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)

The metabolic impact of infusing a large amount of leucine (Leu) or valine (Val) was examined with regard to the corrective effect of total parenteral nutrition (TPN). Rats recovering from severe sepsis received either Leu- or Val-enriched TPN solution for 30 hours. The in vivo behavior of the amino acids administered was explored by a pulse injection of 14C-labeled Leu or Val. The recovery of 14CO2 from Leu increased by 64% in the septic rats of Leu-TPN group (41% of dose; p less than .01), as compared with control rats receiving the same TPN solution, whereas no significant rise in the 14CO2 recovery from Val occurred in the septic rats given Val-TPN (45% of dose) in comparison with the corresponding controls. The enhancement of Leu catabolism to CO2 in the Leu-TPN group was compatible with the alterations of urinary nitrogen excretion, plasma Leu level, and metabolite contents of liver and muscle. The only difference in metabolite levels observed between the two TPN groups was in hepatic total adenine nucleotides. Plasma amino acid levels were largely unaffected by infusion of these TPN solutions highly enriched with branched-chain amino acids (45%), except for an approximately threefold elevation of the Val level in Val-TPN rats. Thus, when administered in a large quantity during such short-term TPN, Leu can exert its metabolic effect without causing an imbalance in plasma amino acids under severe catabolic conditions.
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PMID:Metabolic effect of short-term total parenteral nutrition highly enriched with leucine or valine in rats recovering from severe trauma. 150 53

A steroid binding capacity assay and a radioimmunoassay were both used to measure corticosteroid binding globulin (CBG) in serum samples from 22 patients with sepsis. An approximately 50% discordancy between the two values in one patient suggested the presence of a CBG variant with reduced affinity for cortisol, and this was confirmed by Scatchard analysis. We therefore used the polymerase chain reaction to amplify exons that encode for human CBG from the genomic DNA of this patient. This revealed two mutations within the coding sequences: one of which results in a Leu----His substitution at residue 93 and another which encodes a Ser----Ala substitution at residue 224 of the human CBG polypeptide. To assess the impact of each substitution on the steroid binding affinity of CBG, each mutation was introduced separately into a normal human CBG cDNA, and the normal and mutated cDNAs were expressed in Chinese hamster ovary cells. Scatchard analysis of the CBG produced in culture indicated that the His93 mutation (Kd = 2.24 +/- 1.75 nM) reduced the cortisol binding affinity of CBG (mean +/- SD) significantly (P less than 0.024) when compared to normal CBG (Kd = 0.64 +/- 0.31 nM), while the Ala224 mutation (Kd = 0.63 +/- 0.33 nM) did not influence cortisol binding affinity. We therefore conclude that residue 93 may play an important role in determining the structure of the CBG steroid binding site.
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PMID:A Leu----His substitution at residue 93 in human corticosteroid binding globulin results in reduced affinity for cortisol. 150 7

The effect of the combination of total parenteral nutrition (TPN) and systemic sepsis on mucosal morphology and protein synthesis was investigated. Rats were given a standard TPN mixture consisting of glucose (216 kcal.kg-1.day-1), lipid (24 kcal.kg-1.day-1), and amino acids (1.5 g N.kg-1.day-1) for 5 days. On the 5th day the rats (n = 37) were randomized into four groups according to diet as follows: 1) control nonseptic on standard TPN, 2) control nonseptic on TPN with glutamine, 3) septic on standard TPN, and 4) septic with the TPN supplemented with glutamine. Twenty hours after the injection of Escherichia coli, the rats were given a 4-h constant infusion of [U-14C]leucine to determine the mucosal fractional protein synthesis rates. The following results were obtained. 1) Histological examination showed that systemic sepsis caused tissue damage to the ileum and jejunum. 2) Glutamine supplementation attenuated these changes. 3) There were no visible changes to the colon either from glutamine supplementation or sepsis. 4) Sepsis was associated with an increase in mucosal protein synthesis and decreased muscle synthesis. 5) Addition of glutamine to the TPN mix further increased protein synthesis in the intestinal mucosa of septic rats.
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PMID:Effect of total parenteral nutrition, systemic sepsis, and glutamine on gut mucosa in rats. 151 20

The influence of sepsis on intestinal protein synthesis was studied in rats. Sepsis was induced by caecal ligation and puncture (CLP); control rats were sham-operated. Protein synthesis was measured in vivo in the jejunum and ileum following a flooding dose of [14C]leucine. At 8 h after CLP the protein synthesis rate was increased by approx. 15% in jejunal mucosa, and at 16 h after CLP, the protein synthesis rate was increased by 50-60% in the mucosa and seromuscular layer of both jejunum and ileum. In a second series of experiments, rats were treated with recombinant tumour necrosis factor alpha (rTNF alpha) or recombinant interleukin-1 alpha (rIL-1 alpha) administered at a total dose of 300 micrograms/kg body weight over 16 h. Control rats received corresponding volumes of solvent. Treatment with rTNF alpha resulted in an approx. 25% increase in mucosal protein synthesis in jejunum. Following treatment with rIL-1 alpha, protein synthesis increased by 25% in jejunal mucosa and almost doubled in ileal mucosa. The results suggest that sepsis stimulates intestinal protein synthesis and that this response may, at least in part, be mediated by TNF and/or IL-1.
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PMID:Increased intestinal protein synthesis during sepsis and following the administration of tumour necrosis factor alpha or interleukin-1 alpha. 153 May 89

Leukocyte activation is a property of systemic infection. Animal experiments indicate interleukin-1 (IL-1) as a possible modulator, while contradictory results have been reported from in-vitro stimulation of isolated leukocytes. The purpose of the present study was to investigate the activation of isolated polymorphonuclear (PMN) leukocytes in vitro by preparations of recombinant human IL-1 beta and IL-1 receptor antagonist, which in earlier studies could elicit and abrogate, respectively, a sepsis-like syndrome in rabbits. They have also been shown to influence acute phase protein synthesis in mice and rats, and release of leukocyte cathepsin G in vivo. It was found that recombinant human IL-1 beta elicited a dose-dependent luminol-enhanced chemiluminescence response in isolated human PMN leukocytes in the dose range 8.8 x 10(-11)-8.8 x 10(-8) M. The effect could be blocked by prior treatment with the IL-1 receptor antagonist, indicating a direct effect on the specific IL-1 receptor. Preincubation by IL-1 beta enhanced the effect of a secondary challenge with phorbol 12-myristate 13-acetate or formyl-Met-Leu-Phe by 30-40%. The priming effect of rhIL-1 beta could also be blocked by the specific receptor antagonist. In this study, incubation of PMN leukocytes with rhIL-1 beta failed to induce degranulation of both azurophil (neutrophil proteinase 4/proteinase 3) and specific (lactoferrin) granules. rhIL-1 beta has been shown to induce degranulation in vivo, which is thus indicated as an indirect effect. We conclude that IL-1 beta is a direct and specific, but probably weak stimulator of the PMN leukocyte.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Stimulation of human polymorphonuclear leukocytes by recombinant human interleukin-1 beta. 162 64

Primed neutrophils may contribute to endothelial and end-organ damage after burn injury because of increased endothelial adherence and enhanced toxic oxygen metabolite generation in response to a "second insult" such as bacterial sepsis. The purposes of this study were to determine: (1) whether serum from patients with thermal injury causes priming of the neutrophil NADPH:O2 oxidoreductase, (2) whether time after burn (early vs late) influences neutrophil priming, and (3) whether priming could be attenuated by a specific platelet-activating factor antagonist, WEB2170. Normal human neutrophils were incubated with 10% sera that was obtained from healthy adult controls (normal human sera) and with 10% sera from patients with greater than 30% total body surface area burns, which was collected early (early postburn sera) (i.e., between 12 and 48 hours after burn) or late (late postburn sera) (5 to 15 days, after burn). Priming of the neutrophil oxidase was tested for by measurement of the generation of superoxide anion after a stimulus of 10(-6) mol/L formyl-methionine-leucine-phenylalanine (fMLP). In separate experiments, neutrophils were pretreated with WEB2170 before serum incubation and fMLP stimulation to block any priming that may be mediated by platelet-activating factor. All sera caused an increased rate of superoxide anion production in response to fMLP and thus "primed" the neutrophil NADPH:O2 oxidoreductase. Greater priming occurred after incubation with late postburn sera than with other sera. WEB2170 completely inhibited priming by normal human sera and early postburn sera and partially inhibited priming by late postburn sera.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:WEB2170, a specific platelet-activating factor antagonist, attenuates neutrophil priming by human serum after clinical burn injury: the 1991 Moyer Award. 166 Dec 87

The acute-phase response that follows injury and sepsis is characterized by increased hepatic synthesis of specific secreted proteins while production of albumin is decreased. The effect of burn injury on specific synthesis rates of secreted hepatic proteins has not been reported. In this study, Sprague-Dawley rats received either a 30% flame burn (n = 12) or a sham burn (n = 12) and were allowed to recover for 11 days. Burned animals showed slower weight gains and a 25% to 30% higher resting energy expenditures compared with controls. On postburn day 11, synthesis of secreted hepatic proteins was measured by incorporation of leucine during a 2-hour isolated liver perfusion. Synthesis of total secreted proteins, the seromucoid fraction, and complement component C3 was significantly increased in burned animals, whereas synthesis of albumin was unaltered. In spite of unchanged albumin synthesis, plasma albumin concentrations were 50% lower in burned animals than in control animals throughout the postburn period. These findings suggest that decreased albumin synthesis is not the only mechanism responsible for persistent hypoalbuminemia that follows burn injury.
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PMID:Synthesis of albumin and acute-phase proteins in perfused liver after burn injury in rats. 170 76

The effect of ischemia on hepatic protein synthesis during sepsis is not known, but is of clinical relevance, since hepatic blood flow decreases during the late phase of sepsis. In this study, synthesis of acute-phase proteins was measured in perfused livers of rats 16 hours after sham operation or cecal ligation and puncture. Livers from each group had 45 minutes of complete ischemia or control perfusion. Protein synthesis was measured during two hour perfusion after the ischemia or control period, by determining incorporation of 3H-leucine into total secreted trichloracetic acid precipitated proteins, immunoprecipitated complement component C3 and albumin and phosphotungstenate-precipitated alpha 1-acid glycoprotein. Lactate, glutamine-oxalacetic transaminase (GOT) and glutamic-pyruvic transaminase (GPT) levels in the perfusate were measured during preischemic and postischemic perfusion. Tissue glutathione levels were measured at the end of the perfusion. Synthesis of alpha 1-acid glycoprotein was increased by 100 per cent and albumin synthesis decreased by 46 per cent in septic livers, consistent with an acute-phase response and apparent downregulation of albumin synthesis during early sepsis. Synthesis rates were reduced by 50 to 60 per cent after ischemia in perfused livers from sham operated rats and 70 to 80 per cent in livers from septic rats. Hepatic production of interleukin-1 was not different between the groups during perfusion. GOT and GPT levels increased significantly during ischemia of both nonseptic and septic livers and rapidly returned toward baseline during reperfusion. Lactate levels were higher in perfusate of septic than of nonseptic livers before ischemia and increased further during ischemia. The results suggest that ischemia inhibits production of secreted hepatic proteins similarly in nonseptic and septic livers, but perhaps to a slightly greater extent in septic livers.
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PMID:Effect of ischemia on protein synthesis in the septic liver. 170 61

Mechanisms of nutrient alteration of hepatic protein synthesis during sepsis are unclear. In vitro, arginine downregulates endotoxin-stimulated hepatocyte protein synthesis but in vivo effects are unknown. This study evaluated the effects of supplemental arginine or glycine on fibrinogen (acute-phase protein), histone, albumin, and liver protein synthesis after Gram-negative sepsis in the rat. Adult rats (225 g, n = 36) were randomized to receive isonitrogenous isocaloric total parenteral nutrition supplemented with 264 mg of N per kilogram per day as either arginine or glycine. On day 5, each group was further randomized to control or sepsis. Sepsis was induced by injection of 8 x 10(7) Escherichia coli per 100 g body weight, and then a continuous infusion of [1-14C]leucine was started. The rats were sacrificed 4 hours later. The fractional protein synthesis rates (percent per day) of histone, fibrinogen, albumin, and liver were determined. Supplemental arginine led to significantly increased histone (p less than 0.05, analysis of variance) and fibrinogen (p less than 0.01, analysis of variance) synthesis in the septic rats compared with all other groups. Histone and albumin synthesis were also significantly increased (p less than 0.05) in the arginine-supplemented control group compared with the glycine-supplemented control group. Arginine supplementation during sepsis significantly increased (p less than 0.05) albumin and liver protein synthesis compared with controls. Histones which are involved in DNA synthesis and are rich in arginine may play a role in the host response to stress and sepsis. These in vivo results appear to contradict hepatocyte-Kupffer cell coculture studies perhaps because of the hormonal and cytokine responses to nutrient substrate and acute septicemia.
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PMID:Harry M. Vars Research Award. Arginine supplementation improves histone and acute-phase protein synthesis during gram-negative sepsis in the rat. 171 54

The ideal energy substrate for critically ill patients receiving total parenteral nutrition (TPN) remains controversial. While glucose has been proved to have nitrogen sparing properties in postoperative patients, critically ill patients tolerate glucose loads poorly and fat appears to be an obligatory fuel in sepsis. Furthermore, it is not yet certain whether the changes in whole body protein metabolism induced by critical illness are influenced by the nature of the TPN provided. This study was conducted on patients admitted to a surgical intensive care unit (SICU) who fulfilled the criteria of requiring TPN and mechanical ventilation for at least four days. Patients were randomized to receive either glucose (G) or equicaloric proportions of glucose and lipid (GF) as an intravenous energy source. TPN was commenced early, within 24-48 hr of trauma or surgery and admission to the ICU. Nonprotein calorie intake was 125% of calculated basal energy expenditure. Nitrogen balance was calculated from 24-hr urinary urea excretion. Protein synthesis, turnover, and catabolism were measured on Day 4 of the study using an established radiolabeled C14-leucine technique. Degree of sepsis and illness were calculated using published scores. Fifty patients entered the trial but 32 were excluded by Day 4. Of the 18 patients completing an initial four day study, eight went on to complete a second study on the alternative regimen--a total of 26 studies (14 G, 12 GF). Net protein synthesis was achieved in 18 studies (12 G, 6 FG) and positive nitrogen balance by Day 4 in 22 studies. Four patients on the G regimen were withdrawn due to glucose intolerance while none of the patients on GF developed glucose intolerance or hyperlipidaemia. Both whole body protein synthesis and catabolism correlated significantly with degree of sepsis. The type of TPN fuel used, G and GF, did not appear to influence whole body protein dynamics, both regimens achieving greatly improved whole body protein kinetics.
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PMID:The effect of fuel source on amino acid metabolism in critically ill patients. 174 Sep 40


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