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PubMedDate not supplied

Glycoprotein IIB/IIIA-inhibition and microcirculatory alterations during experimental endotoxemia--an intravital microscopic study in the rat.

OBJECTIVE: Endothelial damage during early endotoxemia has been shown to be leukocyte-independent. Platelet-activating factor (PAF) and serotonin-receptor antagonism are known to reduce leukocyte-independent macromolecular leakage significantly, thereby focusing the field of interest to the platelets. We hypothesized that inhibition of the GP IIb/IIIa receptor, using the unspecific GP IIb/IIIa inhibitor abciximab, would reduce leukocyte-independent endothelial damage during early endotoxemia, and furthermore, that inhibition of the GP IIb/IIIa receptor with abciximab might improve microcirculatory disturbances, seen in a leukocyte-dependent animal model during endotoxemia. METHODS: In male Wistar rats, venular wall shear rate, macromolecular efflux, and leukocyte-endothelial interaction were determined in mesenteric postcapillary venules using intravital microscopy at baseline, 60, and 120 min after the start of the experiment. The experiment was divided into two parts. In the first part, we investigated the effects of the GP IIb/IIIa inhibitor abciximab on leukocyte-independent endothelial permeability during endotoxemia. In the second part of the experiment, we focused on the effects of the GP IIb/IIIa inhibitor abciximab on microcirculatory disturbances during endotoxemic states, without a modification of the leukocyte-endothelial interaction, putting the main emphasis again on endothelial permeability. RESULTS: GP IIb/IIIa inhibition with abciximab resulted in a significant reduction of macromolecular efflux during leukocyte-independent endotoxemia. Both pretreatment with abciximab and post-treatment with abciximab reduced macromolecular leakage during leukocyte-dependent endotoxemia to values comparable to control values, and prevented an increase in leukocyte adherence, that has been reduced to values comparable to control values, too. CONCLUSION: GP IIb/IIIa inhibition, using abciximab, protects against endothelial dysfunction and an increase in leukocyte adherence to the vascular wall during experimental endotoxemia. The protective properties of abciximab on microcirculation seemed to be leukocyte-independent.

Abciximab↗
PubMed2005

Endotoxemia-induced lymphocyte apoptosis is augmented by a hyperinsulinemic-euglycemic clamp.

BACKGROUND: Sepsis and endotoxemia are associated with lymphocyte apoptosis. This has been regarded as harmful, contributing to further immune suppression in already immune-compromised patients. Because normalization of blood glucose improves outcome in critically ill patients, the authors hypothesized that one of the effects of insulin and normoglycemia would be inhibition of lymphocyte apoptosis. Therefore, in this experimental study in pigs, the authors examined the separate and combined effects of acute endotoxemia and a hyperinsulinemic-euglycemic clamp (HEC) on lymphocyte apoptosis. METHODS: After 60 min of stabilization, 38 anesthetized and mechanically ventilated pigs (weight, 35-40 kg) were divided (by randomization performed before the experiment) into four groups and were then studied for 570 min. Group 1 received no intervention. Group 2 received a HEC (5 mm p-glucose, insulin infusion rate of 0.6 mU . kg (-1). min(-1)) for 570 min. Group 3 received a lipopolysaccharide infusion for 180 min. Group 4 was given a combination of a HEC and a lipopolysaccharide infusion. After the 570-min study period, the pigs were killed, and tissue was sampled from the spleen and frozen. In four sections of each sample, the apoptosis of B and T lymphocytes were analyzed using stereologic methods: The number of apoptotic B and T cells was estimated by fluorescence immunohistochemistry with anti-active caspase-3 and either anti-CD21 (B lymphocytes) or anti-CD3epsilon (T lymphocytes). The number of apoptotic B and T lymphocytes was then compared using two-way analysis of variance, and the interaction between endotoxemia and the clamp (hyperinsulinemia and euglycemia) was investigated. RESULTS: Endotoxemia induced apoptosis of B (P < 0.001) and T lymphocytes (P = 0.016) in the spleen, and this effect was independent of the clamp. The ratios of apoptotic cells in the spleen tissue of pigs with and without endotoxemia were 2.4 (confidence interval, 1.7-3.4) and 1.6 (confidence interval, 1.1-2.2) for B and T lymphocytes, respectively. Independent of endotoxin infusion, HEC increased the number of apoptotic lymphocytes (P = 0.029 and P = 0.038 for B and T lymphocytes, respectively). The ratios of the number of apoptotic spleen cells in pigs treated and not treated with HEC were 1.5 (confidence interval, 1.0-2.1) and 1.5 (confidence interval, 1.0-2.1) for B and T lymphocytes, respectively. CONCLUSION: In this porcine model, both endotoxemia and a HEC increased the number of apoptotic B and T lymphocytes in the spleen. Contrary to our hypothesis, lymphocyte apoptosis during acute endotoxemia was augmented by a HEC.

Algorithms↗
PubMed2003

Role of nitric oxide in leukocyte-independent endothelial damage during experimental endotoxemia.

Endothelial damage during early endotoxemia has been shown to be leukocyte independent. Platelet-activating factor and serotonin receptor antagonism has been shown to reduce leukocyte-independent macromolecular leakage significantly. Nevertheless, the exact mechanisms involved in leukocyte-independent endothelial dysfunction are unknown. Therefore, it was the aim of the study to investigate the effects of nitric oxide (NO) on leukocyte-independent endothelial damage during endotoxemia. In male Wistar rats, venular wall shear rate, macromolecular efflux, and leukocyte-endothelial interaction were determined in mesenteric postcapillary venules using intravital microscopy at baseline and at 60 and 120 min after start of the experiment. The animals received fucoidin to prevent leukocyte-endothelial interaction. The experiments were divided into three parts. In part 1, we investigated the effects of the NO-inhibitor L-NAME on leukocyte-independent endothelial damage during endotoxemic and nonendotoxemic conditions. The efficiency of the NO-donor (SIN-1) used, part 2, was investigated by the inhibitory properties of SIN-1 on NO-inhibition-induced macromolecular efflux. Finally, part 3, we analyzed the effects of the NO-donor SIN-1 on endothelial damage during endotoxemia. Both the combined challenge of the animals with L-NAME and endotoxin and the challenge with L-NAME alone resulted in a strong increase in macromolecular efflux, showing significant differences to control groups at an earlier time point than endotoxin challenge alone. Interestingly, combined L-NAME and endotoxin challenge, L-NAME challenge alone, and endotoxin challenge alone showed a similar macromolecular efflux at the end of the experiment. SIN-1 prevented both the increase in macromolecular efflux seen after L-NAME challenge (part 2) and was highly effective in preventing significantly the increase in macromolecular leakage that is seen during leukocyte-independent endotoxemia (part 3). In conclusion, our data indicate that during early states of endotoxemia endogenous NO preserves endothelial integrity in a leukocyte-independent setting. Exogenous NO prevents endothelial damage during early leukocyte-independent endotoxemia. Summarizing these data, endothelial integrity during leukocyte-independent endotoxemia is a NO-mediated event.

Animals↗
PubMed2006

Effects of thrombin inhibition with melagatran on renal hemodynamics and function and liver integrity during early endotoxemia.

Sepsis is associated with an activation of the coagulation system and multiorgan failure. The aim of the study was to examine the effects of selective thrombin inhibition with melagatran on renal hemodynamics and function, and liver integrity, during early endotoxemia. Endotoxemia was induced in thiobutabarbital-anesthetized rats by an intravenous bolus dose of lipopolysaccharide (LPS; 6 mg/kg). Sham-Saline, LPS-Saline, and LPS-Melagatran study groups received isotonic saline or melagatran immediately before (0.75 micromol/kg iv) and continuously during (0.75 micromol.kg(-1).h(-1) iv) 4.5 h of endotoxemia. Kidney function, renal blood flow (RBF), and intrarenal cortical and outer medullary perfusion (OMLDF) measured by laser-Doppler flowmetry were analyzed throughout. Markers of liver injury and tumor necrosis factor (TNF)-alpha were measured in plasma after 4.5 h of endotoxemia. In addition, liver histology and gene expression were examined. Melagatran treatment prevented the decline in OMLDF observed in the LPS-Saline group (P < 0.05, LPS-Melagatran vs. LPS-Saline). However, melagatran did not ameliorate reductions in mean arterial pressure, RBF, renal cortical perfusion, and glomerular filtration rate or attenuate tubular dysfunctions during endotoxemia. Melagatran reduced the elevated plasma concentrations of aspartate aminotransferase (-34 +/- 11%, P < 0.05), alanine aminotransferase (-21 +/- 7%, P < 0.05), bilirubin (-44 +/- 9%, P < 0.05), and TNF-alpha (-32 +/- 14%, P < 0.05) in endotoxemia. Melagatran did not diminish histological abnormalities in the liver or the elevated hepatic gene expression of TNF-alpha, intercellular adhesion molecule-1, and inducible nitric oxide synthase in endotoxemic rats. In summary, thrombin inhibition with melagatran preserved renal OMLDF, attenuated liver dysfunction, and reduced plasma TNF-alpha levels during early endotoxemia.

Animals↗
PubMed2005

Anti-inflammatory effects of intravenous anesthetics on endotoxemia.

Endotoxemia and endotoxin shock are common problems in the intensive care unit and carry a very high mortality rate. Endotoxemia increases production of endogenous cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, and IL-8. Not only endotoxin but also cytokines have been implicated as important factors in the pathophysiology of endotoxic shock and the development of cardiovascular dysfunction in endotoxemia. Recently, it has been shown both in vitro and in vivo that several intravenous anesthetics have anti-inflammatory effects. Thiopental and ketamine inhibit the endotoxin-induced TNF-alpha, IL-1 and IL-8 responses and increase IL-10 release in vitro. Ketamine prevent the pro-inflammatory cytokine (TNF-alpha, IL-1, and IL-6) responses to endotoxemia in vivo. Moreover, thiopental and ketamine suppress the activation of nuclear factor-kappa B induced by endotoxin. Propofol have been proven its anti-inflammatory effects on endotoxemia both in vitro and in vivo, but several studies have shown that propofol does not have any anti-inflammatory effects and deteriorates the inflammatory response to endotoxemia. This article reviews the anti-inflammatory effects of intravenous anesthetics on endotoxemia and endotoxic shock.

Anesthetics, Intravenous↗
PubMed2001

Activation of extracellular signal-regulated kinases, NF-kappa B, and cyclic adenosine 5'-monophosphate response element-binding protein in lung neutrophils occurs by differing mechanisms after hemorrhage or endotoxemia.

Acute lung injury is frequently associated with sepsis or blood loss and is characterized by a proinflammatory response and infiltration of activated neutrophils into the lungs. Hemorrhage or endotoxemia result in activation of cAMP response element-binding protein (CREB) and NF-kappa B in lung neutrophils as well as increased expression of proinflammatory cytokines, such as TNF-alpha and macrophage-inflammatory peptide-2, by these cells. Activation of the extracellular regulated kinase (ERK) pathway occurs in stress responses and is involved in CREB activation. In the present experiments, hemorrhage or endotoxemia produced increased activation of mitogen-activated protein kinase kinase (MEK)1/2 and ERK2 (p42), but not of ERK1 (p44), in lung neutrophils. ERK1, ERK2, and MEK1/2 were not activated in peripheral blood neutrophils after hemorrhage or endotoxemia. Inhibition of xanthine oxidase led to further increase in the activation of MEK1/2 and ERK2 in lung neutrophils after hemorrhage, but not after endotoxemia. Alpha-adrenergic blockade before hemorrhage resulted in increased activation in lung neutrophils of MEK1/2, ERK1, ERK2, and CREB, but decreased activation of NF-kappa B. In contrast, alpha-adrenergic blockade before endotoxemia was associated with decreased activation of MEK1/2, ERK2, and CREB, but increased activation of NF-kappa B. Beta-adrenergic blockade before hemorrhage did not alter MEK1/2 or ERK1 activation in lung neutrophils, but decreased activation of ERK2 and CREB, while increasing activation of NF-kappa B. Beta-adrenergic inhibition before endotoxemia did not affect activation of MEK1/2, ERK1, ERK2, CREB, or NF-kappa B. These data indicate that the pathways leading to lung neutrophil activation after hemorrhage are different from those induced by endotoxemia.

Adrenergic alpha-Antagonists↗
PubMed1999

[Determination of TNF-alpha and endotoxemia in patients with chronic liver diseases].

The incidence of endotoxemia in 153 patients with different liver diseases was determined by Limulus Lysaite Test(LLT). Comparative studies were carried out on the levels of tumour necrosis factor-alpha(TNF-alpha) between positive and negative endotoxemia in patients suffering from chronic liver diseases. At the same time, 58 patients of positive endotoxemia were divided into two groups--bifidobiogen group (38 cases) and control group(20 cases). The patients in bifidobiogen group were treated mainly with daily administration of bifidobiogen for 1 month besides general liver--protection therapy and the bifidobiogen was not given to the control group. The results showed that: 1. Incidence of endotoxemia in 153 patients suffering from various types of liver diseases was 65.36%; the highest rate was found in the patients with severe hepatitis; 2. The TNF-alpha level was obviously increased in the patients of positive endotoxemia; 3. The total efficacy in bifidobiogen group was significantly higher than that in control group. The data suggest that chronic liver diseases are generally complicated with endotoxemia, and TNF-alpha plays an important role in the pathogenesis of endotoxemia. The serum endotoxin level may be reduced after the treatment with bifidobiogen.

Adult↗
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↗