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)

Experimental sepsis in rats induces a restriction in spontaneous food intake and a drop in liver glutathione, cytochrome P-450 (P-450) and aminopyrine demethylase (AD) activity. The present study was designed to assess the effects of antibiotics alone or when combined with food deprivation on these variables. Eighty-nine male Sprague-Dawley rats were assigned to six groups: control (C), acute infection (experimental pyelonephritis, I), acute infection with antibiotics and food given ad lib. (IA), control with antibiotics (CA), acute infection with antibiotics pair-fed to I (IAR), and sham-operated pair-fed to I (SR). Liver glutathione, P-450 and AD activities were reduced by 45.2, 79.8 and 41.2% respectively in group I. Glutathione and AD significantly increased only in those infected rats given antibiotics and allowed free access to food. P-450 did not normalize within the study period in infected rats receiving antibiotics and food repletion. The risk of drug hepatotoxicity in acute septic states is therefore closely related to the nutritional status. From this point of view, nutritional support is almost as important as treatment of infection.
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PMID:Influence of antibiotics and food intake on liver glutathione and cytochrome P-450 in septic rats. 785 19

Critical illness is associated with both immunosuppression and glutathione deficiency. We determined if in vivo depletion of glutathione would adversely affect immune status. Rats with normal glutathione levels and those with glutathione stores depleted by diethyl maleate underwent analysis of splenocyte function and mesenteric lymph node lymphocyte function. Lymphocytes of the spleen and mesenteric lymph nodes were tested for concanavalin A proliferative response and interleukin 2 production. Tumor necrosis factor and interleukin 6 secretion by splenic adherent cells was also measured. Glutathione-depleted animals had significantly decreased lymphocyte proliferation and decreased production of tumor necrosis factor and interleukin 6 but unaltered interleukin 2 production. These findings indicate that in vivo glutathione deficiency impairs macrophage and T-cell function. Because glutathione depletion may occur in sepsis, trauma, and shock, treatments that help maintain glutathione levels may enhance immunocompetence and thus improve the ability of patients to recover from critical illness.
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PMID:Glutathione depletion in rats impairs T-cell and macrophage immune function. 841 77

The protective effects of hydroxyethyl starch-conjugated deferoxamine (HES-DFO), a macromolecular iron chelator, on the initial pathophysiological cascade in septic shock were evaluated following cecal ligation puncture (CLP) in rats. Animals were given an intravenous dose of 3.0 mL of either vehicle (HES) or HES-DFO immediately following completion of the CLP procedure. Animals were sacrificed 30, 60, 120, and 240 min following CLP, and samples of lung, kidney, bowel, and liver were collected for subsequent analysis of glutathione, myeloperoxidase, and evidence for lipid peroxidation based on measurement of thiobarbituric acid reactive substances and conjugated dienes. In addition, the endotoxin levels were determined in the plasma and histomorphological examination was conducted on tissue samples collected at each time point. At almost all time points, a reduction in lipid peroxidation was noted in the HES-DFO-treated rats (p < .05). Glutathione and myoloperoxidase levels were less affected. Lung tissue from animals receiving HEs demonstrated marked microatelectases, septal destruction, and splicing of basal membranes, which were greatly attenuated in animals having received HES-DFO. Similarly, tubulotoxic and mitochondrial damages observed in kidney samples from HES-treated animals were noticeably reduced in the animals having received the chelator. Liver and gut samples demonstrated unspecific inflammatory injury in both groups of animals. In summary, oxygen radical-mediated tissue damage occurs rapidly following CLP-induced sepsis. Based on histological and biochemical endpoints, treatment with the polymeric iron chelator, HES-DFO, significantly attenuates systemic oxidant injury, the degree of protection being most impressive in the lung and kidney.
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PMID:Protective effects of hydroxyethyl starch-deferoxamine in early sepsis. 860

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

Reactive oxygen species, formed in various biochemical reactions, are normally scavenged by antioxidants. Glutathione in its reduced form (GSH) is the most powerful intracellular antioxidant, and the ratio of reduced to oxidised glutathione (GSH:GSSG) serves as a representative marker of the antioxidative capacity of the cell. Several clinical conditions are associated with reduced GSH levels which as a consequence can result in a lowered cellular redox potential. GSH and the redox potential of the cell are components of the cell signaling system influencing the translocation of the transcription factor NF kappa B which regulates the synthesis of cytokines and adhesion molecules. Therefore, one possibility to protect cells from damage caused by reactive oxygen species is to restore the intracellular glutathione levels. Cellular GSH concentration can be influenced by exogenous administration of GSH (as intravenous infusion or as aerosol), of glutathione esters or of GSH precursors such as glutamine or cysteine (in form of N-acetyl-L-cysteine, alpha-lipoic acid). The modulation of GSH metabolism might present a useful adjuvant therapy in many pathologies such as intoxication, diabetes, uremia, sepsis, inflammatory lung processes, coronary disease, cancer and immunodeficiency states.
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PMID:Therapeutic potential of glutathione. 1100 22

The diet of industrialised countries is usually rich in amino acids, which are in part used as a source of calories. However, metabolic alterations are observed in diseased patients and a preferential retention of Sulphurated Amino Acids (SAA) occurs during the inflammatory response. Moreover, it has been demonstrated in a model of an acute sepsis phase of rats that the metabolism of Cysteine is modified. The liver converts Cysteine at a different ratio of Sulphate to Taurine (Tau) i.e. the sulphate production decreases while the Tau conversion increases. The Glutathione (GSH) concentration is greater in the liver, kidneys and other organs and the Cysteine incorporation into proteins is higher in the spleen, lungs and plasma (Acute Phase Proteins) while the Albumin level decreases. The pro-inflammatory cytokines such as Interleukin-1, Interleukin-6 and TNF- alpha are the main initiators that alter protein and amino acid metabolism. Another important phenomenon is the impairment of Methionine conversion to Cysteine during stress. For example, premature infants or AIDS patients are capable of synthesizing Cysteine from Methionine at a much lower rate. Thus, the metabolic flow through the trans-sulphuration path may be inadequate to meet the Cysteine demand under critical conditions. In this complex picture, an SAA supply may contribute to an immune system regulation.
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PMID:The regulation of sulphurated amino acid junctions: fact or fiction in the field of inflammation? 1243 3

Glutathione is quantitatively the most important endogenous scavenger system. Glutathione depletion in skeletal muscle is pronounced following major trauma and sepsis in intensive care unit patients. Also, following elective surgery, glutathione depletion occurs in parallel with a progressive decline in muscle glutamine concentration. The present study was designed to test the hypothesis that glutamine supplementation may counteract glutathione depletion in a human trauma model. A homogeneous group of patients (n = 17) undergoing a standardized surgical procedure were prospectively randomly allocated to receive glutamine (0.56 g x day(-1) x kg(-1)) or placebo as part of isonitrogenous and isocaloric nutrition. Percutaneous muscle biopsies and blood samples were taken pre-operatively and at 24 and 72 h after surgery. The concentrations of muscle glutathione and related amino acids were determined in muscle tissue and plasma. In the control (unsupplemented) subjects, total muscle glutathione had decreased by 47+/-8% and 37+/-11% and reduced glutathione had decreased by 53+/-10% and 45+/-16% respectively at 24 and 72 h after surgery (P < 0.05). In contrast, in the glutamine-supplemented group, no significant post-operative decreases in total or reduced glutathione were seen following surgery. Muscle free glutamine had decreased at 72 h after surgery in both groups, by 41.4+/-14.8% (P < 0.05) in the glutamine-supplemented group and by 46.0+/-14.3% (P < 0.05) in the control group. In conclusion, the present study demonstrates that intravenous glutamine supplementation attenuates glutathione depletion in skeletal muscle in humans following standardized surgical trauma.
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PMID:Glutamine attenuates post-traumatic glutathione depletion in human muscle. 1260 86

Selenium is an essential micronutrient for humans. Critically ill patients with Systemic Inflammatory Response Syndrome (SIRS) and Multiple Organ Dysfunction (MOD) -such as severe sepsis, trauma, severe pancreatitis and critical burns- are exposed to severe oxidative stress. These patients exhibit decreased serum Selenium and selenoenzymes like Glutathione Peroxidase and Selenoprotein P. Selenoenzymes play a major role in protecting cells against lipid peroxidation and they are involved in the inflammatory response regulation. The degree of selenium deficiency correlates with disease severity and the incidence of mortality. In the past years, some clinical trials have studied Selenium supplementation effects in critical illness with SIRS-MOD. This therapeutic strategy could improve the outcome and prognosis in critically ill patients. Few small trials have demonstrated Selenium supplementation beneficial effects, reducing the rate of infectious complications and length of hospital stay. However, no clinical trials using Selenium supplementation in high doses have yet demonstrated significant improvement in mortality. The aims of this review are to evaluate: a) Selenium metabolism, b) the role of selenoenzymes during critical illness, c) clinical studies using Selenium alone or in combination with other antioxidants in critically ill patients and d) to analyze current parenteral Selenium replacement strategies and their results. Further multicentre, well designed randomized, double blind clinical trials about Selenium supplementation in critically ill patients with SIRS and MODS are required and appear to be attractive, necessary and challenging.
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PMID:[Selenium in critically ill patients with systemic inflammatory response]. 1761 71

Sepsis is characterized by severe redox imbalance. Glutathione plays a major role in cellular defenses against oxidative and nitrosative stress. There is limited information on the response of glutathione synthesis in human sepsis. This review proposes a critical analysis of available data on potential factors affecting glutathione synthesis in sepsis. Glutathione is synthesized from its constituent amino acids--glutamate, cysteine, and glycine. Cysteine availability and the activity of the enzyme glutamate cysteine ligase are rate-limiting for glutathione synthesis. Glutathione synthetic capacity is increased in liver and other tissues during the acute phase of experimental sepsis. Potential mechanisms for glutamate cysteine ligase activation in sepsis involve a decreased ratio of reduced/oxidized glutathione as well as the effects of reactive oxygen species, nitric oxide species, proinflammatory cytokines, heat shock proteins, and physical inactivity. Glutathione synthesis can be impaired by cysteine depletion, protein-energy malnutrition, hyperglycemia, glucocorticoid at pharmacologic doses, and decreased secretion of anterior pituitary hormones (growth hormones, thyrotropin, gonadotropins), as often observed in prolonged critical illness.
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PMID:Glutathione metabolism in sepsis. 1771 14

Glutathione S-transferase Pi (GSTP) was originally identified as one of cytosolic phase II detoxification enzymes and also was considered to function via its non-catalytic, ligand-binding activity. We have reported that GSTP played an anti-inflammatory role in macrophages, suggesting that GSTP may have a protective role in inflammation. In this study, we deleted the murine Gstp gene cluster and found that GSTP significantly decreased the mortality of experimental sepsis and reduced related serum level of high mobility group box-1 protein (HMGB1). As HMGB1 is the key cytokine involved in septic death, we further studied the effect of GSTP on HMGB1 release. The results demonstrated that a classic protein kinase C (cPKC) dependent phosphorylation of cytoplasmic GSTP at Ser184 occurred in macrophages in response to lipopolysaccharide (LPS) stimulation. Phosphorylated GSTP was then translocated to the nucleus. In the nucleus, GSTP bound to HMGB1 and suppressed LPS-triggered and cPKC-mediated HMGB1 phosphorylation. Consequently, GSTP prevented the translocation of HMGB1 to cytoplasm and release. Our findings provide the new evidence that GSTP inhibited HMGB1 release via binding to HMGB1 in the nucleus independent of its transferase activity. cPKC-mediated GSTP phosphorylation was essential for GSTP to translocate from cytoplasm to nucleus. To our knowledge, we are the first to report that nuclear GSTP functions as a negative regulator to control HMGB1 release from macrophages and decreases the mortality of sepsis.
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PMID:Glutathione S-Transferase Pi Prevents Sepsis-Related High Mobility Group Box-1 Protein Translocation and Release. 2952 Feb 71


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