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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↗

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↗

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↗

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↗

PubMed1993

Despite maintenance of systemic and regional perfusion, endotoxemia following complement depletion produces hepatocellular dysfunction.

Experimental endotoxemia causes hypotension and a reduction in regional blood flow, including hepatic blood flow. Complement depletion prior to endotoxemia is known to attenuate these perfusion deficits. We depleted complement with cobra venom factor prior to the administration of Escherichia coli lipopolysaccharide in Sprague-Dawley rats and studied the effects of this treatment on systemic hemodynamics, regional hepatic perfusion, and hepatocellular integrity. Complement-depleted endotoxemic rats were compared with untreated rats, rats with complement depletion alone, and rats with endotoxemia alone. Systemic hemodynamics (cardiac index, mean arterial pressure), regional hepatic perfusion (effective hepatic blood flow), and hepatocellular integrity (adenosine triphosphate [ATP], lipid peroxidation) were determined 4-6 hr after the onset of endotoxemia. The endotoxemic animals exhibited a significant decrease in systemic hemodynamic performance and regional perfusion. Complement depletion prior to endotoxemia resulted in preservation of normal systemic and hepatic perfusion. ATP and lipid peroxide levels were significantly abnormal in both groups of endotoxemic animals. Complement depletion alone did not significantly affect any of the variables studied. The maintenance of systemic and regional perfusion during endotoxemia was not cytoprotective implicating direct cellular injury independent of perfusion deficits in the pathogenesis of hepatic failure during endotoxemia.

Adenosine Triphosphate↗

PubMed1986

Endotoxemia after relief of biliary obstruction by internal and external drainage in rats.

Systemic and portal endotoxemia were studied in rats with biliary obstruction and after relief of the obstruction by internal and external drainage. Endotoxemia was increased after bile duct ligation (p less than 0.001) compared with control values. The incidence of systemic and portal endotoxemia was significantly reduced after internal drainage (p less than 0.001). A significantly higher incidence of portal (86 percent) and systemic (57 percent) endotoxemia, however, was found after external drainage. The persistence of endotoxemia after external drainage, when serum bilirubin levels returned to normal units, indicates that bile flow is important in controlling endotoxemia during preoperative biliary drainage. These results suggest that the systemic endotoxemia observed after relief of obstruction by external drainage may contribute to the increased mortality, as found in previous rat studies. This observation may contribute to an understanding of why patients with preoperative external drainage of biliary obstruction have a higher incidence of septic complications.

Animals↗

PubMed1988

Effects of endotoxemia on systemic plasma loss and hematocrit in rats.

Endotoxemia in rats increases plasma extravasation but does not result in continuously rising hematocrit. These contradictory observations led us to design a study in anesthetized rats (C, control rats, n = 10; E, endotoxin rats, n = 10) in which we continuously measured in blood hematocrit (conductivity cell) and changes in concentration of 125I-HSA (human serum albumin) and 51Cr-labeled red cell (51Cr-RBC; multichannel analyzer) in an extracorporeal circuit. In two additional series of experiments we measured in blood samples changes in protein concentration (series II, C: n = 7, E: n = 7) and uptake of intraperitoneally injected 125I-HSA and 51Cr-RBC (reflecting lymph flow rate; series III, C: n = 6, E: n = 7). Endotoxemia was induced by infusion (iv, 0.2 ml/100 g.hr) of Escherichia coli endotoxin (20 mg/kg) from t = 0 to t = 60 min; controls received saline. Experiments ended at t = 120 (series I and II) or 150 min (series III). The endotoxemia resulted in a marked rise of serum lactate (by ca 500% at t = 120); heart rate increased and central venous pressure decreased (by ca 20 and -95% at t = 120, respectively). All rats showed characteristic changes in hematocrit during endotoxemia: an increase from t = 20 to t = 45 (by ca 9%) followed by a decrease to preshock values or less at t = 120. The 51Cr activity per microliter blood cells did not change, indicating that there was no red cell mobilization. Protein concentration and 125I-HSA activity also showed a temporary increase during endotoxemia, but 125I-HSA activity per gram protein was decreased. Peritoneal uptake of 125I-HSA and 51Cr-RBC was significantly increased during endotoxemia (by 200%). We conclude that fluid extravasation during endotoxemia is temporary, mainly concerns plasma water, and is compensated by mechanisms like reabsorption and increased lymph flow, resulting in restoration of plasma volume.

Animals↗

PubMed1982

Effect of paromomycin sulfate on endotoxemia in patients with cirrhosis.

We evaluated, in a randomized double-blind trial, the efficacy of oral paromomycin sulfate administration in the prevention of endotoxemia in 24 cirrhotic patients with endotoxemia. Renal function was evaluated by glomerular-filtration rate and renal plasma flow at the beginning and at the end of the study period. After the administration of paromomycin sulfate, 2 g/day for 4 weeks, endotoxemia disappeared in 10 out of 13 (76.9%) cirrhotic patients with endotoxemia, whereas it became negative in only 3 of the 11 (27.3%) treated with placebo, the difference being significant (P less than 0.05). With regard to correlation of endotoxemia with renal impairment, endogenous creatinine clearance and p-aminohippurate clearance were significantly improved (P less than 0.02) in those patients whose endotoxemia disappeared on paromomycin sulfate administration. We did not find significant improvement, however, neither in liver function or in blood coagulation tests in the same patients. Paromomycin sulfate seems to be effective in the prevention of endotoxemia and the associated renal impairment in cirrhosis in man.

Acute Kidney Injury↗

PubMedDate not supplied

Endotoxemia in horses. A review of cellular and humoral mediators involved in its pathogenesis.

Endotoxemia remains the leading cause of death in horses, being intimately involved in the pathogenesis of gastrointestinal disorders that cause colic and neonatal foal septicemia. Endotoxins, normally present within the bowel, gain access to the blood across damaged intestinal mucosa, or endotoxemia occurs when gram negative organisms proliferate in tissues. Endotoxins are removed from the circulation by the mononuclear phagocyte system, and the response of mononuclear phagocytes to these lipopolysaccharides (LPS) play an important role in determining the severity of clinical disease. Macrophages become highly activated for enhanced secretory, phagocytic and cidal functions by LPS. Macrophage-derived cytokines are responsible for many of the pathophysiologic consequences of endotoxemia. The arachidonic acid metabolites, prostacyclin and thromboxane A2 likely mediate early hemodynamic dysfunction and the leukotrienes may potentiate tissue ischemia during endotoxemia. Interleukin 1 (IL-1) induces fever and is responsible for the inflammatory cascade, which constitutes the acute phase response. Tumor necrosis factor (TNF), an important proximal mediator of the effects of LPS, acts to initiate events and formation of other molecules that affect shock and tissue injury. Systemic administration of TNF produces most of the physiologic derangements that are associated with endotoxemia and antibodies that are directed against TNF significantly reduce LPS-induced mortality in experimental animals. In response to endotoxins, mononuclear phagocytes express thromboplastin-like procoagulant activity (PCA), which initiates microvascular thrombosis. Both IL-1 and TNF induce PCA expression, creating a positive feedback loop for LPS-induced coagulopathy. A macrophage-derived platelet activating factor contributes to coagulation dysfunction and further stimulates arachidonic acid metabolism. The ultimate consequences of endotoxemia are multiple system organ failure and death. The numerous feedback loops and intertwining cascades of mediators during endotoxemia defy simplistic methods of treatment. The optimal therapy likely involves methods to alter the generation of inflammatory mediators by mononuclear phagocytes.

Animals↗

PubMed1995

Reappraisal with meta-analysis of bacteremia, endotoxemia, and mortality in gram-negative sepsis.

Among patients with suspected sepsis, endotoxemia is variably present in association with gram-negative bacteremia. A total of 738 patients with suspected sepsis from 11 studies could be classified into four groups: 131 (18%) patients had both endotoxemia and gram-negative bacteremia (group 1), 87 (12%) had only gram-negative bacteremia (group 2), and 143 (19%) had only endotoxemia (group 3); in 377 (51%) patients neither could be detected (group 4). By the statistical techniques of meta-analysis, the fatality risk for patients with either endotoxemia or gram-negative bacteremia or both was estimated with group-specific case fatality rates from these studies and expressed as an odds ratio (OR; 95% confidence interval [95% CI]) versus patients with these factors absent. This risk was increased marginally when endotoxemia was detected without gram-negative bacteremia (OR, 2.3; 95% CI, 1.3 to 4.0) or the converse (OR, 2.0; 95% CI, 1.0 to 3.8), in contrast to the striking increase when both endotoxemia and gram-negative bacteremia were detected (OR, 6.3; 95% CI, 4.0 to 10.0). Alone, neither endotoxemia nor gram-negative bacteremia is a strong predictor of outcome in patients with suspected sepsis. However, in combination, the two identify a subpopulation with a substantially increased risk of mortality.

Adolescent↗

PubMed1995

Endotoxemia and intestinal mucosal dysfunction after the relief of obstructive jaundice by internal and external drainage in rats.

We studied the effects of external and internal biliary drainage on the development of endotoxemia in a rat model of obstructive jaundice. Male Donryu rats were allocated to four groups: sham operation, common hepatic bile duct ligation (BDL), internal or external biliary drainage after BDL, and biliary drainage after BDL with oral endotoxin administration. Portal and systemic blood endotoxin concentrations were measured and the histomorphology of the intestinal mucosa was examined. Portal endotoxemia was observed 7 days after BDL and both portal and systemic endotoxemia were observed after 14 days. Portal endotoxemia was reversed by both internal and external biliary drainage and systemic endotoxemia was prevented. The ratio of villous height to crypt depth in the mucosa of the terminal ileum was decreased in rats with external drainage. Oral administration of endotoxin induced marked disruption of the mucosal epithelium in rats with external biliary drainage, but not in rats with internal biliary drainage. Significant increases in portal and systemic blood endotoxin concentrations were observed only in the external drainage group after oral endotoxin administration. The relief of biliary obstruction effectively relieved portal endotoxemia. External biliary drainage, however, has the potentially deleterious effect of disrupting the intestinal mucosa, which may promote the development of endotoxemia. These findings have implications for the use of biliary drainage procedures to reduce postoperative complications in jaundiced patients.

Animals↗

PubMed1991

Increased sensitivity to endotoxemia by tissue necrosis.

In this study the interaction of endotoxemia and ischemic organ injury was investigated in a rat model. Animals received lipopolysaccharide to induce endotoxemia and were simultaneously subjected to renal ischemia. If only renal ischemia was induced, moderate azotemia occurred and all animals survived. Lipopolysaccharide treatment caused neither renal failure nor death. However, rats with both endotoxemia and renal ischemia showed severe azotemia, and 50% of the animals died within 48 hours. The observed mortality rate is unlikely related to renal failure since animals subjected to bilateral nephrectomy did not die within 48 hours after treatment with lipopolysaccharide. To further exclude the role of renal failure in the enhanced effect of endotoxemia, experiments were performed in which ischemic kidneys were excised from littermates and were placed in the abdomens of lipopolysaccharide-treated animals. A similar effect was observed: 50% of the animals died within 48 hours. Azotemia did not occur. Since tumor necrosis factor (TNF) is an important cytokine involved in endotoxemia-induced morbidity and death, we studied the role of TNF in our model. Plasma levels of TNF were increased during endotoxemia. Concomitant renal ischemic injury did not influence the concentration of TNF. When animals were treated with recombinant TNF and were subsequently subjected to renal ischemic injury, again a 50% mortality was observed, a rate similar to that in lipopolysaccharide-treated animals. We conclude that the sensitivity to endotoxemia is enhanced by tissue necrosis and may lead to death in the experimental model used in this study.

Animals↗

PubMed1990

Development and reversal of endotoxemia and endotoxin-related death in obstructive jaundice.

Gut-derived endotoxemia has been implicated in postoperative complications in patients with jaundice. It is thought that absence of bile in the gut predisposes to portal absorption of endotoxin and endotoxemia is reversed by oral bile salt replacement or internal biliary drainage and return of bile to the gut, but not by external drainage. We believe that the importance of gastrointestinal bile flow has been overestimated and biliary obstruction and the integrity of hepatocyte and Kupffer cell function are more important in the development and reversal of endotoxemia. In experiment 1, serum endotoxin concentrations were measured in control rats (n = 10) after choledochovesical fistula (n = 15) and bile duct ligation (n = 15) and after relief of biliary obstruction by internal drainage (choledochoduodenostomy; n = 8) and sterile external drainage (choledochovesical fistula; n = 8), with a quantitative limulus assay. In experiment 2, mortality rates were measured in similar groups 48 hours after administration of oral endotoxin (5 mg/100 gm) and intravenous lead acetate (5 mg/100 gm). Bilirubin levels were elevated in bile duct ligation (192 +/- 13 mumols/L) compared with control animals and those with choledochovesical fistula, internal drainage, and external drainage (10.6 +/- 1.5 mumols/L). In experiment 1, significant portal endotoxemia and systemic endotoxemia occurred in bile duct ligation (portal, 130.4 +/- 12.9 pg/ml; systemic, 91.8 +/- 11.0 pg/ml) but not in choledochovesical fistula (portal, 49.3 +/- 17.1 pg/ml; systemic, 27.2 +/- 11.5 pg/ml). Relief of obstruction by both internal and external drainage reversed endotoxemia. In experiment 2, significant death occurred in bile duct ligation (13 of 15) but not in choledochovesical fistula (3 of 15), and relief of obstruction by both internal and external drainage prevented death. These results confirm that biliary obstruction is a more important factor than is gastrointestinal bile flow in the development and reversal of endotoxemia.

Animals↗

PubMed1995

Hepatic nitric oxide production following acute endotoxemia in rats is mediated by increased inducible nitric oxide synthase gene expression.

In the present studies, we analyzed the effects of acute endotoxemia on hepatocyte nitric oxide production and functional activity. Treatment of rats with 5 mg/kg of lipopolysaccharide (LPS), which induces acute endotoxemia, caused an increase in nitric oxide production in the liver, as measured by electron paramagnetic spin trapping, which was evident within 6 hours. This was associated with expression of inducible nitric oxide synthase (iNOS) messenger (m) RNA in hepatocytes and in sinusoidal cells throughout the liver lobule. Acute endotoxemia also caused alterations in hepatic structure, including hypertrophy, vacuolization, and chromosomal emargination, however these changes were not apparent for 24 to 48 hours. Hepatocytes isolated from endotoxemic rats released increased amounts of nitric oxide, measured by nitrite production, in response to interferon gamma (gamma-IFN) alone or in combination with LPS, tumor necrosis factor alpha, macrophage-colony stimulating factor, granulocyte/macrophage-colony stimulating factor, or hepatocyte growth factor. These results show that hepatocytes are sensitized by acute endotoxemia to respond to inflammatory mediators and growth factors. Increased nitrite production by hepatocytes was due to increased expression of iNOS mRNA and protein and was correlated with the time following induction of acute endotoxemia. Thus, cells isolated 48 hours after induction of acute endotoxemia released significantly more nitrite than cells recovered after 6 hours, a response that was not due to alterations in hepatocyte viability. Hepatocytes isolated from endotoxemic rats also exhibited a marked increase in proliferative capacity when compared with cells from control rats. Nitric oxide production by hepatocytes in vitro was associated with inhibition of cell growth and protein synthesis, which was reversed by the nitric oxide synthase inhibitor, NG-monomethyl-l-arginine (L-NMMA). Agarose gel electrophoresis showed extensive cytoplasmic DNA fragmentation in hepatocytes treated with LPS and gamma-IFN, a characteristic of apoptosis, which was also reversed by L-NMMA. These results, together with our findings that treatment of rats with an inhibitor of nitric oxide synthase partially reversed the structural alterations in the liver associated with acute endotoxemia suggest that nitric oxide may contribute to the pathophysiologic response to this bacterially derived toxin.

Acute Disease↗

PubMed2000

Effect of endotoxemia on hepatic portal and sinusoidal blood flow in rats.

A decrease in liver blood flow leads to dysfunction of hepatocytes and Kupffer cells, with subsequent local and systemic liberation of proinflammatory mediators that may maintain systemic inflammatory response syndrome (SIRS) and may lead to multiple organ dysfunction syndrome (MODS). There is only limited knowledge on the hepatic micro- and macrocirculation during sepsis or endotoxemia. Therefore, the aim of our study was to investigate alterations in hepatic portal blood flow (PBF) and sinusoidal blood flow (SBF) during endotoxemia. In male Wistar rats endotoxemia was induced by continuous infusion of 2 mg/kg/h lipopolysaccharides from Escherichia coli 026:B6 immediately after baseline measurements (n = 8). The control group (n = 8) received an equivalent volume of Ringer's solution. Mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), PBF, and SBF were measured at baseline and 60 and 120 min after induction of endotoxemia. PBF was measured using an ultrasonic flow probe that was positioned around the portal vein. SBF was detected by in vivo videomicroscopy of the left liver lobe. In the LPS group MAP decreased, but CO remained at baseline values. During endotoxemia PBF decreased significantly from 23 +/- 3 to 15 +/- 4 mL/min (60 min) and 16 +/- 3 mL/min (120 min). SBF also significantly decreased to 68.5% (60 min) and 57.1% (120 min) of baseline value. Our results demonstrate that during early endotoxemia hepatic macro- and microcirculatory perfusion is significantly decreased despite unchanged CO. This early reduction of hepatic perfusion might be caused by an increased hepatic vessel resistance as a consequence of liberation of vasoconstrictive mediators or/and by a decrease in intestinal perfusion.

Animals↗