatocyte membrane permeability, as measured by sucrose permeability studies, in endotoxin-tolerant livers than in controls. Analysis of bile acid composition of bile from endotoxin-tolerant livers demonstrated that they excreted greater amounts of total bile acids, in particular TLCA and taurocholate, than controls. These results demonstrated a protective effect of endotoxin-tolerance against TLCA toxicity which may result from an altered interaction of TLCA with liver membranes and an increased clearance of TLCA.

Animals↗
PubMed1982

Ibuprofen in canine endotoxin shock.

The participation of prostaglandins in the physiologic alterations of endotoxin shock has been well established with the aid of prostaglandin synthetase inhibitors. Our study was designed to investigate the potential of ibuprofen, a highly specific cyclooxygenase inhibitor, to reverse the hemodynamic and acid base abnormalities of canine endotoxin shock. Mean blood pressure fell to 49.8 +/- 6.6 mm Hg in dogs given endotoxin by 5 min after injection, and remained below 83 mm Hg for the duration of the 120-min observation period. In animals given endotoxin followed by ibuprofen, a similar initial drop of systemic blood pressure was seen, but it subsequently recovered to 150.2 +/- 4.1 mm Hg by 120 min (P less than 0.001). Cardiac index increased in animals given ibuprofen (2.3 +/- 0.28 liter/m2 per min) compared with animals given endotoxin alone (1.0 +/- 0.09 liter/m2 per min) by termination of the experiment. The arterial pH dropped in endotoxin treated animals to 7.18 +/- 0.03 by 120 min. Ibuprofen prevented the acidosis, the final pH in ibuprofen and endotoxin treated animals measuring 7.36 +/- 0.01. We conclude that ibuprofen protects against the hypotension, acidosis, and depression of cardiac index of canine endotoxin shock.

Animals↗
PubMed2006

Endotoxin induced peritonitis elicits monocyte immigration into the lung: implications on alveolar space inflammatory responsiveness.

BACKGROUND: Acute peritonitis developing in response to gram-negative bacterial infection is known to act as a trigger for the development of acute lung injury which is often complicated by the development of nosocomial pneumonia. We hypothesized that endotoxin-induced peritonitis provokes recruitment of monocytes into the lungs, which amplifies lung inflammatory responses to a second hit intra-alveolar challenge with endotoxin. METHODS: Serum and lavage cytokines as well as bronchoalveolar lavage fluid cells were analyzed at different time points after intraperitoneal or intratracheal application of LPS. RESULTS: We observed that mice challenged with intraperitoneal endotoxin developed rapidly increasing serum and bronchoalveolar lavage fluid (BALF) cytokine and chemokine levels (TNFalpha, MIP-2, CCL2) and a nearly two-fold expansion of the alveolar macrophage population by 96 h, but this was not associated with the development of neutrophilic alveolitis. In contrast, expansion of the alveolar macrophage pool was not observed in CCR2-deficient mice and in wild-type mice systemically pretreated with the anti-CD18 antibody GAME-46. An intentional two-fold expansion of alveolar macrophage numbers by intratracheal CCL2 following intraperitoneal endotoxin did not exacerbate the development of acute lung inflammation in response to intratracheal endotoxin compared to mice challenged only with intratracheal endotoxin. CONCLUSION: These data, taken together, show that intraperitoneal endotoxin triggers a CCR2-dependent de novo recruitment of monocytes into the lungs of mice but this does not result in an accentuation of neutrophilic lung inflammation. This finding represents a previously unrecognized novel inflammatory component of lung inflammation that results from endotoxin-induced peritonitis.

Animals↗
PubMed2000

Recurrent intraocular inflammation in endotoxin-induced uveitis.

PURPOSE: Endotoxin-induced uveitis (EIU) in rats and mice peaks 24 hours after endotoxin injection and is commonly assumed to be a monophasic disease. This study examined intraocular inflammation at later time points to determine whether endotoxin injection can induce recurrent intraocular inflammation in strains of mice with high or moderate levels of susceptibility to EIU. METHODS: EIU was elicited in two mouse strains with high (C3H/HeN) and moderate (FVB/N) susceptibility, by means of intraperitoneal injections of Salmonella typhimurium endotoxin. Inflammatory cells in the anterior and posterior segments of the eye were counted by a masked observer on histologic sections of eyes from 1 to 17 days after endotoxin injection. RESULTS: A bimodal distribution of inflammatory cell infiltration was noted in eyes from C3H/HeN mice. As previously reported, inflammation peaked at 24 hours after endotoxin injection. However, a second, more pronounced peak of intraocular inflammation occurred approximately 5 days after endotoxin injection. FVB/N mice had a single peak of intraocular inflammation 4 days after injection. CONCLUSIONS: Endotoxin injection in C3H/HeN elicits recurrent intraocular inflammation. The previously unrecognized second peak of inflammation is more severe than the initial inflammatory disease. Studies on this second inflammatory peak may be useful in determining the pathogenesis of recurrent uveitis in humans.

Animals↗
PubMed1998

[The establishment of endotoxin limits which satisfy animal welfare considerations in the testing of porcine vaccines]

Endotoxin (lipopolysaccharide, LPS) is a constituent of the cell walls of gram-negative bacteria and is found in many vaccines produced from these bacteria. High levels of endotoxin can give rise to a range of pathophysiological reactions, and adverse reactions tend to be seen in animals following vaccination. In this study, pigs of various ages and weights were vaccinated with licensed porcine vaccines and the endotoxin content of the vaccines was determined with the LAL, conducted according to DAB 10. The experiments followed the DAB guidelines relating to the safety testing of veterinary vaccines. The animals were monitored for 48 h after vaccination, their body temperatures were measured, and blood samples were taken for analysis and for the determination of plasma endotoxin levels. There was a clear relationship between vaccine endotoxin content and changes in blood cell counts and in the clinical picture. Elevated plasma endotoxin levels correlated with the occurrence of initial leucopenia followed by leucocytosis as well as with clinical symptoms ranging from refusal of food and depression to shock-like symptoms. After 24 h, normal physiological values were regained. Young animals weighing between 10 and 40 kg were found to be very sensitive to elevated endotoxin content in vaccines. The differences in individual reactions could be due not only to differences in vaccine endotoxin content, but also to differences in the reactivity of the organism, and in the type of bacteria used or in the composition of the vaccine.

Journal Article↗
PubMedDate not supplied

Multiple organ platelet sequestration, hemodynamics, and gas exchange in endotoxin shock and the effects of aspirin-terbutaline treatment.

We studied the effects of two different drugs on multiple organ platelet sequestration, hemodynamics, and respiratory function during endotoxin shock. Twenty-eight sheep (four groups) were anesthetized and ventilated. Group AT-E received aspirin and terbutaline 30 min before and group E-AT 30 min after Escherichia coli endotoxin. Group E also received endotoxin but no drug treatment (shock controls), and group C received neither endotoxin nor drug treatment. There was a marked platelet trapping in the lungs and in the liver immediately after administration of endotoxin in groups E and E-AT, but after 4 hr it was less pronounced in group E-AT than in the endotoxin controls (P < 0.05). In the pretreated animals (group AT-E) there was no increase in platelet sequestration until almost 2 hr after endotoxin both in the lungs and the liver, but at the end of the study (240 min) there was no difference between the pre- and posttreated groups. No significant changes occurred in the kidneys and spleen in any of the groups. In groups E and E-AT the endotoxin infusion resulted in 200% rise in pulmonary artery pressure (PAP) and a sharp decrease in mean arterial pressure (MAP; 25-30%), respiratory compliance (CT; 50%), arterial oxygen tension (PaO2; 70%) as well as in oxygen delivery index (DO2; 30-40%) within 30 min. After 4 hr the PAP had decreased significantly in group E-AT, but remained high in group E (> 100% higher than in group C). Also MAP, PaO2, DO2 and CT improved slightly in group E-AT, while they remained low in group E.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

The adjuvant effect of pertussis endotoxin protein in modulating the immune response to cholera toxoid in mice.

Endotoxin protein represents a group of immunobiologically active p polypeptides which are associated with the lipopolysaccharide endotoxin in the outer membrane of Gram-negative bacteria. To study the adjuvant effect of endotoxin protein, CF-1 mice were immunized intraperitoneally with graded doses of glutaraldehyde-inactivated cholera toxoid with and without endotoxin protein prepared from Bordetella pertussis, Salmonella typhi or Vibrio cholerae. Immune responsiveness was assessed by measuring resistance to intravenous challenge with cholera enterotoxin and by serum antitoxin responses. The results showed that endotoxin protein from S. typhi can enhance the 50% protective dose (PD50) of cholera toxoid five to 12-fold, the endotoxin protein from V. cholerae enhances the PD50 six to seven fold at most, but the endotoxin protein from B. pertussis can enhance the PD50 some 27-fold. Furthermore, within the variability of both the mouse protection test and the rabbit intracutaneous assay of toxin induced vascular permeability, mouse serum neutralizing antitoxin levels correlated with the greater degree of resistance of the mice to the toxin challenge. The adjuvant effect also has been demonstrated by measuring the appearance of antitoxin specific plaque forming cells derived from mouse lymphocyte cultures. After seven days of culture in the presence of endotoxin protein and cholera toxoid, the number of plaque forming cells to cholera toxin coated sheep erythrocytes was enhanced some 28 times as compared to the cultures exposed to the cholera toxoid alone.

Adjuvants, Immunologic↗
PubMed1986

Protective action of calcium entry blockers in endotoxin shock.

Calcium entry blockers (CEBs) have been reported to protect against cellular necrosis caused by experimental ischemia and the beneficial effect has been related to prevention of ischemia-induced calcium overload by the CEBs. Since circulatory shock can be expected to produce generalized tissue hypoxia, the possibility that CEBs might be beneficial in shock produced by endotoxin was investigated. In control male Wistar rats, a 10-mg/kg dose of E. coli endotoxin (Difco 0127:B8) produced a fall in blood pressure and a transient increase followed by a progressive slowing of the heart rate. Mortality 48 hours after endotoxin (10 mg/kg) was 84%. The calcium entry blockers (CEBs) verapamil, nitrendipine, and nilvadipine [corrected], administered i.v. 15 min before endotoxin, produced a dose-dependent reduction in mortality. The CEBs were less effective when given as post-treatment (15 to 30 min after endotoxin). Measurements of total tissue and mitochondrial calcium levels in control rats revealed that endotoxin did not produce an increase in the calcium content of heart, lung, pancreas, small intestine, kidney, and aorta. Since increased cellular calcium levels did not occur in response to endotoxin, the protection induced by CEBs in endotoxin shock does not appear to be related to prevention of calcium overload; however, the possibility that the CEBs may beneficially prevent an excessive accumulation of calcium in discrete cells or intracellular compartments (which may not be detected by our methods) cannot be excluded.

Animals↗
PubMed1986

Effects of methylprednisolone on renal nerve response to stimulation of medullary pressor area in endotoxin-induced hypotension.

The purpose of this study was to determine the effects of glucocorticoids on central sympathetic outflow during endotoxic hypotension in anesthetized rabbits. All animals were given E. coli endotoxin (1 mg/kg) intravenously. In the control group, mean blood pressure (MBP) fell significantly after endotoxin. Endotoxin also caused a significant reduction of renal nerve activity (NA) simultaneously with a decrease in MBP. Peak responses in MBP and NA to repetitive stimulation of the medullary pressor area were attenuated significantly 60 min after endotoxin. Both peak and total activities of renal nerve discharges (RNDe) evoked by the electrical stimulation of the medullary pressor area were significantly reduced. There were no significant differences in the time course changes in the above parameters between the control group and the treated group. Following a vehicle injection in the control group, these parameters decreased by endotoxin progressively declined until the end of the experiment. When methylprednisolone (MPSS, 30 mg/kg) was injected intravenously 60 min after endotoxin, decreases in MBP and NA induced by endotoxin recovered gradually toward preendotoxin levels. Thirty minutes after MPSS administration levels of MBP and NA were significantly higher than those in the control group. Responsiveness in MBP and NA to the repetitive stimulation of the medullary pressor area increased significantly after the treatment with MPSS. Peak activities of RNDe 30 min after MPSS were augmented significantly and total activities of RNDe recovered to preendotoxin levels. Both endotoxin and MPSS did not affect MBP, NA, and RNDe responses following stimulation of the thoracic sympathetic chain. These findings suggest that methylprednisolone may have improved the impaired central blood pressure regulatory circuits during endotoxic hypotension through a facilitation of neuronal excitability, resulting in an enhancement of central sympathetic outflow.

Animals↗
PubMed1987

Thoracic peridural block in experimental endotoxin shock.

The influence of thoracic peridural block (PDB) on the metabolic and hemodynamic changes in endotoxin shock were investigated in rabbits. During the first 6 h of endotoxin shock, sensomotoric and sympathetic blockade distal to spinal segment T4 was achieved by intermittent administration of bupivacaine into a thoracic peridural catheter. The increase of plasma glucose, lactate, and free glycerol 2 h after endotoxin (50 micrograms/kg) administration was prevented by PDB. Animals with PDB had an accelerated clearance of glucose as indicated by a shorter plasma half-life of intravenously injected glucose (0.33 g/kg) 1 h after endotoxin administration. Hemodynamic parameters were measured during the first 210 min after endotoxin application. Compared with controls, PDB reduced mean arterial pressure and total peripheral resistance. PDB did not affect the initial increase of right ventricular pressure or the progressive decrease in O2 consumption and cardiac output after the endotoxin injection. The mortality at 24 h was not significantly reduced by the PDB (controls, n = 22: 68%; PDB, n = 21: 57%). The results demonstrate that thoracic PDB effectively blocks the sympathetic response in endotoxin shock. Hence, PDB causes peripheral vasodilatation, and, moreover, the metabolic data are consistent with an inhibition of the reactive glycogenolytic and lipolytic responses in shock. Although PDB altered the metabolic disturbances caused by endotoxin shock, mortality was not significantly affected.

Animals↗