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PubMed1991

Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay.

Plasma endotoxin concentration was measured in 85 patients with alcoholic liver disease (alcoholic cirrhosis (n = 64), alcoholic hepatitis without cirrhosis (n = 11), fatty liver (n = 10), and in patients with non-alcoholic cirrhosis (n = 15]. Endotoxin concentration was determined with an improved chromogenic substrate assay, using individual standard curves for each plasma sample. In patients with alcoholic cirrhosis the mean endotoxin concentration was significantly higher than in patients with non-alcoholic cirrhosis (p less than 0.05). In addition, distinctly higher endotoxin concentrations (greater than 20 pg/ml) were more frequently observed in patients with alcoholic cirrhosis than in non-alcoholic cirrhosis (34.4 vs. 14.3%, p less than 0.05). Mean endotoxin concentration was not significantly higher in cirrhotics with ascites or esophageal varices as compared with the subgroup without ascites or esophageal varices. The endotoxin concentration did not correlate with serum bilirubin, prothrombin concentration or serum enzyme activities. In patients with alcoholic liver disease, however, endotoxin concentration revealed a negative correlation (p less than 0.05) with the concentration of high density lipoprotein cholesterol. On admission endotoxin concentrations in alcoholics with fatty liver were similarly elevated as observed in alcoholic cirrhosis. In six out of 12 patients with fatty liver or alcoholic hepatitis, in whom a second sample of plasma was investigated after 6 to 8 days, endotoxemia was no longer detectable; in the remaining patients, the endotoxin concentration decreased markedly. The results indicate that, irrespective of the stage of liver disease, alcohol abuse favours the development of endotoxemia. They support the hypothesis that gut-derived endotoxins might play a role in the initiation and aggravation of alcohol-induced liver disease.

Adult↗
PubMed1989

Characteristics of 2,3,7,8-tetrachlorodibenzo-p-dioxin induced endotoxin hypersensitivity: association with hepatotoxicity.

Hepatic clearance is a major route of endotoxin detoxification. In the present study, the potential relationship between TCDD-induced endotoxin hypersensitivity and hepatotoxicity was examined. Acute doses of 50, 100, or 200 micrograms TCDD/kg body weight induced an endotoxin hypersensitive state in B6C3F1 mice as demonstrated by increased mortality 24-48 h following i.v. injection of endotoxin. This hypersensitive state occurred when endotoxin was administered 7 days following TCDD exposure, but not 1 day post-TCDD exposure. TCDD did not affect endogenous serum endotoxin levels. However, clearance of injected endotoxin was significantly inhibited following exposure to TCDD. Six hours post endotoxin treatment serum triglycerides were significantly increased in TCDD/endotoxin-treated mice compared to either treatment alone. Methylprednisolone and uridine were both examined in this model due to their roles in inflammation and RNA synthesis, respectively. Both compounds significantly reversed the mortality associated with the combined exposure. [3H]Uridine incorporation into liver was decreased following TCDD treatment alone, further suggesting impaired RNA synthesis. Studies performed on congenic mice indicate that the observed effects segregate with the Ah locus. The ability of methylprednisolone and uridine to reverse the mortality associated with TCDD/endotoxin treatment is consistent with an inflammatory response and impaired hepatic detoxification mechanisms. Thus, changes in hepatic handling of endotoxin, caused by progressive TCDD-induced liver dysfunction, may be responsible for the endotoxin hypersensitivity.

Alanine Transaminase↗
PubMed1990

Altered responses to modulators of guanine nucleotide binding protein activity in endotoxin tolerance.

The effects of cholera toxin or pertussis toxin and nonhydrolyzable GTP analogs on Salmonella enteritidis endotoxin stimulation of iTxB2 and i6-keto-PGF1 alpha synthesis in control and endotoxin tolerant rat peritoneal macrophages were determined. Pretreatment with pertussis toxin alone had no effect on basal macrophage iTxB2 or i6-keto-PGF1 alpha production, but pertussis toxin (0.1, 1.0 and 10 ng/ml) significantly inhibited endotoxin-stimulated iTxB2 and i6-keto-PGF1 alpha synthesis. Pretreatment with cholera toxin, which did not affect basal iTxB2 or i6-keto-PGF1 alpha synthesis, significantly enhanced endotoxin-induced synthesis of iTxB2 and i6-keto-PGF1 alpha. The effects of pertussis and cholera toxin with or without endotoxin were significantly (P less than 0.05) less in macrophages from endotoxin tolerant rats compared to control macrophages. GTP[gamma-S] (100 microM) significantly increased iTxB2 synthesis and significantly augmented endotoxin-stimulated iTxB2 synthesis in control macrophages (P less than 0.05). However, in macrophages from endotoxin tolerant rats the effect of GTP[gamma-S] on iTxB2 synthesis was significantly less (P less than 0.05) compared to control macrophages. Collectively, these data suggest that: (1) guanine nucleotide binding regulatory proteins mediate endotoxin-stimulated arachidonic acid metabolism in rat peritoneal macrophages; and (2) endotoxin tolerance induces alterations in guanine nucleotide binding protein activity.

Animals↗
PubMed1994

Regional blood flow distribution in endotoxin-treated dogs: modification by ibuprofen.

PURPOSE: The aim of this study was to determine whether the improved hemodynamic profiles reported with cyclooxygenase inhibition during sepsis include improvements in tissue perfusion is unknown. Our hypothesis was that cyclooxygenase inhibition with ibuprofen will prevent the endotoxin-induced alterations in regional blood flow distribution from developing and/or restore the endotoxin-induced loss of responsiveness to intravascular volume expansion. METHODS: We measured cardiac output, regional blood flow, and total systemic shunt flow in dogs using radiolabeled 15-microns microspheres. These parameters were assessed in control (N = 10) and endotoxin-treated animals (N = 7). Additional endotoxin-treated animals (N = 7) were also pretreated with ibuprofen. RESULTS: Compared with controls, endotoxin-treated animals exhibited marked reductions in blood flow to most systemic organs that were not reversed with large, intravenous saline infusions (ie, isotonic saline; 40 mL/kg; N = 4). By contrast, although ibuprofen pretreatment (12.5 mg/kg; N = 7) completely prevented the reductions in mean arterial pressure caused by endotoxin from occurring, it did little to prevent the development of endotoxin-induced alterations in regional blood flow distribution. Nonetheless, in contrast to the endotoxin-treated animals, there were significant increases in cardiac output and blood flow to several organs after saline infusion in the ibuprofen-pretreated animals. CONCLUSIONS: Cyclooxygenase inhibition with ibuprofen has few direct effects on regional blood flow distribution after endotoxin. However, cyclooxygenase inhibition with ibuprofen does attenuate the endotoxin-induced decrease in vascular responsiveness to intravenous saline infusion.

Animals↗
PubMed1994

Perfusion-related factors of endotoxin release during cardiopulmonary bypass.

To investigate whether the release of endotoxin during cardiopulmonary bypass (CPB) is determined by perfusion-related factors, endotoxin concentrations were determined before, during, and after CPB in 21 male patients (age range 45-75 years) undergoing elective coronary artery bypass grafting. Hemodynamic parameters and oncotic pressure were also measured. Significant increases in endotoxin concentrations were observed after the start of CPB (P < 0.005), before aortic cross-clamp release (P < 0.05), and after aortic cross-clamp release (P < 0.05). The median endotoxin concentration after cessation of CPB was 0.264 EU/ml (range < 0.036-0.480 EU/ml). Endotoxin concentrations derived from the prime solutions were not contributory. Positive correlations were found between arterial pressure after the start of CPB and the endotoxin concentration 10 min after (r = 0.58, P < 0.01) and between the duration of aortic cross-clamping and the endotoxin concentration after the cessation of CPB (r = 0.64, P < 0.005). Arterial pressure after the start of CPB, the duration of aortic cross-clamping, and decrease in oncotic pressure appeared to be independent variables in a forward variable selection model that predicted endotoxin concentrations after CPB. We conclude that in patients undergoing elective coronary artery bypass grafting, an early phase of endotoxin release during CPB could be demonstrated, and that this is due to vasoconstriction. The endotoxin concentrations after the cessation of CPB were determined by early vasoconstriction, duration of aortic cross-clamping, and hypo-oncotic hemodilution.

Aged↗
PubMed2004

Role of tumor necrosis factor-alpha in down-regulation of hepatic cytochrome P450 and P-glycoprotein by endotoxin.

We investigated the role of tumor necrosis factor-alpha (TNF-alpha) in the down-regulation of hepatic P-glycoprotein and cytochrome P450 (CYP) by endotoxin, using TNF-alpha gene-deficient (TNF-alpha-/-) mice. In the case of P-glycoprotein, endotoxin (10 mg/kg) significantly decreased the expression of hepatic P-glycoprotein in wild-type mice 6 h, but not 24 h, after intraperitoneal injection, with no significant differences in the constitutional expression of P-glycoprotein between wild-type mice and TNF-alpha-/- mice. However, endotoxin had no effect on the expression of P-glycoprotein in TNF-alpha-/- mice either 6 or 24 h after injection. When doxorubicin was administered intravenously to TNF-alpha-/- mice treated 6 h earlier with and without endotoxin, no significant differences in the plasma concentrations of doxorubicin 3 h after injection were observed between endotoxin-treated and untreated TNF-alpha-/- mice. These results suggest that TNF-alpha plays a pivotal role in the down-regulation of P-glycoprotein by endotoxin. In the case of CYP, the constitutive expression of hepatic CYP3A2 and CYP2C11 had a tendency to decline in TNF-alpha-/- mice compared with that in wild-type mice. Endotoxin significantly decreased the expression of hepatic CYP3A2 and CYP2C11 in wild-type mice 24 h after injection, and that decreased expression was significantly greater in TNF-alpha-/- mice than wild-type mice. When antipyrine was administered intravenously to wild-type mice and TNF-alpha-/- mice treated 24 h earlier with endotoxin, the plasma concentrations of antipyrine in TNF-alpha-/- mice 3 h after injection were significantly higher than those in wild-type mice. These findings suggest that TNF-alpha plays a key role in endotoxin-induced down-regulation of hepatic P-glycoprotein, as well as plays a protective role in the regulation of hepatic CYP3A2 and CYP2C11 against endotoxin-induced acute inflammatory response. In TNF-alpha-/- mice, other cytokines appear to function as compensation for the lack of endogenous TNF-alpha.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Endotoxin exposure and atopic sensitization in adult pig farmers.

BACKGROUND: Recent studies have reported a low prevalence of atopic sensitization and respiratory allergy in children growing up on farms. OBJECTIVES: We sought to evaluate the dose-response relationship between endotoxin and atopic sensitization in adult farmers and to assess the effect on respiratory health outcomes. METHODS: Data on endotoxin exposure and serum IgE levels were available for 162 pig farmers from a cross-sectional case-control study, with case selection on the basis of respiratory symptoms. Exposure to endotoxin was modeled in detail, and respiratory health effects were assessed during a medical examination. Exploratory analysis was done by using nonparametric modeling and was followed by classical parametric regression. RESULTS: IgE to one or more common allergens was detected in sera from 28 (17%) farmers. The average (geometric mean) total serum IgE levels was 37 IU/mL (geometric SD, 4 IU/mL). A strong inverse relationship was found between endotoxin and sensitization to common allergens for exposures of 75 ng/m 3 or less, with an odds ratio of 0.03 (95% CI, 0.0-0.34) for a 2-fold increase in endotoxin. For endotoxin exposure of greater than 75 ng/m 3 , the association was weak (odds ratio, 1.2 [95% CI, 0.38-3.6]). No association was found between endotoxin exposure and total serum IgE levels. Endotoxin was associated with increased airway hyperresponsiveness to histamine and lower lung function in sensitized farmers, without evidence of a nonlinear relationship. CONCLUSIONS: The prevalence of atopic sensitization in adult pig farmers is low. Endotoxin or related exposures might protect from sensitization, even in an adult working population exposed to high levels of endotoxin, but is a risk factor for increased airway hyperresponsiveness and low lung function.

Adult↗
PubMed2005

Infant home endotoxin is associated with reduced allergen-stimulated lymphocyte proliferation and IL-13 production in childhood.

BACKGROUND: Infant endotoxin exposure has been proposed as a factor that might protect against allergy and the early childhood immune responses that increase the risk of IgE production to allergens. OBJECTIVE: Using a prospective study design, we tested the hypothesis that early-life endotoxin exposure is associated with allergen- and mitogen-induced cytokine production and proliferative responses of PBMCs isolated from infants with a parental history of physician-diagnosed asthma or allergy. METHODS: We assessed household dust endotoxin at age 2 to 3 months and PBMC proliferative and cytokine responses to cockroach allergen (Bla g 2), dust mite allergen (Der f 1), cat allergen (Fel d 1), and the nonspecific mitogen PHA at age 2 to 3 years. RESULTS: We found that increased endotoxin levels were associated with decreased IL-13 levels in response to cockroach, dust mite, and cat allergens, but not mitogen stimulation. Endotoxin levels were not correlated with allergen- or mitogen-induced IFN-gamma, TNF-alpha, or IL-10. Increased endotoxin levels were associated with decreased lymphocyte proliferation after cockroach allergen stimulation. An inverse, although nonsignificant, association was also found between endotoxin and proliferation to the other tested stimuli. CONCLUSION: Increased early-life exposure to household endotoxin was associated with reduced allergen-induced production of the TH2 cytokine IL-13 and reduced lymphoproliferative responses at age 2 to 3 years in children at risk for allergy and asthma. Early-life endotoxin-related reduction of IL-13 production might represent one pathway through which increased endotoxin decreases the risk of allergic disease and allergy in later childhood.

Allergens↗
PubMed2003

Chorioamnionitis induced by subchorionic endotoxin infusion in sheep.

OBJECTIVE: This study was undertaken to determine whether subchorionic endotoxin infusion causes chorioamnionitis and preterm lung maturation, as occurs after intra-amniotic endotoxin. STUDY DESIGN: From day 118 of pregnancy, sheep received infusions of endotoxin (subchorionic 7.5 mg/d, n=11; intra-amniotic 2.5 mg/d, n=9) until delivery of lambs at 120 or 124 days. Other sheep received a single intra-amniotic injection of endotoxin (10 mg, n=7) at 118 days before delivery at 124 days. Controls (n=9) received equivalent saline solution treatments. RESULTS: Chorioamnionitis accompanied all endotoxin treatments. Lung inflammation occurred after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. Umbilical arterial pH was lower and Pco(2) was higher than control after subchorionic endotoxin. Lung compliance and surfactant were increased after intra-amniotic endotoxin infusion or injection but not after subchorionic endotoxin. CONCLUSION: Chorioamnionitis may result from inflammatory stimuli at various intrauterine sites, with different sites causing different fetal effects and not all cases of chorioamnionitis being accompanied by enhanced lung maturation.

Amnion↗
PubMed1992

Dose-dependent pulmonary effects of inhaled endotoxin in guinea pigs.

As a cell wall component of gram-negative bacteria, endotoxin is thought to play a significant role in the respiratory effects of inhaled organic dusts which are microbially contaminated. Assessment of occupational survey data and clinical studies suggests that few measureable, acute functional changes occur below 30-50 ng/m3 endotoxin (as sampled in airborne dust with a vertical elutriator). Little information is available on the inflammatory effects of inhaled endotoxin at these low concentrations. The present study examined the dose-response relationship between inhaled endotoxin and functional, biochemical, and histological endpoints in the lungs of guinea pigs. Animals were exposed to 0.03 to 50.5 micrograms/m3 aerosolized endotoxin or the vehicle water for 4 hr. At 2 hr into exposure, significant decreases in specific airway conductance were observed only in animals exposed to 9.6 and 50.5 micrograms/m3 endotoxin (17.3 +/- 1.2 and 35.5 +/- 0.5% decreases from baseline values, respectively (mean +/- SE)). Total cell count and lactate dehydrogenase levels in bronchoalveolar lavage fluid were significantly elevated at 24 hr after exposure in all endotoxin-exposed groups except the lowest dose, 0.03 micrograms/m3 (P < 0.05). Polymorphonuclear leukocyte influx into the alveolar region was also dependent on the concentration of inhaled endotoxin. Thus, LDH activity, a biochemical marker of cell injury, and total cell counts and polymorphonuclear leukocytes, markers of inflammation, were more sensitive indices of adverse pulmonary effects from inhaled endotoxin than a functional measurement. These results suggest that subtle inflammatory changes may occur at airborne endotoxin concentrations which may produce no acute respiratory symptoms.

Administration, Inhalation↗
PubMed1997

L-canavanine and dexamethasone attenuate endotoxin-induced suppression of ischaemia-reperfusion arrhythmias.

The role of inducible nitric oxide synthase in the antiarrhythmic effects of Escherichia coli endotoxin was examined in an anaesthetised rat model of myocardial ischaemia (7 min occlusion) and reperfusion (7 min) arrhythmias by using its specific blocker L-canavanine (100 mg/kg) and dexamethasone (5 mg/kg), which inhibits its expression. Endotoxin (1 mg/kg) or its solvent saline was administered intraperitoneally 4 h before the occlusion of the left coronary artery and L-canavanine or dexamethasone was administered 1 h before endotoxin or saline injection. The mean arterial blood pressure of rats receiving endotoxin was significantly lower than that of saline-treated controls, and neither L-canavanine nor dexamethasone prevented the hypotension exerted by endotoxin. However, during both the occlusion and reperfusion periods, endotoxin significantly reduced the total number of ectopic beats (e.g., during reperfusion, saline: 1177 +/- 183, n = 11; endotoxin: 248 +/- 91, n = 9; P < 0.005) and the duration of ventricular tachycardia (e.g., during occlusion, saline: 30.9 +/- 5.7 s; endotoxin: 1.8 +/- 0.9 s; P < 0.0001) while L-canavanine or dexamethasone treatment abolished the reduction exerted by endotoxin. Therefore we conclude that endotoxin possesses significant antiarrhythmic (protectant) effects in this rat model of ischaemia-reperfusion arrhythmias, and that its mechanism appears to involve the inducible nitric oxide synthase since both L-canavanine and dexamethasone inhibited this phenomenon.

Analysis of Variance↗
PubMed1988

Endotoxins in culture medium for human in vitro fertilization.

Endotoxins were detected in a few batches of culture medium during the authors' human in vitro fertilization program. Two distinct levels of endotoxins were assayed: greater than 1 ng/ml and less than 1 ng/ml. The source of endotoxin was traced to culture media obtained from a reputable manufacturing company. The incidence of fertilization per patient was not significantly affected by the presence of endotoxins, but fertilization assessed on the overall number of oocytes was significantly reduced (53%) when endotoxin levels were greater than 1 ng/ml compared with an assay negative for endotoxins (66%) (P = 0.047). The percentage of oocytes cleaving after the observation of two pronuclei was not significantly different, but the degree of fragments observed in the conceptus was significantly more severe if the endotoxin level reached 1 ng/ml. In this investigation, the incidence of pregnancy was 8% when the endotoxin level was greater than 1 ng/ml, 30% if less than 1 ng/ml, and 32% if no endotoxins were detected. This study suggests that, although endotoxins may be present in the culture medium at a deleterious level of at least 1 ng/ml, fertilization and cleavage will be obtained, but there will be a significant increase in the incidence of conceptuses with cytoplasmic fragments; this may result in a reduction in the incidence of pregnancy.

Cells, Cultured↗
PubMed2003

Attenuation by intravenous 2-chloroadenosine of acute lung injury induced by live escherichia coli or latex particles added to endotoxin in the neutropenic state.

Although neutrophil depletion can reduce the level of acute lung injury (ALI) induced by Escherichia coli endotoxin, that induced by live E coli cannot be attenuated even in neutropenia. This suggests that live E coli cause ALI by way of an mechanism independent of circulating neutrophil. Tumor necrosis factor-alpha (TNF-alpha), which is released from monocytes and macrophages, is a proinflammatory cytokine that is recognized as a central mediator of several forms of inflammation. In this controlled experimental study, we examined the effects of an adenosine-receptor agonist, 2-chloroadenosine (2CA), that has suppressive effects on various cell types and TNF-alpha, on endotoxin plus latex particles, and on ALI induced by live E coli in the neutropenic state. We studied 42 guinea pigs rendered neutropenic by means of intraperitoneal cyclophosphamide administration. Experimental groups consisted of (1) a saline-solution control group; (2) an endotoxin (0.2 mg/kg)-treated group; (3) a group treated with endotoxin plus 2CA (10 micro g/kg); (4) a group treated with latex (2 x 10(9)/kg); (5) a group exposed to endotoxin and latex; (6) a group exposed to endotoxin, latex, and 2CA; (7) a group exposed to E coli (2 x 10(9)/kg); and (8) a group exposed to E coli and 2CA. The injection of endotoxin alone in neutropenic animals did not increase the indexes of ALI (lung tissue/plasma ratio [T/P] and lung wet weight/dry weight ratio [W/D], calculated with the use of iodine 125-labeled albumin). In contrast, these indexes were increased in the endotoxin-and-latex groups compared with those of the control group. ALI in the endotoxin-and-latex group was attenuated by intravenous 2CA. The intravenous injection of live E coli also caused increases in T/P, W/D, and plasma TNF-alpha, but thse were limited by 2CA. In summary, ALI induced by latex particles added to endotoxin and live E coli in the neutropenic state was attenuated by 2CA, suggesting a partial contribution of various cell types or humoral mediators as a neutrophil-independent pathway in its pathogenesis.

2-Chloroadenosine↗
PubMed2001

Detoxification of endotoxin by aluminum hydroxide adjuvant.

Langmuir adsorption isotherms of endotoxin and aluminum-containing adjuvants at pH 7.4 and 25 degrees C revealed that aluminum hydroxide adjuvant has a greater adsorption capacity (283 microg/mg Al) and adsorption coefficient (1.3x10(4) ml/miccrog) than aluminum phosphate adjuvant (3.0 microg/mg Al, 0.20 ml/microg). The difference in endotoxin adsorption was related to two adsorption mechanisms: electrostatic attraction and covalent bonding. The isoelectric point (iep) of endotoxin is approximately 2. An electrostatic attractive force will be present with aluminum hydroxide adjuvant (iep=11.4), and an electrostatic repulsive force will operate with aluminum phosphate adjuvant (iep=4.6). Endotoxin contains two phosphate groups in the lipid A portion. Covalent bonding occurs with surface aluminum in aluminum hydroxide adjuvant but is inhibited by surface phosphate in aluminum phosphate adjuvant. In-vitro desorption experiments using components of interstitial fluid showed that endotoxin adsorbed by aluminum hydroxide adjuvant was not desorbed by interstitial anions (5 mM phosphate or 2.7 mM citrate) or interstitial proteins (25 mg albumin/ml). The effect of aluminum-containing adjuvants on the systemic response of Sprague-Dawley rats to a 15 microg/kg subcutaneous dose of endotoxin was determined by measuring the serum concentration of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). TNF-alpha and IL-6 were observed in the group which received an endotoxin solution or endotoxin and aluminum phosphate adjuvant. No TNF-alpha or IL-6 was detected in the group that received endotoxin and aluminum hydroxide adjuvant. Aluminum hydroxide adjuvant detoxifies endotoxin by adsorbing it in the vaccine and then not releasing it in interstitial fluid upon administration.

Adjuvants, Immunologic↗
PubMed2000

Adsorption of endotoxin on glass in the presence of rhIL-11.

Poor recovery of spiked endotoxin in the Limulus amebocyte lysate assay (LAL assay) was observed in the presence of recombinant human interleukin-11 (rhIL-11), a cationic, hydrophobic protein. Detection of endotoxin activity remaining in the empty glass tubes in which endotoxin and rhIL-11 mixtures were incubated indicated adsorption of endotoxin on glass. At low concentrations of rhIL-11, a correlation between endotoxin adsorbed on glass and a decrease of endotoxin in solution was observed. Adsorption of rhIL-11 on glass correlated with adsorption of endotoxin, which indicates that rhIL-11 mediates adsorption of endotoxin on glass. Consequently, adsorption of endotoxin on glass may occur in the presence of other substances which bind to both of endotoxin and glass.

Adsorption↗
PubMed2002

Endotoxin potentiates hepatocyte apoptosis in cholestasis.

BACKGROUND: Cholestasis is a component of liver disease of almost any etiology, including septic liver injury. The cellular mechanisms of liver injury in cholestasis and sepsis remain unresolved. We evaluated apoptosis, a well-orchestrated and potentially reversible mechanism of cell death, in bile duct-ligated and endotoxin-injected rats. STUDY DESIGN: Male Sprague-Dawley rats were randomly assigned to six groups (n = 6-9): bile duct-ligated+endotoxin (B+E), sham+endotoxin (S+E), bile duct-ligated (B), sham (S), endotoxin (E), and normal (N). On day 1, the bile ducts of B+E and B rats were ligated and severed. S+E and S animals underwent biliary manipulation only. On day 3, B+E, S+E, and E groups received 3 mg/kg endotoxin i.v.. On day 4, livers from all rats were excised, fixed, and stained (hematoxylin and eosin and terminal deoxynucleotidyl transferase dUTP nick-end labeling [TUNEL]). Portions were frozen for DNA fragmentation analysis. Caspase 3 activity was determined using isolated hepatocytes. RESULTS: Livers from all groups (B+E, S+E, E, and B) except normal and sham displayed apoptosis by hematoxylin and eosin staining, TUNEL staining, and DNA fragmentation. Histologic evaluation revealed 10% to 20% necrosis in endotoxin-treated animals (B+E, S+E, and E). Caspase 3 activity was significantly higher in endotoxin-treated animals versus animals without endotoxin (treated 0.450 +/- 0.08 versus nontreated 0.135 +/- 0.05, p < 0.0001) (mean +/- SD). CONCLUSIONS: Cholestatic livers had apoptosis without progression to necrosis. When exposed to the second insult of endotoxin, cholestatic livers received an acute on chronic apoptotic trigger, and proceeded to necrosis. Endotoxin was a potent hepatotoxic insult because all treated rat livers displayed both apoptosis and necrosis.

Alanine Transaminase↗
PubMed2003

The Gram-negative bacterium Chlamydia trachomatis L2 stimulates tumor necrosis factor secretion by innate immune cells independently of its endotoxin.

The endotoxin of Chlamydia trachomatis L(2), the causative agent of lymphogranuloma venerum, has been described as an endotoxin with an atypical structure and weak stimulatory activity. It is, however, unclear whether chlamydial endotoxin plays a role in the stimulation of innate immune cells upon contact with the whole microorganism C. trachomatis L(2). We show here that chlamydial endotoxin and, as expected, Escherichia coli O55:B5 endotoxin depend on Toll-like receptor 4 without depending on Toll-like receptor 2 to stimulate bone marrow-derived dendritic cells to secrete tumor necrosis factor (TNF). In contrast, the whole microorganism C. trachomatis L(2) induces TNF secretion by innate immune cells independently of Toll-like receptor 4, while stimulation by E. coli O55:B5 depends on Toll-like receptor 4. Furthermore, although TNF secretion of the macrophage cell line RAW264.7 with chlamydial or E. coli O55:B5 endotoxin as well as with the bacterium E. coli O55:B5 is inhibited by the endotoxin-neutralizing compound polymyxin B, C. trachomatis L(2)-induced secretion of TNF cannot be reduced. In accordance with the literature, the potential of chlamydial endotoxin is more than 100-fold weaker than E. coli O55:B5 endotoxin on all cell types tested. We conclude that chlamydial endotoxin is unlikely to be involved in C. trachomatis L(2)-induced release of TNF by innate immune cells.

Animals↗
PubMed2000

Endotoxin causes up-regulation of endothelin receptors in cultured hepatic stellate cells via nitric oxide-dependent and -independent mechanisms.

Hepatic stellate cells (HSC) and their transformed phenotype found in the chronically injured liver play important roles in hepatic physiology and pathology. HSC produce and react to a potent contractile peptide endothelin-1 (ET-1) and also synthesize a vasorelaxant nitric oxide (NO) upon stimulation with endotoxin. However, whether endotoxin affects ET-1 system of HSC and if this is a mechanism of endotoxin-induced hepatic injury is not known. We characterized synthesis of ET-1 and NO and ET-1 receptors in cultured quiescent and transformed HSC subjected to endotoxin treatment. Endotoxin (1 - 1000 ng ml(-1)) stimulated synthesis of ET-1 and NO and up-regulated ET-1 receptors in both cell types. Inhibition of NO synthesis by N(G)-monomethyl-L-homoarginine strongly inhibited endotoxin-induced increase in ET-1 receptors in transformed HSC but produced small additional increase in quiescent HSC. Inhibition of soluble guanylyl cyclase by 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one blocked the effect of endotoxin on ET-1 receptors in both cell types. Moreover, ET-1 receptors were increased in both cell types during earlier time points (1 - 4 h) of endotoxin treatment in the absence of the stimulation of NO synthesis. These results demonstrate that endotoxin up-regulates ET-1 receptors in HSC by NO-dependent and -independent mechanisms. Such effects of endotoxin can be of importance in acute endotoxemia and during chronic injury of the liver.

Animals↗