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PubMed1983

Incidence of endotoxemia in pigs with ischemic hepatic necrosis treated by hemodialysis. Prevention of endotoxemia with lactulose.

The incidences of endotoxemia and bacteremia were evaluated in 30 pigs with ischemic hepatic necrosis treated by hemodialytic procedures. Prior to induction of hepatic ischemia, ten pigs underwent bowel cleansing by means of an oral dose of magnesium sulfate, and 20 received a combination of magnesium sulfate and lactulose. Endotoxemia and bacteremia seldom occurred during the development of hepatic encephalopathy, but the incidence of both increased markedly shortly before death. Pigs pretreated with magnesium sulfate and lactulose however did not develop preterminal endotoxemia. A significant relation between endotoxemia or bacteremia and survival was not found, irrespective of pretreatment with lactulose. Of the positive limulus tests, 67% were accompanied by a positive blood culture, while 42% of all positive blood cultures were associated with a positive limulus test. Dialysis with dialysates contaminated with endotoxins did not increase the risk of endotoxemia. It is concluded that in an animal model of ischemic hepatic necrosis (1) endotoxemia and bacteremia appear mainly in the preterminal stage, but do not influence the duration of survival significantly; (2) lactulose prevents endotoxemia and (3) dialytic procedures do not increase the risk of endotoxemia and bacteremia.

Animals↗
PubMed1979

Endotoxemia and endotoxemia diagnostics.

After the study of a group of severely burned patients with septicemia the authors reached the conclusion that the diagnosis of endotoxemia should be based on the following criteria: clinical condition, laboratory results and autopsy findings. Clinical findings can be subdivided into anamnestic data (such as age, liver function etc.) and direct clinical observation (taking into account states of stress and some specific surgical procedures). The most significant laboratory findings in the investigated group of patients were hypoxy, metabolic acidosis, lowered platelet count and positive Limulus test. Autopsy findings corresponded to findings in septicemia and shock. The authors also discuss the significance of activated lymphocyte accumulation in the liver following endotoxin administration in animals.

Acidosis↗
PubMed2004

[The role of bacterial translocation and endotoxemia in pathogenesis of obturation ileus, caused by colorectal carcinoma. Limulus test--a method for quick diagnostics of endotoxemia].

Colorectal carcinoma is one of most common diseases in human body. Often it is presented for the first time by its complicated forms--obturation, perforation, bleeding etc. Most common is the obturation of the large bowel. His clinic is caused not only by intoxication of carcinoma, but by massive flow of endotoxin in systemic circulation. In this publication we are trying to explain changes in human body and we offer a test for quick and early diagnosis--Limulus test.

Bacterial Translocation↗
PubMed1980

The role of prostaglandins in endotoxemia: comparisons in response in the nonpregnant, maternal, and fetal models. I. Prostaglandins and the pulmonary effect of experimental endotoxemia.

The mechanism of respiratory distress in sepsis is unknown. Previous work has shown elevations of prostaglandins during sepsis. This study reveals a correlation between levels of prostaglandins F 2 alpha and E and pulmonary hypertension and other parameters of respiratory distress in oophorectomized ewes subjected to endotoxin. The use of prostaglandin synthetase inhibitors prior to endotoxin prevented the rise in prostaglandins and the development of respiratory distress.

Animals↗
PubMed2006

Nitric oxide modifies the sarcoplasmic reticular calcium release channel in endotoxemia by both guanosine-3',5' (cyclic) phosphate-dependent and independent pathways.

OBJECTIVES: a) To determine whether decreased sarcoplasmic calcium release channel (CRC) activity is a mechanism by which myocardial contractility is reduced in endotoxemia; b) to determine whether nitric oxide modulates CRC activity in endotoxemia; and c) to examine two nitric oxide signaling pathways in relation to CRC function in endotoxemia. DESIGN: Randomized, prospective using a rat model of endotoxemia. SETTING: : Research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: Endotoxemia was induced by lipopolysaccharide administration. The effects of nitric oxide were studied using the highly selective inducible nitric oxide synthase inhibitor N-(3-(aminomethyl)benzyl)acetamidine dihydrochloride (1400W) and the specific guanylyl cyclase inhibitor 1-H (1, 2, 4)oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). MEASUREMENTS AND MAIN RESULTS: We assessed myocardial contractility, myocardial nitric oxide content, and guanosine-3',5' (cyclic) phosphate (cGMP) content. We determined CRC activity by calcium release and ryanodine binding assays. We followed these variables at four time points through the course of endotoxemia. We found that myocardial contractility and CRC activity were decreased in late but not in early endotoxemia. Furthermore, inducible nitric oxide synthase inhibition with 1400W restored contractility and CRC activity in late endotoxemia but paradoxically worsened these variables in early endotoxemia. Through the use of the guanylyl cyclase inhibitor ODQ, we demonstrate that nitric oxide acts through cGMP-mediated mechanisms in early and late endotoxemia. We investigated cGMP-independent pathways by assessing the oxidative status of the CRC. We found that in late endotoxemia, nitric oxide decreased the number of free thiols, demonstrating that nitric oxide also acts through cGMP-independent pathways. CONCLUSIONS: Nitric oxide has a dual effect on the CRC in endotoxemia. At low concentrations, as measured in early endotoxemia, nitric oxide stabilizes the CRC through cGMP-mediated mechanisms. In late endotoxemia, high nitric oxide concentrations decrease channel activity through both cGMP-dependent and cGMP-independent mechanisms.

Animals↗
PubMed2000

Effects of propofol on hemodynamic and inflammatory responses to endotoxemia in rats.

OBJECTIVE: To document the effects of propofol on the hemodynamic and inflammatory responses to endotoxemia in an animal model. DESIGN: Randomized, prospective laboratory study. SETTING: University experimental laboratory. SUBJECTS: Thirty-two male rats. INTERVENTIONS: The animals were randomly assigned to one of four groups: a) endotoxemia group (n = 8), which received intravenous Escherichia coli endotoxin (15 mg/kg over 2 mins); b) control group (n = 8), which was treated identically to the endotoxemia group except for the substitution of 0.9% saline for endotoxin; c) propofol group (n = 8), which was treated identically to the control group but also received propofol (10 mg/kg bolus, followed by infusion at 10 mg/kg/hr) immediately after the injection of 0.9% saline; and d) propofol-endotoxemia group (n = 8), which was treated identically to the endotoxemia group with the additional administration of propofol (10 mg/kg bolus, followed by infusion at 10 mg/kg/hr) immediately after endotoxin injection. MEASUREMENTS AND MAIN RESULTS: Hemodynamics, arterial blood gases, and acid-base status were recorded and the blood propofol concentrations and plasma cytokine concentrations were measured during the 5-hr observation. Microscopic findings of lung tissue for each group were obtained at necropsy. The systolic arterial pressure and heart rate of the propofol-endotoxemia group were similar to those of the endotoxemia group. The increases in the plasma cytokine (tumor necrosis factor, interleukin-6, and interleukin-10) concentrations, in the base deficit, and in the infiltration of neutrophils in the air space or vessel walls of the lungs were attenuated in the propofol-endotoxemia group compared with the endotoxemia group. CONCLUSIONS: Propofol attenuated cytokine responses, base deficit, and activation of neutrophils to endotoxemia. These findings suggest that propofol may inhibit inflammatory response and prevent the development of metabolic acidosis during endotoxemia.

Animals↗
PubMed2000

Expression of interleukin-18 in the lung after endotoxemia or hemorrhage-induced acute lung injury.

Hemorrhage and endotoxemia are important risk factors for the development of acute lung injury. Interleukin (IL)-18 is a recently described cytokine released in its mature, active form after pro-IL-18 is cleaved by the IL-1 converting enzyme (ICE). IL-18 has multiple immunomodulating properties, including induction of interferon-gamma (IFN-gamma), IL-1beta, tumor necrosis factor-alpha, and intercellular adhesion molecule-1. To examine the possible involvement of IL-18 in acute lung injury, we examined its expression, as well as that of IFN-gamma, IL-12, and ICE, using murine hemorrhage or endotoxemia models. The amounts of IL-18 messenger RNA (mRNA) increased in the lung after hemorrhage or endotoxemia. However, only endotoxemia was associated with elevations in lung and plasma concentrations of IL-18 protein. ICE expression was increased in the lungs after endotoxemia but not after hemorrhage. Although IFN-gamma expression increased in the lungs after hemorrhage or endotoxemia, elevations in lung IL-12 mRNA levels were found only after endotoxemia. These results indicate that hemorrhage and endotoxemia induce different patterns of immunomodulatory cytokine expression in the lungs. In particular, differences in the expression of ICE after hemorrhage or endotoxemia may affect generation of the active forms of downstream cytokines, including IL-18. IFN-gamma expression in the lungs after hemorrhage appears to occur through a pathway independent of IL-12 and IL-18. IL-18 may play a role in modulating the development of acute lung injury after endotoxemia but not after hemorrhage.

Animals↗
PubMed2004

[Effects of Radix Salviae Miltiorrhizae on the PMN-EC adhesion in vitro at the early stage of endotoxemia].

OBJECTIVE: To evaluate the effects of Radix Salviae Miltiorrhizae (RSM) on the PMN-EC adhesion in vitro at the early stage of endotoxemia, and to probe into the mechanism there in involved. METHODS: The rabbit endotoxemia model was made, and one group was treated with RSM injection (2 ml/kg) instantly and 24 h after the modeling of endotoxemia. PMN-EC adhesion rate, adhesion molecule (CD11a/CD18 and CD11b/CD18) and TNF-alpha level were measured instantly, 2 h, 4 h, 8 h, 16 h, 24 h and 48 h after endotoxemia modeling. RESULTS: It was found that after the modeling of endotoxemia, the levels of CD11a/CD18, CD11b/CD18 and PMN-EC adhesion rate instantly increased in the endotoxemia group and RSM group, they went up to the peak at 4 h in the endotoxemia group, and at 2 h, 4 h, 8 h, 16 h, 24 h and 48 h, they were markedly lower in the RSM group than in the endotoxemia group (P < 0.05). The TNF-alpha level in the endotoxemia group began to increase 2 h after the modeling and reached to the peak at 8 h, with its level still higher than normal at 48 h, while the RSM group had lower level of TNF-alpha at all time-points(P < 0.05). CONCLUSION: The data from this animal experiment indicate that Radix Salviae Miltiorrhizae can decrease PMN-EC adhesion rate and the levels of CD11a/CD18, CD11b/CD18 and TNF-alpha in case of endotoxemia so as to improve the microcirculation.

Animals↗
PubMed1997

Preoperative glutamine loading does not prevent endotoxemia in cardiac surgery.

BACKGROUND: The presence of endotoxemia is relatively common in cardiac surgery patients and it may modify the metabolic and hemodynamic responses peri- and postoperatively. Impaired gut fuel metabolism may contribute to the disturbed function and deterioration of the intestinal mucosal barrier and the development of bacterial translocation and endotoxemia. Glutamine may protect the gut mucosal barrier during marginal or insufficient perfusion. METHODS: We studied the effects of glutamine supplementation on endotoxemia and blood levels of tumor necrosis factor (TNF) during and after extracorporeal circulation (ECC) and the effects of endotoxemia on systemic and regional (splanchnic and leg) hemodynamics and metabolism after cardiac surgery. Nineteen elective coronary bypass patients were randomly assigned to receive preoperatively for 12 h either an infusion of glucose and a balanced amino acid solution (AA-group) or a solution containing 1/5 of total nitrogen as alanyl-glutamine (ALAGLN-group). RESULTS: Glutamine and amino acid loading before ECC did not protect from peri- or postoperative endotoxemia. Endotoxemia was detected in 5 vs. 7 of patients during ECC and 6 vs. 5 of patients postoperatively in the ALAGLN-group vs. AA-group, respectively. More than half of the patients at every measurement had an increased level of TNF. There was no consistent difference between the arterial and hepatic vein endotoxin- or TNF-concentrations. Endotoxemia did not modify systemic or regional hemodynamics and metabolism after cardiac operation. CONCLUSION: Glutamine did not prevent endotoxemia during or after cardiac surgery. An increased level of TNF was common and observed also in some patients without endotoxemia. Endotoxemia did not modify regional or whole-body metabolic patterns or hemodynamics.

Amino Acids↗
PubMed2001

Endotoxemia and acute-phase proteins in major abdominal surgery.

BACKGROUND: Translocation of endotoxin is a controversial issue. The ability of plasma to inactivate endotoxin is an indirect measure of endotoxemia. Endotoxin is a potent stimulator of the inflammatory response and affects the innate immune system. OBJECTIVE: To elucidate the kinetics of endotoxemia and the ability of plasma to inactivate endotoxin in patients with major abdominal operations. To demonstrate the early time course of the acute-phase proteins C-reactive protein (CRP), serum amyloid A (SAA), alpha(1)-antitrypsin, alpha(2)-macroglobulin, transferrin, and interleukin 6 (IL-6), and to correlate them with the amount of endotoxemia. METHODS: Twenty patients with elective major abdominal operation and 10 healthy controls were investigated. Blood was collected preoperatively, during the operation and regularly up to 12 days after surgery. Endotoxin was measured by Limulus amebocyte lysate test (LAL), the ability of plasma to inactivate endotoxin by modified LAL, the acute-phase proteins nephelometrically, and IL-6 by enzyme-linked immunosorbent assay (ELISA). RESULTS: Preoperative endotoxin plasma level (0.026 +/- 0.004 EU/mL) did not differ from healthy volunteers but increased during operation (0.09 +/- 0.02 EU/mL, P = 0.02). Endotoxemia peaked 1 hour after the surgical procedure (0.16 +/- 0.03 EU/mL; P <0.0001 versus preoperative) and decreased to almost normal values after 48 hours. The capability of plasma to inactivate endotoxin was significantly reduced during (recovery, 0.16 +/- 0.03 EU/mL), 1 hour (0.25 +/- 0.04 EU/mL) and 24 hours (0.16 +/- 0.02 EU/mL) after the operation compared with preoperative (0.068 +/- 0.01 EU/mL) values. Plasma IL-6 was significantly increased for 48 hours with a peak 1 hour after surgery (470 +/- 108 pg/mL). CRP peaked at 210 +/- 19 mg/L (P <0.0001 versus preoperative) 48 hours after operation and was significantly elevated for the rest of the observation period. SAA was significantly increased 24 hours after surgery (249 +/- 45 mg/L) and peaked additional 48 hours later (456 +/- 86 mg/L). alpha(1)-Antitrypsin, although a positive acute-phase protein, decreased initially to 1.38 +/- 0.1 g/L (preoperative, 2.33 +/- 0.18 g/L; P <0.0001) and increased thereafter until day 12 (3.05 +/- 0.35 g/L, P = 0.11 versus preoperative). The same was true for alpha(2)-macroglobulin (preoperative, 2.2 +/- 0.16 g/L; intraoperative, 1.36 +/- 0.13 g/L; day 5, 2.8 +/- 0.4 g/L). Transferrin decreased already during surgery (1.6 +/- 0.1 g/L versus preoperative 2.8 +/- 0.17 g/L, P <0.0001) and remained on this level for 5 days. Correlation analysis revealed a relationship between endotoxemia and the ability of plasma to inactivate endotoxin (r = 0.67, P <0.0001) and also a relation between intraoperative endotoxemia on one hand and alpha(2)-macroglobulin (-0.53 > r > -0.6, P <0.05) as well as alpha(1)-antitrypsin (0.64 > r >0.55, P <0.05) on the other. CONCLUSION: Major abdominal surgery is associated with transient endotoxemia and a transient reduced endotoxin inactivation capacity of the plasma. Endotoxemia correlates with the endotoxin inactivation capacity. The surgical procedure causes substantial changes in plasma concentrations of acute-phase proteins. alpha(2)-Macroglobulin and alpha(1)-antitrypsin correlate moderately with endotoxemia.

Abdomen↗
PubMedDate not supplied

Monocyte CD14 changes and endotoxemia after major hepatectomy.

BACKGROUND/AIMS: This study was designed to ascertain whether decreases in membrane CD14 (mCD14), the endotoxin receptor on the surface of the monocyte cell membrane, reflect the presence of endotoxemia, and whether endogenous endotoxemia is present after hepatectomy. METHODOLOGY: First, in cases with a definitive clinical diagnosis of endotoxemia, we determined the serum endotoxin level by the ES (Endospesy) method, from the percentage of cells positive for membrane CD14, from the CD14 fluorescence intensity (MFI-CD14), and from the quantification of soluble CD14 (sCD14); and calculated the diagnostic accuracy obtained with each. Next, in 13 cases of extended hepatectomy (in excess of lobectomy) the mCD14-positive rates were determined around the time of the operation, and compared with the clinical courses of infection foci, if any, and other findings. RESULTS: The diagnostic accuracy of endotoxemia obtained by ES, mCD14, MFI-CD14 and sCD14 were 77.3%, 95.5%, 86.7% and 66.7%, respectively, so that the highest was given by the positive mCD14 cell rate. Although no infectious complication was detected in any of the 9 patients in whom the mCD14-positive rates changed within the normal range, of the 4 patients in whom the mCD14-positive rates fell, 2 had cholangitis due to gram-negative bacilli, one who was infected by central vein catheterization, was thought to have exogenous endotoxemia; and the fourth, in whom no clear focus of infection was detected, ran a temperature of 38 degrees C (over 100 degrees F) of unknown origin for 16 days. In this last patient, gram-negative bacilli were detected in both the saliva and the gastric juice, and so endogenous endotoxemia was suspected. CONCLUSIONS: These results show that decrease in the mCD14-positive rate is more accurately diagnostic of endotoxemia than the endotoxin value obtained by the ES method, and was considered to be a definitive diagnosis of endotoxemia. In addition, from the reduction of the mCD14-positive rate after extended hepatectomy, it was considered that endogenous endotoxemia occurred in one case out of 13 (8%).

Endotoxemia↗
PubMed2001

Role of NF-kappaB in endotoxemia-induced alterations of lung neutrophil apoptosis.

Acute lung injury is frequently associated with endotoxemia and is characterized by the accumulation in the lungs of large numbers of neutrophils activated to produce proinflammatory mediators. In the setting of acute lung injury, the percentage of apoptotic cells among lung neutrophils is decreased. The transcriptional regulatory factor NF-kappaB is activated in neutrophils and other pulmonary cell populations after endotoxemia and appears to play a central role in the development of the acute inflammatory process that leads to lung injury. Because NF-kappaB can modulate apoptosis through increasing expression of anti-apoptotic proteins, activation of NF-kappaB may contribute to the alterations in lung neutrophil apoptosis associated with acute lung injury. In the present experiments, endotoxemia resulted in decreased apoptosis and increased expression of anti-apoptotic mediators among lung neutrophils. Amounts of A1, A20, and Bcl-x(L), anti-apoptotic proteins whose transcription is dependent on NF-kappaB, were increased in lung neutrophils after endotoxemia. Inhibition of nuclear translocation of NF-kappaB increased the percentage of apoptotic lung neutrophils after endotoxemia, but not back to the levels found in unmanipulated animals. Although inhibition of nuclear translocation of NF-kappaB prevented endotoxemia-induced increases in Bcl-x(L), A1, and A20 in lung neutrophils, this intervention did not prevent endotoxemia-associated elevation of Mcl-1, an anti-apoptotic protein primarily under the transcriptional regulation of CREB. These results demonstrate that mechanisms independent of NF-kappaB activation play an important role in modulating lung neutrophil apoptosis after endotoxemia.

Active Transport, Cell Nucleus↗
PubMed1999

Mechanisms of lung neutrophil activation after hemorrhage or endotoxemia: roles of reactive oxygen intermediates, NF-kappa B, and cyclic AMP response element binding protein.

Acute inflammatory lung injury occurs frequently in the setting of severe infection or blood loss. Accumulation of activated neutrophils in the lungs and increased pulmonary proinflammatory cytokine levels are major characteristics of acute lung injury. In the present experiments, we examined mechanisms leading to neutrophil accumulation and activation in the lungs after endotoxemia or hemorrhage. Levels of IL-1 beta, TNF-alpha, and macrophage inflammatory protein-2 mRNA were increased in lung neutrophils from endotoxemic or hemorrhaged mice compared with those present in lung neutrophils from control mice or in peripheral blood neutrophils from endotoxemic, hemorrhaged, or control mice. The transcriptional regulatory factors NF-kappa B and cAMP response element binding protein were activated in lung but not blood neutrophils after hemorrhage or endotoxemia. Xanthine oxidase inhibition, achieved by feeding allopurinol or tungsten-containing diets, did not affect neutrophil trafficking to the lungs after hemorrhage or endotoxemia. Xanthine oxidase inhibition did prevent hemorrhage- but not endotoxemia-induced increases in proinflammatory cytokine expression among lung neutrophils. Hemorrhage- or endotoxemia-associated activation of NF-kappa B in lung neutrophils was not affected by inhibition of xanthine oxidase. cAMP response element binding protein activation was increased after hemorrhage, but not endotoxemia, in mice fed xanthine oxidase-inhibiting diets. Our results indicate that xanthine oxidase modulates cAMP response element binding protein activation and proinflammatory cytokine expression in lung neutrophils after hemorrhage, but not endotoxemia. These findings suggest that the mechanisms leading to acute inflammatory lung injury after hemorrhage differ from those associated with endotoxemia.

Animals↗
PubMed1993

Hemodynamic changes associated with thermodilution cardiac output determination in canine acute blood loss or endotoxemia.

Since the technique of thermodilution (TD) cardiac output measurement, per se, causes hemodynamic alterations, the author examined whether the alterations elicited by iced injectate are augmented in the presence of acute blood loss or endotoxemia, compromised conditions frequently associated with critically ill patients. Acute blood loss (N = 8) and endotoxemia (N = 8) were induced by withdrawing arterial blood approximately 20-30 ml.kg-1 over 30 min and by a slow intravenous infusion of E. coli endotoxin 2.5-3.0 mg.kg-1 over 10 min, respectively, in anesthetized dogs. The magnitudes of decreases in mean arterial and pulmonary artery pressures during slowing of heart rate (HR) following injection of iced injectate 3 ml were slightly less in acute blood loss than in normovolemia, whereas in endotoxemia the degree of mean arterial pressure decrease during slowing of HR following iced injectate 3 ml was slightly less as compared with that before endotoxemia. However, the alterations in other hemodynamic variables following injection of iced injectate 3 ml were similar between dogs with and without acute blood loss or endotoxemia. No profound hemodynamic changes were observed during any TD cardiac output measurements under both conditions. Cardiac output estimated by TD correlated closely with pulmonary blood flow measured by electromagnetic flowmeter in endotoxemia (r > 0.9) but not during acute blood loss. These results indicate that TD cardiac output determination does not cause serious hemodynamic alterations in endotoxemia or acute blood loss, and can estimate right ventricular output accurately in endotoxemia but not in acute blood loss.

Acidosis↗
PubMed1999

Neutrophil apoptosis in the lung after hemorrhage or endotoxemia: apoptosis and migration are independent of IL-1beta.

Hemorrhage and endotoxemia are associated with neutrophil accumulation in the lungs and the development of acute inflammatory lung injury. Because alterations in the rate of apoptosis may affect the number and function of neutrophils in the lungs, we determined the percentage of neutrophils undergoing apoptosis in the lungs of control, hemorrhaged, or endotoxemic mice. In control mice, 18.5 +/- 1.2% of pulmonary neutrophils were apoptotic. The proportion of apoptotic neutrophils in the lungs was significantly decreased 1 h after hemorrhage (6.5 +/- 1.6%, P < 0.01 compared to control) or endotoxemia (7.0 +/- 0.9%, P < 0.01 compared to control). Between 1 and 24 h after endotoxemia or hemorrhage, the proportion of apoptotic neutrophils in the lung remained significantly depressed compared to that in control, unmanipulated mice. By 48 h, the proportion of apoptotic neutrophils returned to baseline levels in the lungs of hemorrhaged (21.4 +/- 1.4%) or endotoxemic (16.4 +/- 1. 6%) mice. Lung neutrophil IL-1beta mRNA was significantly increased from that of control mice [i.e., 0.12 +/- 0.06 relative absorbance units (RAU)] 1 h after hemorrhage (5.19 +/- 0.068 RAU, P < 0.05 compared to control) or endotoxemia (8.90 +/- 1.53 RAU, P < 0.01 compared to control). In IL-1beta-deficient mice, there was no significant difference in lung neutrophil apoptosis or neutrophil entry into the lung after hemorrhage or endotoxemia compared to wild-type mice. Our results show that apoptosis among lung neutrophils is decreased for more than 24 h after hemorrhage or endotoxemia. Although IL-1beta expression is increased in lung neutrophils under these conditions, IL-1beta is not responsible for either the influx of neutrophils into the lung or the reduction of apoptosis in neutrophil populations after hemorrhage or endotoxemia.

Animals↗
PubMed2002

Comparative study of the endotoxemia and endotoxin tolerance on the production of Th cytokines and macrophage interleukin-6: differential regulation of indomethacin.

Endotoxin tolerance reduces the capacity of monocytes to produce proinflammatory cytokines, results in cellular immune paralysis, and down-regulates the production of helper T (Th)1 type cytokines with a shift toward a Th2 cytokine response. Prostaglandin (PG)E2 in the immune system also results in macrophage inactivation and the suppression of Th1 activation and the enhancement of Th2 activation. However, the inhibitory effects of PGE2 on the altered polarization of the Th cell and macrophage interleukin (IL)-6 production characterized in part by cellular immune paralysis in a state of endotoxin tolerance is unclear. This study was undertaken, using indomethacin, to investigate the role of endogenous PGE2 on the Th cytokines and macrophage IL-6 production in a state of endotoxin tolerance compared to those with endotoxemia mice, wherein, in this latter case, the increased production of proinflammatory cytokines and PGE2 is exhibited. Endotoxemia was induced by injection of lipopolysaccharide (LPS; 10 mg/kg in saline) ip. once in BALB/c mice, and endotoxin tolerance was induced by pretreatment with LPS (1 mg/kg in saline) injected i.p. daily for two consecutive days and then with LPS 10 mg/kg on day 4. Splenocytes or macrophages were obtained from endotoxemia and endotoxin tolerance models pretreated with indomethacin, and then cytokine production was induced by Con A-stimulated splenocytes for the Th cytokine assays and LPS-stimulated macrophages for the IL-6 assay. Our results showed that endotoxemia led to significantly reduced IL-2 and IL-4 production, to significantly increased IL-6 production, whereas interferon (IFN)-gamma production was not affected. Indomethacin in the case of endotoxemia markedly attenuated IFN-gamma and IL-6 production and didnt reverse IL-2 and IL-4 production. Endotoxin tolerance resulted in the significantly reduced production of IL-2 and IFN-gamma and the significantly increased production of IL-4 and IL-6. Indomethacin in endotoxin tolerance greatly augmented IL-2 production, significantly decreased IL-4 production, and slightly attenuated IL-6 production. These findings indicate that endogenous PGE2 may mediate the suppressed Th1 type immune response, with a shift toward a Th2 cytokine response in a state of endotoxin tolerance, whereas endotoxemia may be regulated differentially. Also, endogenous PGE2 may mediate macrophage IL-6 production in the case of endotoxemia to a greater extent than in the case of endotoxin tolerance.

Animals↗
PubMed2004

Despite minimal hemodynamic alterations endotoxemia modulates NOS and p38-MAPK phosphorylation via metalloendopeptidases.

In the present study, we hypothesized that endotoxemia produces metalloendopeptidase (MEPD)-dependent generation of endothelin-1 (ET-1) and alters NOS expression correlating with p38-mitogen-activated protein kinase (MAPK) phosphorylation in thoracic aorta. Male Sprague-Dawley rats (350-400 g) were subjected to two groups randomly; sham-treated (N = 10) and lipopolysaccharide (LPS)-treated (N = 10) (E. coli LPS 2 mg/kg bolus + 2 mg/kg infusion for 30 min). The animals in each group were further subdivided into vehicle and MEPD inhibitor phosphoramidon (1 mg/kg bolus, PHOS)-treated groups. LPS produces a significant decrease in mean arterial pressure (MAP) at 2 h post endotoxemia that was blocked by PHOS. PHOS attenuated LPS-induced increase in tumor necrosis factor-alpha (TNF-alpha) concentration at 2- and 24 h post-LPS administration. LPS significantly elevated plasma concentrations of ET-1 at 2- and 24 h post endotoxemia. An upregulated preproET-1 expression following both LPS and MEPD inhibition was observed in thoracic aorta at 2 h post treatment. PHOS effectively blocked conversion of preproET-1 to ET-1 in thoracic aorta locally at 24 h post treatment in endotoxic rats. PHOS inhibited LPS-induced upregulation of inducible NOS (iNOS), downregulation of endothelial NOS (eNOS) and elevation of NO byproducts (NOx) in thoracic aorta. PHOS also blocked LPS-induced upregulated p38-MAPK phosphorylation in thoracic aorta at 24 h post endotoxemia. The data revealed that LPS induces MEPD-sensitive inflammatory response syndrome (SIRS) at 2- and 24 h post endotoxemia. We concluded that inhibition of MEPD not only decreases the levels of ET-1 but also simultaneously downregulates protein expression of iNOS and phosphorylated p38-MAPK while increasing eNOS in thoracic aorta during SIRS in endotoxemia. We suggest that MEPD-dependent ET-1 and NO mechanisms may be involved in endotoxemia-induced altered p38-MAPK phosphorylation.

Animals↗
PubMed2005

Inhibition of endogenous hydrogen sulfide formation reduces the organ injury caused by endotoxemia.

Hydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the role of H2S in the organ injury caused by severe endotoxemia in the rat. Male Wistar rats were subjected to acute endotoxemia (Escherichia coli lipopolysaccharide (LPS) 6 mg kg(-1) intravenously (i.v.) for 6 h) and treated with vehicle (saline, 1 ml kg(-1) i.v.) or DL-propargylglycine (PAG, 10-100 mg kg(-1) i.v.), an inhibitor of the H2S-synthesizing enzyme cystathionine-gamma-lyase (CSE). PAG was administered either 30 min prior to or 60 min after the induction of endotoxemia. Endotoxemia resulted in circulatory failure (hypotension and tachycardia) and an increase in serum levels of alanine aminotransferase and aspartate aminotransferase (markers for hepatic injury), lipase (indicator of pancreatic injury) and creatine kinase (indicator of neuromuscular injury). In the liver, endotoxemia induced a significant increase in the myeloperoxidase (MPO) activity, and in the expression and activity of the H2S-synthesizing enzymes CSE and cystathionine-beta-synthase. Administration of PAG either prior to or after the injection of LPS dose-dependently reduced the hepatocellular, pancreatic and neuromuscular injury caused by endotoxemia, but not the circulatory failure. Pretreatment of rats with PAG abolished the LPS-induced increase in the MPO activity and in the formation of H2S and in the liver. These findings support the view that an enhanced formation of H2S contributes to the pathophysiology of the organ injury in endotoxemia. We propose that inhibition of H2S synthesis may be a useful therapeutic strategy against the organ injury associated with sepsis and shock.

Alanine Transaminase↗