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)

Sepsis increases phosphocreatine (PCr) breakdown and reduces PCr stores in skeletal muscle. To determine if systemic infection impairs mitochondrial function, in vivo 13P magnetic resonance spectroscopy (31P MRS) studies of the gastrocnemius muscle were performed in virus-free male Wistar rats 24 or 48 hr after cecal ligation and 18-gauge needle single puncture (24 degrees CLP, n = 16; 48 degrees CLP, n = 15) or sham operation (24 degrees SHAM, n = 18; 48 degrees SHAM, n = 13). Physiologic saline (6 ml/100 g body wt) was injected intraperitoneally for fluid resuscitation. Water but no food was allowed in all animals. High resolution (8.45 Tesla) 31P MRS spectra, obtained at rest and during exercise using a 1.4-cm surface coil, were used to calculate PCr/ATP, PCr/P(i) ratios, and intracellular pH. Steady-state muscle exercise was induced by supramaximal sciatic nerve stimulation at 10 Hz for 10 min. Recovery of PCr/(PCr + P(i)) ratios after exercise was fitted to a monoexponential curve. The resultant function was used to calculate the half time for PCr recovery, the initial PCr resynthesis rate, and the maximal oxidative ATP synthesis rate, which reflect the rephosphorylation of ADP and are therefore measures of mitochondrial oxidative capacity. PCr/ATP ratios decreased by 12 and 11%, 24 and 48 hr after CLP, respectively. The PCr/P(i) ratios decreased incrementally (7% in 24 degrees CLP vs 23% in 48 degrees CLP animals). Twenty-four hours after operation the half time for PCr recovery was shortened while the initial PCr resynthesis rate and maximal oxidative ATP synthesis rate were accelerated in CLP animals compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The duration of infection modifies mitochondrial oxidative capacity in rat skeletal muscle. 763 Jan 22

Protein breakdown plays a major role in muscle growth and atrophy. However, the regulation of muscle proteolysis by nutritional, hormonal and mechanical factors remains poorly understood. In this review, the methods available to study skeletal muscle protein breakdown, and our current understanding of the role of 3 major proteolytic systems that are well characterized in this tissue (ie the lysosomal, Ca(2+)-dependent and ATP-ubiquitin-dependent proteolytic pathways) are critically analyzed. ATP-ubiquitin-dependent proteolysis is discussed in particular since recent data strongly suggest that this pathway may be responsible for the loss of myofibrillar proteins in many muscle-wasting conditions in rodents. In striking contrast to either the lysosomal or the Ca(2+)-dependent processes, ATP-ubiquitin-dependent protein breakdown is systematically influenced by nutritional manipulation (fasting and dietary protein deficiency), muscle activity and disuse (denervation atrophy and simulated weightlessness), as well as pathological conditions (sepsis, cancer, trauma and acidosis). The hormonal control of this pathway, its possible substrates, rate-limiting step, and functional associations with other proteolytic systems are discussed.
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PMID:Regulation of ATP-ubiquitin-dependent proteolysis in muscle wasting. 784 Aug 73

We tested the role of different intracellular proteolytic pathways in sepsis-induced muscle proteolysis. Sepsis was induced in rats by cecal ligation and puncture; controls were sham operated. Total and myofibrillar proteolysis was determined in incubated extensor digitorum longus muscles as release of tyrosine and 3-methylhistidine, respectively. Lysosomal proteolysis was assessed by using the lysosomotropic agents NH4Cl, chloroquine, leupeptin, and methylamine. Ca(2+)-dependent proteolysis was determined in the absence or presence of Ca2+ or by blocking the Ca(2+)-dependent proteases calpain I and II. Energy-dependent proteolysis was determined in muscles depleted of ATP by 2-deoxyglucose and 2.4-dinitrophenol. Muscle ubiquitin mRNA and the concentrations of free and conjugated ubiquitin were determined by Northern and Western blots, respectively, to assess the role of the ATP-ubiquitin-dependent proteolytic pathway. Total and myofibrillar protein breakdown was increased during sepsis by 50 and 440%, respectively. Lysosomal and Ca(2+)-dependent proteolysis was similar in control and septic rats. In contrast, energy-dependent total and myofibrillar protein breakdown was increased by 172% and more than fourfold, respectively, in septic muscle. Ubiquitin mRNA was increased severalfold in septic muscle. The results suggest that the increase in muscle proteolysis during sepsis is due to an increase in nonlysosomal energy-dependent protein breakdown, which may involve the ubiquitin system.
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PMID:Sepsis stimulates nonlysosomal, energy-dependent proteolysis and increases ubiquitin mRNA levels in rat skeletal muscle. 798 81

Although it is known that decreased high-energy phosphates contribute to organ dysfunction following shock, it remains unknown whether changes in lymphocyte energetics contribute to the profound immune dysfunction that occurs in late septic shock. Moreover, while studies have shown that ATP-MgCl2 treatment after hemorrhagic shock improves tissue ATP levels and organ function, it remains unknown whether lymphocyte high-energy phosphates and immune functions are similarly affected by this agent after sepsis. To study this, sepsis was induced in C3H/HeN (endotoxin sensitive) mice by cecal ligation and puncture (CLP) and they were then treated intraperitoneally with ATP-MgCl2 or saline vehicle. Sham animals received laparotomy, but not CLP. Splenic lymphocytes were harvested 24 hr after treatment and ATP levels were determined by ultraresolution 31P NMR. Lymphocyte proliferative capacity was determined by [3H]-thymidine incorporation following mitogenic stimulation. Host survival was assessed following CLP with and without ATP-MgCl2 treatment. Prolonged sepsis caused a significant decrease (decreases 67 +/- 12% vs Sham) in lymphocyte ATP levels which were correlated with decreased lymphocyte proliferative capacity in response to mitogenic stimulation (64 +/- 17 x 10(3) vs. 232 +/- 43 x 10(3) counts per minute (cpm) in Sham; P < 0.05). Treatment with ATP-MgCl2 at the onset of sepsis significantly increased lymphocyte ATP levels (increases 32 +/- 15% vs CLP) and proliferative response to mitogenic stimuli (218 +/- 37 x 10(3) cpm, CLP/ATP-MgCl2; P < 0.05). Improved lymphocyte function in this group correlated with a significant increase in overall survival (20% CLP vs 70% CLP/ATP-MgCl2; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Energetics of lymphocyte "burnout" in late sepsis: adjuvant treatment with ATP-MgCl2 improves energetics and decreases lethality. 801 8

The mechanism responsible for sepsis-induced myocardial depression is not known. To determine if sepsis-induced myocardial depression is caused by inadequate free energy available for work, we studied myocardial energy metabolism in a canine model of sepsis. Escherichia coli-infected (n = 18) or sterile (n = 16) fibrin clots were implanted intraperitoneally into beagles. Myocardial function and structure was assessed using radionuclide ventriculograms, echocardiograms, and light and electron microscopy. The adequacy of energy metabolism was evaluated by comparing catecholamine-induced work increases [myocardial O2 consumption (MVO2) and rate pressure product (RPP)] with a simultaneously obtained estimate of intracellular free energy [phosphocreatine-to-adenosine triphosphate ratio (PCr:ATP)] determined by 31P-magnetic resonance spectroscopy. When compared with control animals, septic animals had a decrease in left ventricular ejection fraction (EF, P < 0.0001) on day 1 and fractional shortening (FS, P < 0.0003) on day 2 after clot implantation. On day 2, neither septic nor control animals had statistically significant decreases in PCr:ATP, despite catecholamine-induced increases in MVO2 and RPP (mean maximal increases in septic animals 135 +/- 31 and 51 +/- 10%, respectively). Light and electron microscopic findings showed that hearts of septic animals, compared with control animals, had a greater degree of morphological abnormalities. Thus, in a canine model of sepsis with alterations in myocyte ultrastructure and documented myocardial depression (decreased EF and FS), intracellular free energy levels (PCr:ATP) were maintained despite catecholamine-induced increases in myocardial work (increased MVO2 and RPP), suggesting high-energy synthetic capabilities are not limiting cardiac function.
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PMID:Myocardial energy metabolism and morphology in a canine model of sepsis. 814 77

Hemorrhagic shock causes severe depression of macrophage functions and is associated with increased susceptibility to sepsis. Because hemorrhagic shock and resuscitation encompasses several pathophysiological conditions, such as hypotension, low-flow conditions, hypoxia, and reperfusion injury, it remains unknown whether severe hypotension in the absence of blood loss has any adverse effects on macrophage functions. To study this, systemic arterial hypotension was induced in C3H/HeN mice for 15 min by intravenous infusion of sodium nitroprusside or ATP-MgCl2. Peritoneal macrophages (PM) was harvested 20 h later with lavage. Antigen presentation was measured by coculturing PM with the D10.G4.1 Th cell clone. Tumor necrosis factor (TNF), interleukin (IL)-6, IL-1, and prostaglandin (PG) E2 levels in supernatants of PM stimulated with lipopolysaccharide were measured with bioassays or radioimmunoassay. Systemic arterial hypotension resulted in a significant decrease of PM capacity to present antigen. Although the release of TNF, IL-6, and IL-1 by PM was unaltered after hypotension, PGE2 release by PM was significantly elevated compared with the control group. These data indicate that chemically induced systemic arterial hypotension without blood loss leads to a depression of antigen presentation, which may be caused by elevated release of the immunosuppressive eicosanoid PGE2.
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PMID:Chemically induced hypotension increases PGE2 release and depresses macrophage antigen presentation. 847 8

Studies have shown that Kupffer cell and splenic macrophage, as well as peritoneal macrophage antigen presentation function, was significantly depressed following hemorrhage and remained so for at least 96 hours after resuscitation. Although macrophage antigen presentation was depressed, in all the cell populations studied, it was only the Kupffer cells which were upregulated to produce increased inflammatory cytokines. Furthermore, Kupffer cells from hemorrhaged animals exhibited enhanced, as opposed to reduced toxicity by peritoneal and splenic macrophages. This correlated well with increased cell-associated TNF on Kupffer cells. as well as increased capacity of Kupffer cells to release inflammatory cytokines after hemorrhage. It, therefore, could be postulated that while the enhanced Kupffer cell cytotoxicity may be beneficial in the destruction of pathogens seen in the liver due to bacterial translocation, this same activity may also contribute directly or indirectly to hepatocellular dysfunction and injury which is seen following hemorrhagic shock. Nonetheless, the depression in various immune functions after hemorrhage and resuscitation was comparable in both endotoxin-tolerant and -intolerant mice. Thus, it is debatable whether the alterations in immune function seen after hemorrhage are primarily due to the release of endotoxin into the blood stream during and/or following the hemorrhagic insult. Although translocation and/or endotoxemia occurs following severe hemorrhage, endotoxin may not be the sole or primary agent responsible for the induction of immunodepression after hemorrhage. The depressed Kupffer cell functions and increased inflammatory cytokine release by these cells can be significantly improved by post-treatment of animals with chloroquine, ibuprofen, diltiazem or ATP-MgCl2. Thus, these agents offer new therapeutic modalities in restoring the depressed Kupffer cell immune functions and in the treatment of generalized immunosuppression, as well as for decreasing the susceptibility to sepsis which is observed following severe blood loss.
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PMID:The role of bacterial translocation on Kupffer cell immune function following hemorrhage. 852 26

Septic rats showed an enhanced expression in skeletal muscle of both 1.2 (500%) and 2.4 (530%) kb mRNAs for the peptide ubiquitin, which reflects the activity of the ATP-ubiquitin-dependent proteolytic system. An acute intravenous administration of 100 micrograms/kg body weight of human recombinant tumour necrosis factor-alpha (TNF) also resulted in an important increase in the levels of ubiquitin mRNAs in rat skeletal muscle, while administration of a similar amount of human recombinant interleukin-1-beta did not. The results presented here, together with previous observations demonstrating that TNF increases the conjugation of proteins with ubiquitin in rat skeletal muscle (1), suggest that the ubiquitin system for non-lysosomal protein degradation could have a very important role in the mechanism triggered by TNF which is responsible for enhanced muscle proteolysis in sepsis and other pathological states.
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PMID:Ubiquitin gene expression in skeletal muscle is increased during sepsis: involvement of TNF-alpha but not IL-1. 855 6

Catabolites of purine nucleotides were measured in the cerebrospinal fluid (CSF) of newborn infants with sepsis, seizures and hydrocephalus using isocratic reversed-phase HPLC. The inosine levels in the CSF of the infants with any of the illnesses were significantly higher when compared with the controls. There was a tendency for hypoxanthine levels to be higher in the group of children with hydrocephalus. No significant differences in the concentrations of xanthine, adenine and uric acid were found. The inosine concentration in the CSF is proposed to be a more sensitive indicator of brain injury than the levels of other CSF purines. The levels of all purine metabolites measured in the CSF showed large individual variations. The ratio between hypoxanthine (as an indicator of ATP breakdown) and uric acid (as a scavenger of oxygen free radicals) concentration is proposed as a new criterion to be used in the evaluation of brain injury.
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PMID:Concentration of purine compounds in the cerebrospinal fluid of infants suffering from sepsis, convulsions and hydrocephalus. 856 8

There is accumulating evidence that inflammatory cytokines are involved in the pathophysiology of cardiac dysfunction found in sepsis, myocardial infarction and acute rejection after heart transplantation. Although there are some previous reports on cytokines and myocardial depression, myocardial energy metabolism caused by cytokines have not been established yet. The purpose of the present study is to determine if the IL-2 effect on contractile function is related to impaired energy production. In isolated perfused rabbit hearts (n = 6), we measured developed pressure, ATP and phosphocreatine by 31P-NMR spectroscopy during and after a 5 minute infusion of IL-2 (200 U/ml/min). Although there was slightly increased inorganic phosphate which might be affect on myocardial contractility reduced, high energy phosphate and intracellular pH did not change by IL-2 infusion, suggesting another mechanism for myocardial depression caused by inflammatory cytokine, IL-2.
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PMID:[Cardiac disfunction and myocardial energy metabolism caused by interleukin-2 (IL-2)]. 872 57


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