Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen synthase kinase 3beta (GSK-3beta) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. Dysregulation of GSK-3beta has been implicated in the pathogenesis of several diseases including sepsis. Here we investigate the effects of 2 chemically distinct inhibitors of GSK-3beta, TDZD-8 and SB216763, on the circulatory failure and the organ injury and dysfunction associated with hemorrhagic shock. Male Wistar rats were subjected to hemorrhage (sufficient to lower mean arterial blood pressure to 35 mmHg for 90 min) and subsequently resuscitated with shed blood for 4 h. Hemorrhage and resuscitation resulted in an increase in serum levels of (a) creatinine and, hence, renal dysfunction, and (b) alanine aminotransferase and aspartate aminotransferase and, hence, hepatic injury. Treatment of rats with either TDZD-8 (1 mg/kg, i.v.) or SB216763 (0.6 mg/kg, i.v.) 5 min before resuscitation abolished the renal dysfunction and liver injury caused by hemorrhagic shock. In addition, TDZD-8, but not SB216763, attenuated the increase caused by hemorrhage and resuscitation in plasma levels of the proinflammatory cytokine interleukin 6 and also of the anti-inflammatory cytokine interleukin 10. Neither of the GSK-3beta inhibitors however affected the delayed fall in blood pressure caused by hemorrhagic shock. Thus, we propose that inhibition of GSK-3beta may represent a novel therapeutic approach in the therapy of hemorrhagic shock.
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PMID:Glycogen synthase kinase-3beta inhibitors protect against the organ injury and dysfunction caused by hemorrhage and resuscitation. 1668 13

The role of A3 adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-alpha 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5'N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
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PMID:A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis. 1677 64

Parenteral nutrition-associated cholestasis (PNAC) is a complication not uncommon in the pediatric population. In severe cases, patients require a liver transplant. To our knowledge, we report the only case of PNAC with end-stage liver failure in a child with short bowel syndrome that resolved with a change in caretaker. Until his care was transferred from his abusive parents, he was frequently admitted for infection and sepsis. His liver function vastly improved from aspartate aminotransferase (AST) 3139 units/L, conjugated bilirubin 25.9 mg/dL to AST 47 units/L, direct bilirubin 0.3 mg/dL under the care of his attentive foster mother, and a liver transplant was no longer necessary. Bacterial infection and sepsis are risk factors correlated with patients with PNAC requiring liver transplant. Prevention of infection by a good caregiver may be a means to reduce the incidence of PNAC.
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PMID:Parenteral nutrition-associated cholestasis related to parental care. 1677 46

There are many complex pathophysiologic changes of the coagulation system in sepsis. The fibrinolytic system was evaluated in septic children using the global fibrinolytic capacity (GFC), a new technique reflecting the overall fibrinolytic activity. The study consisted of 24 children with sepsis, 36 children with sepsis plus disseminated intravascular coagulation (DIC), and 20 healthy age-matched control individuals. Compared with controls, 86% of sepsis patients and 87% of sepsis plus DIC patients had decreased GFC levels. Between the sepsis plus DIC and sepsis groups there was no significant difference in terms of GFC levels. While 19 patients (52.7%) died in the sepsis plus DIC group, only three patients (12.5%) died in the sepsis group. When survivors and nonsurvivors were compared in terms of coagulation tests, there were significant differences for protein C, antithrombin, platelet, fibrinogen, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and white blood cell values. In conclusion, the level of GFC reduced in most of the pediatric sepsis patients but no difference was observed between patients with sepsis and patients with sepsis plus DIC. While inhibition of fibrinolysis is an important finding in sepsis, the mortality is mainly associated with the presence of end-organ damage and the status of coagulation parameters.
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PMID:Global fibrinolytic capacity in pediatric patients with sepsis and disseminated intravascular coagulation. 1698 53

Fasciolosis is recognized as an important human disease. Wistar rats experimentally infected with Fasciola hepatica were examined using data obtained in the advanced chronic state of the disease (200, 300 and 400 days post-infection, dpi). Pigment stones (PS) and bile specimens were collected. The same procedure was applied in control rats. Liver tests were determined using stored serum samples. Bacteriological bile culture revealed viable bacteria (Escherichia coli, 45% of cases, Enterococcus faecalis, 45% and Klebsiella pneumoniae, 10%). The presence of bacterobilia was associated with liver serum enzymes, including aspartate aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT), alkaline phosphatase (AP) and total bilirubin levels. Multivariate analysis suggested an association between bacterobilia and the following factors: duration of parasitic infection and intensity of parasitic infection supported the impression that the obstruction caused by advanced chronic fasciolosis in the rat may be related to biliary sepsis. Extrapolation to human infection in fasciolosis hyperendemic areas is discussed. In conclusion, the results of the rodent model should lead to a reconsideration of treatment features in human disease, i.e. therapeutic strategies should not only include a parasitic treatment but also consider the possibility of bacterial co-infection.
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PMID:High risk of bacterobilia in advanced experimental chronic fasciolosis. 1706 56

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.
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PMID:Effects of thrombin inhibition with melagatran on renal hemodynamics and function and liver integrity during early endotoxemia. 1706 59

The liver can be injured and its functions altered by activation of the coagulation and inflammatory processes in sepsis. The objective of the present study was to investigate the pattern of protease- activated receptors (PARs) over time in a model of acute liver injury induced by lipopolysaccharide (LPS); and whether PARs play a role in this process and exert their effects through inflammation and coagulation. Levels of tumor necrosis factor-a (TNF-a) were significantly expressed 1 h after LPS administration followed by: i) an increase in levels of tissue factor, factor VIIa, thrombin and plasminogen activator inhibitor-1; ii) unchanged or steady levels of tissue factor pathway inhibitor; and iii) subsequent deposition of fibrin in the liver tissue, that led to the elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), which are associated with liver injury. The expression of all PAR isoforms (1-4) was elevated, and each isoform had a distinct cellular localization (hepatocytes, Kupffer cells, the portal triad area, and central veins) and a time-dependent pattern of expression. The immuno-reactivity of PAR2 and 4 in Kupffer cells was intense. Interestingly, PAR2 blocking peptide improved the healing of liver injuries, an effect that was associated with suppression of TNF-a elevation, and normalization of coagulation and fibrinolysis. This ultimately led to decreased fibrin formation in the injured liver. The present study reveals a distinct chronological expression and cellular localization of PARs in LPS-mediated liver injury and shows that blockade of PAR2 may play a crucial role in treating liver injury, via normalization of inflammation, coagulation and fibrinolytic pathways.
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PMID:Chronological expression of PAR isoforms in acute liver injury and its amelioration by PAR2 blockade in a rat model of sepsis. 1713 80

Cholestasis is a major complication in sepsis although the underlying mechanisms remain elusive. The aim of this study was to evaluate the role of P-selectin and leukocyte recruitment in endotoxemia-associated cholestasis. C57BL/6 mice were challenged intraperitoneally with endotoxin (0.4 mg/kg), and 6 h later the common bile duct was cannulated for determination of bile flow and biliary excretion of bromosulfophthalein. Mice were pretreated with an anti-P-selectin antibody or an isotype-matched control antibody. Leukocyte infiltration was determined by measuring hepatic levels of myeloperoxidase. Tumor necrosis factor-alpha and CXC chemokines in the liver was determined by ELISA. Liver damage was monitored by measuring serum levels of alanine aminotransferase and aspartate aminotransferase. Apoptosis was quantified morphologically by nuclear condensation and fragmentation using Hoechst 33342 staining. Endotoxin induced a significant inflammatory response with increased TNF-alpha and CXC chemokine concentrations, leukocyte infiltration, liver enzyme release, and apoptotic cell death. This response was associated with pronounced cholestasis indicated by a >70% decrease of bile flow and biliary excretion of bromosulfophthalein. Immunoneutralization of P-selectin significantly attenuated endotoxin-induced leukocyte infiltration reflected by a >60% reduction of hepatic myeloperoxidase levels. Interference with P-selectin decreased endotoxin-mediated hepatocellular apoptosis and necrosis, but did not affect hepatic levels of tumor necrosis factor-alpha and CXC chemokines. Of interest, inhibition of P-selectin restored bile flow and biliary excretion of bromosulfophthalein to normal levels in endotoxin-challenged animals. Our study demonstrates for the first time that P-selectin-mediated recruitment of leukocytes, but not the local production of proinflammatory mediators, is the primary cause of cholestasis in septic liver injury.
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PMID:Sepsis-associated cholestasis is critically dependent on P-selectin-dependent leukocyte recruitment in mice. 1725 63

Severe burn induces the activation of an inflammatory cascade that contributes to the development of subsequent immunosuppression, increased susceptibility to sepsis, as well as generation of reactive oxygen radicals and lipid peroxidation, leading to multiple organ failure. In the present study, we investigated whether rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand is protective against burn-induced remote organ injury. Under brief ether anaesthesia, shaved dorsum of the rats were exposed to 90 degrees C (burn group) or 25 degrees C (control group) water bath for 10s. Rosiglitazone (4 mg/kg) or saline was administered intraperitoneally immediately after and at the 12th hour of the burn. Rats were decapitated 24h after injury and the tissue samples from lung, liver, and kidney were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, and creatinine, blood urea concentrations (BUN) were determined to assess liver and kidney function, respectively. Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and lactate dehydrogenase (LDH) were also assayed. Severe skin scald injury (30% of total body surface area) caused a significant decrease in GSH level, and significant increases in MDA level, MPO activity and collagen content of tissues. Similarly, serum ALT, AST and BUN levels, as well as LDH, IL-1 beta and TNF-alpha were elevated in the burn group as compared to the control group. Rosiglitazone treatment reversed all these biochemical indices. According to the findings of the present study, rosiglitazone possesses a anti-inflammatory effect that prevents burn-induced damage in remote organs and protects against organ damage.
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PMID:Rosiglitazone, a PPAR-gamma ligand, protects against burn-induced oxidative injury of remote organs. 1746 12

Sepsis is the leading cause of death for intensive care patients. Lipopolysaccharide (LPS) administration to animals under anesthesia is a strategy for the study of uncontrolled release of proinflammatory cytokines. Anesthetics have been indicated that they can specially affect immune responses, such as the inflammatory response. Pentobarbital is an anesthetic used mainly in animal studies. Thus, the effect of pentobarbital on tumor necrosis factor-alpha (TNF-alpha) release was determined. The results revealed that pentobarbital suppressed the expression of TNF-alpha mRNA and its proteins, which may result from the decrease in the activities of nuclear factor-kappaB and activator protein 1 and the reduction of the expression of p38 mitogen-activated protein kinase by pentobarbital. After the inhibitory activity of the pentobarbital for TNF-alpha release was proven in vivo, the cytotoxic effects of LPS were examined in vivo with or without pentobarbital treatments. In vivo results indicated that plasma levels of alanine aminotransferase, aspartate aminotransferase, lactic dehydrogenase, creatine kinase, serum urea nitrogen, and amylase decreased dramatically in the anesthetic group with pentobarbital administration. Finally, the effect of pentobarbital on TNF-alpha-related cell death was monitored in vitro, and the results indicated the pentobarbital could directly enhance the viabilities of cells under the treatment of TNF-alpha and protected cells from apoptosis induced by deferoxamine mesylate-induced hypoxia. These results suggest that pentobarbital significantly influences the LPS-induced inflammatory response and protects cells from death directly and indirectly induced by TNF-alpha. The information provides a perspective to re-evaluate the results of the experiments in which animals were anesthetized with pentobarbital. The anti-inflammatory effects of the drugs may have been caused by the synergistic effect of pentobarbital.
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PMID:The reduction of tumor necrosis factor-alpha release and tissue damage by pentobarbital in the experimental endotoxemia model. 1754 46


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