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)

Membrane Ca2+ flux and net protein catabolism were studied in the skeletal muscle during experimental sepsis. Sterilized rat fecal pellets with (septic) or without (sterile) gram-negative bacteria, Escherichia coli [10(2) colony-forming units (cfu)] and Bacteroides fragilis (2 x 10(3) cfu), were implanted into the abdomens of male Sprague-Dawley rats (110-120 g). Septic and sterile rats were febrile and hyperlactacidemic on day 1 postimplantation. These responses subsided by day 2 in sterile but not septic rats. Initial Ca2+ flux, estimated from measurements of 45Ca uptake by soleus muscles in vitro, was elevated on day 1 in both sterile and septic rats and on day 2 and 3 in septic rats only. The septic rat soleus muscle showed a significantly increased net protein catabolic response (measured as tyrosine release by soleus muscle, in vitro) over that found in muscles of sterile rats on day 1-3 postimplantation. The increase in Ca2+ flux in septic (day 1-3 postimplantation) and sterile (day 1 only) rats was abolished when the rats were treated with the calcium channel blocker diltiazem. In unoperated control rat soleus muscles the Ca2+ ionophore, ionomycin, concomitantly caused an increase in Ca2+ flux and net protein catabolism. Overall, the present study suggested that altered cellular Ca2+ regulation plays a role in the net protein catabolic response in the skeletal muscle during sepsis.
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PMID:Skeletal muscle Ca2+ flux and catabolic response during sepsis. 821 38

This study of the plasma aminogram was done on 35 patients with a moderate to high level of stress and/or sepsis. For the criteria of illness, the SAPS (Simplified Acute Physiological Score) was used on their admission to the intensive Care Unit, and the diagnosis of sepsis was established according to the criteria of Jacobs and Boone. The stress level was calculated according to Bistrian. The plasma aminogram was determined with High Resolution Liquid Chromatography. The plasma samples were taken while nutrient units containing what is considered a standard solution of amino acids were infused. The eight essential amino acids (EAA) and 10 non-essential were quantified. The ratio of ramified to aromatic amino acids (RAA/AAA) was calculated by Fisher's criteria. An increase in AAA (phenylalanine, p < 0.001, and tyrosine, NS) and sulphur containing amino acids (methionine, p < 0.001) was found. The RAA were within normal ranges (valine) or increased (leucine, p < 0.001 and isoleucine, p < 0.001). The RAA/AAA ratio was reduced, p < 0.0001. Glycine was increased, p < 0.0001 and alanine reduced, p < 0.05. Glutamine and glutamic acid were reduced, p < 0.0001 and p < 0.01 as was arginine, p < 0.001. No difference was found in the total concentration of AA. The results confirm the standard plasma aminogram described in situations of metabolic stress and/or sepsis.
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PMID:[Plasma aminogram in critical patients]. 846 96

Recent studies suggest that sepsis-induced increase in muscle proteolysis mainly reflects energy-ubiquitin-dependent protein breakdown. We tested the hypothesis that glucocorticoids activate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis. Rats underwent induction of sepsis by cecal ligation and puncture or were sham-operated and muscle protein breakdown rates were measured 16 h later. The glucocorticoid receptor antagonist RU 38486 or vehicle was administered to groups of septic and sham-operated rats. In other experiments, dexamethasone (2.5 or 10 mg/kg) was injected subcutaneously in normal rats. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Energy-dependent proteolysis was determined in incubated muscles depleted of energy with 2-deoxyglucose and 2,4-dinitrophenol. Levels of muscle ubiquitin mRNA and free and conjugated ubiquitin were determined by Northern and Western blot, respectively. RU 38486 inhibited the sepsis-induced increase in total and myofibrillar energy-dependent protein breakdown rates and blunted the increase in ubiquitin mRNA levels and free ubiquitin. Some, but not all, sepsis-induced changes in ubiquitin protein conjugates were inhibited by RU 38486. Injection of dexamethasone in normal rats increased energy-dependent proteolysis and ubiquitin mRNA levels. The results suggest that glucocorticoids regulate the energy-ubiquitin-dependent proteolytic pathway in skeletal muscle during sepsis.
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PMID:Energy-ubiquitin-dependent muscle proteolysis during sepsis in rats is regulated by glucocorticoids. 856 53

Neutrophils play a key role in the pathophysiology of septic multiple organ dysfunction syndrome (MODS) through excessive release of toxic granule components and reactive oxygen metabolites with consequent tissue destruction. The increase of senescent neutrophils during sepsis indicates a potential breakdown of autoregulatory mechanisms including apoptotic processes to remove activated neutrophils from inflammatory sites. Therefore, neutrophil apoptosis of patients with severe sepsis and its regulatory mechanisms were investigated. Spontaneous neutrophil apoptosis from patients with severe sepsis was significantly reduced in comparison to healthy individuals. Cytokines detected in the circulation during sepsis (tumor necrosis factor-alpha [TNF-alpha], interferon-gamma [IFN-gamma], granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]) inhibited neutrophil apoptosis in both groups, though the effect was more distinct in neutrophils from healthy humans. Addition of lipopolysaccharide (LPS) to neutrophils from healthy humans markedly (P < .05) reduced apoptosis which was partially restored through addition of anti-TNF-antibody. Interleukin-10 (IL-10) counteracted (P < .05) inhibition of neutrophil apoptosis induced by LPS, recombinant human (rh) TNF-alpha, rhIFN-gamma, rhG-CSF, and rhGM-CSF, whereas rhIL-4 or rhIL-13 were ineffective. Reduced neutrophil apoptosis during sepsis was concomitant with increased tyrosine phosphorylation, while IL-10 markedly inhibited tyrosine phosphorylation in LPS-stimulated neutrophils. These results identify proinflammatory cytokines and IL-10 as strong regulators of spontaneous neutrophil apoptosis during sepsis. Inhibition as well as acceleration of neutrophil apoptosis seems to be associated with alterations of signal transduction pathways.
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PMID:Interleukin-10 counterregulates proinflammatory cytokine-induced inhibition of neutrophil apoptosis during severe sepsis. 934 17

Cell wall compounds of gram-positive bacteria are capable of inducing the biosynthesis of proinflammatory cytokines in CNS cells in a similar way as lipopolysaccharide (LPS) of gram-negative bacteria does. Astrocytes, which lack the CD14 LPS receptor, have also been shown to respond to LPS-stimulation by increased cytokine synthesis. However, almost nothing is known about signaling steps involved in this process. We have therefore examined signaling events in primary cultures of rat astrocytes and the human astrocytoma cell line U373MG, brought about by LPS and pneumococcal cell walls (PCW). Of particular interest to us was the tyrosine phosphorylation patterns and activation states of three members of the mitogen activated protein kinase (MAPK) family, i.e., extracellular signal-regulated protein kinase (erk)-1, erk-2, and the recently identified p38. We show that LPS and PCW initiate tyrosine phosphorylation and activation of erk-1, erk-2, and p38 in a dose-dependent fashion. Inhibitors of tyrosine phosphorylation were able to alleviate this effect and also blocked cytokine production of astrocytes. Both, LPS- and PCW-induced responses of astrocytic cells required the presence of soluble CD14 (sCD14) present in serum. Unraveling the signaling steps induced by bacterial compounds in cells of the CNS may potentially help to elucidate the pathomechanisms of meningitis and central nervous complications of sepsis and may offer options for novel treatment strategies.
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PMID:Lipopolysaccharide and pneumococcal cell wall components activate the mitogen activated protein kinases (MAPK) erk-1, erk-2, and p38 in astrocytes. 948 15

Sepsis is associated with reduced protein synthesis and increased protein degradation in skeletal muscle. We examined the effects of insulin-like growth factor I (IGF-I) on protein synthesis and breakdown in muscles from nonseptic and septic rats. Sepsis was induced by cecal ligation and puncture; control rats were sham operated. Extensor digitorum longus muscles were incubated in the absence or presence of IGF-I at concentrations ranging from 100 ng/ml to 10 micrograms/ml. Total and myofibrillar protein breakdown rates were measured as net release of tyrosine and 3-methylhistidine, respectively. Protein synthesis was determined by measuring incorporation of [U-14C]phenylalanine into protein. IGF-I stimulated protein synthesis in a dose-dependent fashion in muscles from both sham-operated and septic rats, with a maximal effect seen at a hormone concentration between 500 and 1,000 ng/ml. IGF-I inhibited total and myofibrillar protein breakdown in muscles from sham-operated rats, whereas in muscles from septic rats, IGF-I had no effect on protein breakdown, even at high concentrations. The results suggest that protein breakdown in skeletal muscle becomes resistant to IGF-I during sepsis and that this resistance reflects a postreceptor defect.
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PMID:IGF-I stimulates protein synthesis but does not inhibit protein breakdown in muscle from septic rats. 948 20

Bacterial lipopolysaccharide induces tyrosine phosphorylation of paxillin, actin reorganization, and opening of the transendothelial paracellular pathway through which macromoles flux. In this study, lipid A was shown to be the bioactive portion of the lipopolysaccharide molecule responsible for changes in endothelial barrier function. We then studied whether endotoxin-neutralizing protein, a recombinant peptide that is derived from Limulus antilipopolysaccharide factor and targets lipid A, could block the effects of lipopolysaccharide on protein tyrosine phosphorylation, actin organization, and movement of 14C-bovine serum albumin across bovine pulmonary artery endothelial cell monolayers. In the presence of serum, a 6-h exposure to lipopolysaccharide (10 ng/ml) increased transendothelial 14C-albumin flux compared to the simultaneous media control. Coadministration of endotoxin-neutralizing protein (> or =10 ng/ml) with lipopolysaccharide (10 ng/ml) protected against lipopolysaccharide-induced barrier dysfunction. This protection was dose dependent, conferring total protection at endotoxin-neutralizing protein/lipopolysaccharide ratios of > or =10:1. Similarly, endotoxin-neutralizing protein was capable of blocking the lipopolysaccharide-induced endothelial cell responses that are prerequisite to barrier dysfunction, including tyrosine phosphorylation of paxillin and actin depolymerization. Finally, endotoxin-neutralizing protein cross-protected against lipopolysaccharide derived from diverse gram-negative bacteria. Thus, endotoxin-neutralizing protein offers a novel therapeutic intervention for the vascular endothelial dysfunction of gram-negative sepsis and its attendant endotoxemia.
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PMID:Endotoxin-neutralizing protein protects against endotoxin-induced endothelial barrier dysfunction. 952 59

Physiological stressors such as sepsis and tissue damage initiate an acute immune response and cause transient systemic insulin resistance. This study was conducted to determine whether tumor necrosis factor-alpha (TNF-alpha), a cytokine produced by immune cells during skeletal muscle damage, decreases insulin responsiveness at the cellular level. To examine the molecular mechanisms associated with TNF-alpha and insulin action, we measured insulin receptor substrate (IRS)-1- and IRS-2-mediated phosphatidylinositol 3-kinase (PI 3-kinase) activation, IRS-1-PI 3-kinase binding, IRS-1 tyrosine phosphorylation, and the phosphorylation of two mitogen-activated protein kinases (MAPK, known as p42(MAPK) and p44(MAPK)) in cultured C2C12 myotubes. Furthermore, we determined the effects of TNF-alpha on insulin-stimulated 2-deoxyglucose (2-DG) uptake. We observed that TNF-alpha impaired insulin stimulation of IRS-1- and IRS-2-mediated PI 3-kinase activation by 54 and 55% (P < 0.05), respectively. In addition, TNF-alpha decreased insulin-stimulated IRS-1 tyrosine phosphorylation by 40% (P < 0.05). Furthermore, TNF-alpha repressed insulin-induced p42(MAPK) and p44(MAPK) tyrosine phosphorylation by 81% (P < 0.01). TNF-alpha impairment of insulin signaling activation was accompanied by a decrease (P < 0.05) in 2-DG uptake in the muscle cells (60 +/- 4 vs. 44 +/- 6 pmol. min-1. mg-1). These data suggest that increases in TNF-alpha may cause insulin resistance in skeletal muscle by inhibiting IRS-1- and IRS-2-mediated PI 3-kinase activation as well as p42(MAPK) and p44(MAPK) tyrosine phosphorylation, leading to impaired insulin-stimulated glucose uptake.
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PMID:TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. 1032 78

Sepsis often provokes various neurological disorders. Because many neurologic symptoms are caused by changes in neurotransmissions, we investigated the relationship between behavioral alterations and changes in activities of the monoaminergic systems in rats. Sepsis was induced by cecal ligation and puncture. A step-through passive avoidance test was used for the behavioral evaluation. Passive avoidance retention in animals subjected to learning immediately before the septic or sham operation was examined after 24 or 48 h. Retention performance in animals subjected to learning 24 h after the operation was also examined after a further 24 h. Plasma concentrations of amino acids were determined 24 h after the operation. The activities of the brain monoaminergic systems were evaluated by ratios of metabolites to monoamines. Marked damage was found in the septic rats in the blood analysis 24 h after the operation. The plasma concentrations of tyrosine and arginine in the septic rats were decreased to 69% and 70% of those in the sham-operated animals, respectively. Retention performance was impaired in the septic rats when they were subjected to learning 24 h after the operation, but it was not impaired when animals were subjected to learning before the septic operation. The brain concentration of serotonin was increased in the cerebral cortex, striatum, and hippocampus 48 h after the septic operation, but not after 24 h. The concentration of 5-hydroxyindoleacetic acid, a metabolite of serotonin, was increased in the above three regions both 24 and 48 h after the operation, but not in the hypothalamus. Facilitation of the serotonergic activity in the telencephalon and hippocampus is suggested to be involved in the impairment of learning ability in sepsis.
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PMID:Sepsis facilitates brain serotonin activity and impairs learning ability in rats. 1035 May 63

Kupffer cells, a majority of the body's fixed macrophages, are a major site of bacterial lipopolysaccharide (LPS) metabolism and are mediators in the body's response to sepsis. Uptake of LPS is different in Kupffer cells than other macrophages. Signal transduction in other macrophages in response to LPS involves phosphorylation of proteins in the 50-60 kDa range. We hypothesized that Kupffer cells may have unique signal transduction pathways in response to LPS. Rat Kupffer cells were exposed to LPS (1 microgram/mL) for varying times ranging from 15 to 90 min. Cell lysates were Western blotted using an anti-phosphotyrosine antibody. The blots showed an increase in the amount of tyrosine phosphorylation on two proteins of 119 kDa and 83 kDa. The effects of varying LPS concentration (1 ng/mL-1 microgram/mL) showed an increasing amount of phosphorylation with increasing LPS concentration. To associate the importance of tyrosine phosphorylation in the response of Kupffer cells to LPS, the tyrosine kinase inhibitors, tyrphostin, lavendustin, and genisten were used to study the effects of inhibiting phosphorylation on TNF-alpha production. Kupffer cells were preincubated in the presence of the inhibitor and exposed to LPS (1 microgram/mL). TNF-alpha was measured in the conditioned media by ELISA. A 70% or greater decrease in TNF-alpha production was observed. When phagocytosis of latex beads by rat Kupffer cells was measured in vivo using intravital video microscopy, LPS treatment significantly increased uptake. This increase in phagocytosis was inhibited by tyrphostin. These results show what may be unique phosphorylation events in Kupffer cells that are related to LPS induced production of TNF-alpha.
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PMID:Tyrosine kinase activation in LPS stimulated rat Kupffer cells. 1035 46


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