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)

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

Intrahepatic cholestasis in the setting of extrahepatic bacterial infection has been attributed to the effects of endotoxin and cytokines such as tumor necrosis factor-alpha (TNF-alpha) on bile acid transport. To define the mechanism of sepsis-associated cholestasis, taurocholate transport was examined in basolateral (bLPM) and canalicular (cLPM) rat liver plasma membrane vesicles derived from control and endotoxin [lipopolysaccharide (LPS)]-treated animals and in plasma membrane vesicles prepared after TNF-alpha treatment. Na(+)-dependent [3H]taurocholate uptake and both membrane-potential-dependent and ATP-dependent [3H]taurocholate transport were reduced in bLPM and cLPM vesicles, respectively, after LPS treatment. In membrane vesicles from TNF-alpha-treated animals, Na(+)-dependent [3H]taurocholate uptake was also reduced. Northern blot hybridization, using cDNA probes for the putative sinusoidal bile acid transporter (Ntcp) and canalicular ecto-adenosinetriphosphatase, demonstrated decreased mRNA levels after LPS and TNF-alpha treatment. Immunoblot analysis of membrane extracts from LPS-treated animals revealed decreased levels of these putative bile acid transporters. Impaired bile acid transport at the sinusoidal and canalicular membrane domains by these and other mediators of the inflammatory response may account for sepsis-associated cholestasis.
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PMID:Effect of endotoxin on bile acid transport in rat liver: a potential model for sepsis-associated cholestasis. 876 Jan 17

The availability of adequate substrate for energy homeostasis is a minimal requirement for vital organ function that normally is provided through dietary intake. When dietary sources of nutrients are inadequate, the body relies on alternate sources of energy provided by gluconeogenesis, lipolysis, and ketogenesis. Sepsis is associated with disruption of virtually all these provisional sources of energy substrate (see Fig. 4). In addition, sepsis impairs the function of the glycolytic pathway, the integrity of which is necessary for glucose to be used effectively for energy production. These abnormalities, coupled with disruption of the intracellular energy-producing machinery (e.g., glycolytic and gluconeogenic enzymes, mitochondria) eventually lead to a reduction in intracellular ATP. Furthermore, a reduction in intracellular ATP can undermine virtually all the energy-consuming functions of the cell, including energy substrate formation (e.g., failed gluconeogenesis), antioxidant production, and calcium homeostasis. High levels of intracellular calcium, in turn, are known to activate many potentially destructive enzymatic pathways (e.g., proteases, phospholipases, endonucleases) that further diminish cell function and may result in cell death. In this context, iCa2+ accumulation may play an important role in the progression from early sepsis to MODS, the most common cause of mortality in the ICU.
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PMID:Metabolic consequences of sepsis. Correlation with altered intracellular calcium homeostasis. 879 64

Low dose ATP-MgCl2 is reported to cause selective pulmonary vasodilation during hypoxic and thromboxane mimetic-induced constriction. In addition, it has been shown to increase cardiac output and improve cellular function during circulatory shock. Based on these properties we hypothesized that ATP-MgCl2 might ameliorate the cardiopulmonary manifestations of sepsis secondary to group B streptococci (GBS). We studied 14 anesthetized, mechanically ventilated piglets who received a continuous infusion of GBS (7.5 x 10(7) colony-forming units/kg/min) and were randomly assigned to a treatment group that received a continuous infusion of ATP-MgCl2 at 0.6 mumol/kg/min or a control group that received normal saline as placebo. Comparison of the hemodynamic measurements, pulmonary mechanics, and arterial blood gases over the first 120 min of ATP-MgCl2 infusions with those of the control group revealed the following: GBS infusion caused significant increases in mean pulmonary artery pressure, pulmonary vascular resistance (PVR), mean systemic arterial blood pressure, systemic vascular pressure (SVR), and PVR/SVR ratio with decreases in cardiac output and stroke volume. ATP-MgCl2 caused significant reduction in mean pulmonary artery pressure (p < 0.001), PVR (p < 0.0001), mean systemic arterial blood pressure (p < 0.003), SVR (p < 0.01), and PVR/SVR ratio (p < 0.03) with improvement in cardiac output (p < 0.001) and stroke volume (p < 0.01). The partial pressure of arterial O2 (p < 0.04), and pH (p < 0.001) were higher and the partial pressure of arterial CO2 (p < 0.02) lower in ATP-MgCl2-treated animals. Also dynamic lung compliance was higher (p < 0.001) and pulmonary airway resistance lower (p < 0.001) in treated animals. Median survival in control animals was 153 min, whereas all treated animals survived to 240 min (p < 0.001). These data demonstrate that ATP-MgCl2 ameliorates the deleterious cardiopulmonary manifestations of GBS sepsis and results in improved survival in a young animal model.
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PMID:Effects of ATP-magnesium chloride on the cardiopulmonary manifestations of group B streptococcal sepsis in the piglet. 884 33


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