Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased production of interleukin-1 and tumor necrosis factor-alpha (TNF-alpha) have been implicated in the pathophysiology of a variety of diseases including circulatory shock. The present study evaluated the efficacy of FR167653 (1-[7-(4-fluorophenyl)-1,2,3,4-tetrahydro-8-pyridylpyrazolo[5,1-c] [1,2,4]triazin-2-yl]-2-phenylethanedione sulfate monohydrate), a dual inhibitor of interleukin-1 and TNF-alpha production, to protect rabbits from the shock and lethality induced by lipopolysaccharide. In this sepsis model, FR167653 at a dose of 0.32 mg/kg per h ameliorated the 7-day mortality from 93% in the placebo group to 47% in the FR167653-treated group and, at doses of 0.10-0.32 mg/kg per h, attenuated the hypotensive response to lipopolysaccharide challenge and returned mean arterial blood pressure to almost normal levels. The increases in plasma interleukin-1 and TNF-alpha levels evoked by lipopolysaccharide administration were also inhibited by treatment with FR167653, which was efficacious at doses of 0.1-0.32 mg/kg per h. In addition, FR167653 treatment attenuated the increases in plasma creatinine concentrations consistent with renal damage in a dose-dependent manner. These findings suggested that FR 167653 has a beneficial potential as a drug for septic shock or multiple organ dysfunction syndrome.
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PMID:FR167653, a dual inhibitor of interleukin-1 and tumor necrosis factor-alpha, ameliorates endotoxin-induced shock. 920 May 56

Changes in the activities of protein kinase A (PKA, or cAMP-dependent protein kinase) in rat heart during different cardiodynamic phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture. Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals killed at 9 and 18 h, respectively, after cecal ligation and puncture. Cardiac PKA was extracted and partially purified by acid precipitation, ammonium sulfate fractionation, and DEAE-cellulose chromatography. PKA was eluted from DEAE-cellulose column with a linear NaCl gradient. Two peaks of PKA, type I (eluted at low ionic strength) and type II (eluted at high ionic strength), were collected and their activities were determined based on the rate of incorporation of [gamma-32P]ATP into histone. Results obtained show that during early sepsis, both type I and type II PKA activities were unaffected. During late sepsis, type I PKA activities were stimulated by 66.7-97.7%, while type II PKA activities remained constant. Kinetic analysis of the data on type I PKA during late sepsis reveals that the Vmax values for ATP, cAMP, and histone were increased by 84.7, 66.7, and 97.7%, respectively; while the Km values for ATP, cAMP, and histone were unaltered. These data indicate that type I PKA is activated in rat heart during late hypodynamic phase of sepsis. Since kinase-mediated phosphorylation plays an important role in regulating myocardial function and metabolism, an activation of type I PKA during late sepsis may contribute to the development of altered myocardial function during hypodynamic phase of sepsis.
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PMID:Protein kinase a activity is increased in rat heart during late hypodynamic phase of sepsis. 924 15

Changes in the activities of protein kinase A (PKA) (cAMP-dependent protein kinase) in various regions of rat myocardium during different cardiodynamic phases of sepsis were studied in an attempt to understand the pathophysiology of cardiac dysfunction during sepsis. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 hr, respectively, after CLP. Cardiac PKA was extracted and partially purified by acid precipitation, ammonium sulfate fractionation, and DEAE-cellulose chromatography. PKA was eluted from DEAE-cellulose column with a linear NaCl gradient. Two types of PKA, Type I (eluted at low ionic strength) and Type II (eluted at high ionic strength), were collected, and their activities were determined based on the rate of incorporation of [gamma-32P]ATP into histone. Under physiological conditions, Type I PKA activities were unevenly distributed (left atrium > right atrium > pacemaker region > left ventricle > right ventricle > ventricular septum) while Type II PKA activities were evenly distributed among different regions of myocardium. During early sepsis, Type I PKA activities remained unchanged while Type II PKA activities were activated by 32 and 70% in right atrium and pacemaker regions, respectively. During late sepsis, Type I PKA activities were stimulated by 228% in ventricular septum while Type II PKA activities were not affected. These data demonstrate that different PKA activities exist in various regions of the myocardium and that PKA activities were preferentially activated in certain areas during the progression of sepsis. Since PKA plays an important role in the regulation of myocardial function and metabolism, the activation of PKA in different regions of myocardial during different stages of sepsis may contribute to the altered cardiac function during the progression of sepsis.
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PMID:Differential activation of protein kinase A in various regions of myocardium during sepsis. 929 85

In vivo cysteine metabolism during the inflammatory state has been studied minimally. We investigated cysteine metabolism (i.e. taurine, sulfate and glutathione formation) using a single dose of [35S] cysteine in septic rats that had been injected with live Escherichia coli into the tail vein and in control, pair-fed rats. Cysteine metabolites were separated by ion exchange chromatography, and radioactivity was counted in the different fractions. Radioactivity incorporated in tissue proteins was also measured after protein precipitation. [35S]Sulfate production was significantly lower in septic rats than in pair-fed rats. [35S]Taurine contents were significantly lower only in kidneys, spleen and gastrointestinal tract of septic rats. The higher production of [35S] taurine in the livers (the major site of taurine production) of septic rats could have a protective effect against oxidation. Glutathione concentrations were also significantly greater in liver, spleen, kidneys and gastrocnemius muscle of septic rats, presumably in order to combat oxidative stress induced by sepsis. [35S]Cysteine incorporation in glutathione was significantly higher in spleen and kidneys but not in liver of septic rats compared to pair-fed rats. This could be explained by the fact that, in liver, a greater amount of labeled glutathione had been utilized for host defense, or by a high level in glutathione turnover. Finally, [35S]cysteine incorporation into protein, in septic rats, was significantly greater than in pair-fed rats in spleen, lung and particulary in whole plasma proteins other than albumin, which mainly represent the acute-phase proteins. These data suggest an increased requirement for cysteine during sepsis in rats.
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PMID:Metabolism of cysteine is modified during the acute phase of sepsis in rats. 943 Jun 9

Heparin induced extracorporeal lipoprotein fibrinogen precipitation (HELP) is an established procedure for removal of low-density lipoprotein (LDL) cholesterol, lipoprotein (a), and fibrinogen in patients with severe hypercholesterolemia. In vitro studies revealed that HELP also removes endotoxin, tumor necrosis factor alpha (TNF-alpha) and C-reactive protein (CRP). With the intention to treat, we applied this procedure to 4 patients with severe gram-negative sepsis with highly elevated endotoxin blood levels. Nine treatments were performed, 6 using the standard HELP precipitating buffer and 3 without addition of heparin to the precipitating buffer. Heparin was omitted from the precipitating buffer to avoid fibrinogen depletion in patients at risk (low fibrinogen, postoperative). The average processed plasma volume was 3,386 ml in the standard and 2,963 ml in the modified treatment. Mean reductions (%) in plasma solute concentrations were (standard/ modified procedure) as follows: endotoxin, 50/57; TNF-alpha, 25/5; CRP, 49/55; fibrinogen, 49/6; total cholesterol, 38/5; and apolipoprotein B (Apo B), 41/2. Both treatment modalities were equally effective in removing endotoxin and CRP. With the modified precipitation buffer, fibrinogen was not removed. To further simplify the extracorporeal treatment, we have designed a closed-loop circuit with 2 adsorbers in series, one for removal of TNF-alpha (dextran sulfate modified cellulose) and the other for removal of endotoxin (DEAE-cellulose). In vitro evaluation confirmed very efficient endotoxin and TNF-alpha removal from plasma. This system is very simple, operates at physiological pH, and uses adsorbers already in clinical use for other purposes.
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PMID:HELP apheresis in the treatment of sepsis. 945 25

The objective of our study is to determine whether aggressive tocolysis in patients with preterm premature rupture of membranes between 24 and 34 weeks gestation improves neonatal outcome. Patients with documented preterm premature rupture of membranes between 24 and 34 weeks gestation were prospectively randomized to group I, aggressive tocolysis with intravenous magnesium sulfate, or to group II, no tocolysis. The lecithin/sphingomyelin ratio was determined upon hospital admission and every 48-96 hours until delivery. Both groups received weekly steroids and antibiotics pending culture results and were promptly delivered when chorioamnionitis, fetal stress, or an Lecithin/sphingomyelin ratio of > or = 2.0 occurred. The study group involved 145 patients. No statistically significant differences between groups I (n = 78) and II (n = 67) were observed regarding demographic characteristics, gestational age at enrollment or at delivery, latency, development of clinical chorioamnionitis, birth weight, number of days in neonatal intensive care unit, days on oxygen or ventilatory support, frequency of hyaline membrane disease, necrotizing enterocolitis, intraventricular hemorrhage, neonatal sepsis, or neonatal mortality. Our data suggest that tocolysis in patients with preterm premature rupture of membranes does not significantly improve perinatal outcome.
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PMID:Preterm premature rupture of membranes: aggressive tocolysis versus expectant management. 950 62

Antithrombin (AT) is a single-chain glycoprotein in plasma and belongs to the family of the serpins. It is synthesized in liver parenchymal cells, and its plasma concentration is between 112-140 mg/L. AT is a unique inhibitor of the clotting system and neutralizes most of the enzymes generated during activation of the clotting cascade, especially thrombin, factors Xa and IXa. Equimolar, irreversible complexes are formed between AT and the enzymes. The interaction between AT and the activated clotting factors is at least 1,000-fold increased in the presence of heparins. Heparins bind to multiple sites of the AT molecule resulting in a steric reconfiguration. Heparins contain a specific pentasaccharide unit which is the minimum requirement for AT binding. The glycosaminoglycan (GAG) heparan sulfate found on endothelial cell surfaces also contains this pentasaccharide and can thus "activate" AT. It is believed that much of the physiological inactivation of enzymes by AT occurs on the endothelium, mediated by heparan sulfate. The binding of AT to the GAGs also releases prostacyclin which possesses strong antiinflammatory properties. Deficiencies of AT are inherited or acquired. Only acquired defects due to increased consumption are discussed, most notably AT in DIC, especially DIC in sepsis. During acute DIC, clotting factors and inhibitors are consumed faster than they can be reproduced. This consumption of AT is of great significance in DIC and sepsis, and plasma AT levels predict outcome. AT levels drop early in sepsis and laboratory signs of DIC can already be found in patients with SIRS and early sepsis. The important role of AT in DIC and sepsis is the basis for considering antithrombin concentrates as an additional therapeutic modality.
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PMID:Antithrombin: its physiological importance and role in DIC. 951 76

Changes in protein kinase C (PKC) (calcium- and phospholipid-dependent protein kinase) activity in rat heart during different cardiodynamic phases of sepsis were studied in an attempt to understand the pathophysiology of altered myocardial function during sepsis. Sepsis was induced by cecal ligation and puncture. Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after cecal ligation and puncture. Cardiac PKC was extracted and partially purified by ammonium sulfate fractionation and diethylaminoethyl-cellulose chromatography. PKC activity was assayed on the basis of the rate of incorporation of 32P from [gamma-32P]adenosine triphosphate into histone. The results show that during early sepsis, cytosolic PKC activity was increased by 42-73%, whereas membrane associated PKC activity was unchanged. During late sepsis, both cytosolic and membrane associated PKC activities remained unchanged. Kinetic analysis of the data on cytosolic PKC during the early phase of sepsis reveals that the Vmax (maximal velocity) values for Ca2+, phosphatidylserine, and diacylglycerol were increased by 58, 42, and 50%, respectively, with no changes in their Km (substrate concentration required for half-maximal enzyme activity) values. These data indicate that cytosolic PKC activity was activated in rat heart during the early hyperdynamic phase of sepsis. Because PKC mediated phosphorylation plays an important role in regulating myocardial contractility, an activation in cytosolic PKC may contribute to the development of a hypercardiodynamic state during the early phase of sepsis.
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PMID:Protein kinase C activity is increased in rat heart during the early hyperdynamic phase of sepsis. 952 27

Changes in protein kinase C (PKC) (calcium- and phospholipid-dependent protein kinase) activity in rat liver during different metabolic phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into three groups: control, early sepsis, and late sepsis. Early and late sepsis refers to those animals sacrificed at 9 and 18 h, respectively, after CLP. Hepatic PKC was extracted and partially purified by ammonium sulfate fractionation and DEAE-cellulose chromatography. PKC activity was assayed based on the rate of incorporation of 32p from [gamma-32P]ATP into histone. The results show that during early sepsis, both membrane-associated and cytosolic PKC activities remained relatively unaltered. During late sepsis, membrane-associated PKC was unaffected while cytosolic PKC activity was decreased by 19.5-34.4%. Kinetic analysis of the data on cytosolic PKC during late phase of sepsis reveals that the Vmax values for ATP, histone, Ca2+, phosphatidylserine, and diacylglycerol were decreased by 23.4, 22.1, 19.5, 25, and 34.4%, respectively, with no changes in their Km values. These data indicate that cytosolic PKC activity was inactivated in rat liver during late hypoglycemic phase of sepsis. Since PKC-mediated phosphorylation plays an important role in regulating hepatic glucose metabolism, an inactivation of cytosolic PKC may contribute to the development of hypoglycemia during late phase of sepsis.
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PMID:Inactivation of protein kinase C in rat liver during late hypoglycemic phase of sepsis. 956 54

Heparin Cofactor II (HCII) is a glycoprotein in human plasma which inactivates thrombin rapidly in the presence of dermatan sulfate. Inhibition occurs by formation of a stable equimolar complex between HCII and thrombin. HCII association with thrombotic events has not always been observed, thus decreased HCII does not appear to be a strong risk factor for thromboembolic events. Reduced HCII levels have been detected in different clinical conditions, such as hepatic failure, disseminated intravascular coagulation, thalasemina, sickle cell anemia. Increased physiological levels have been found in pregnant women and oral contraception. In our laboratory, we measured HCII plasmatic levels in the normal Buenos Aires city population and in patients under different clinical conditions, such as sepsis, diabetis, burns, oral anticoagulation and in patients treated with heparin, hyperhomcysteinemia in whom septic and diabetic patients showed decreased values. HCII thrombin inhibition possibly takes place in extravascular sites where dermatan sulfate is present. HCII activity would be important in the regulation of wound healing, inflammation, or neuronal development.
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PMID:[Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic role]. 1034 31


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