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 (0.01 seconds)

Muscle protein degradation and intracellular protease activities were investigated in disseminated intravascular coagulation (DIC), which is frequently associated with severe catabolic states such as sepsis and multiple organ failure. DIC was introduced in rats by repeated intravenous thrombin injections. Saline was injected in control rats. In the 28 rats (14 with DIC and 14 controls), the bilateral soleus (SOL) muscles were incubated in an oxygenated medium without cycloheximide (CH) to determine the release of tyrosine (Tyr) into the incubated medium. From 24 rats (12 with DIC and 12 controls), the SOL and extensor digitorum longus (EDL) muscles were harvested to measure the activities of proteasome and of cathepsins L and B. The contralateral muscles were incubated in a medium with 0.5 mM CH to determine the release of Tyr and 3-methylhistidine (3-MH). The release of Tyr without CH (net proteolysis) from SOL muscles with DIC was greater than in controls (218 +/- 83.3 vs. 145 +/- 47.7 pmol/mg/h. However, the release of Tyr and 3-MH with CH (total proteolysis) and the activities of proteasome and cathepsins in DIC were nearly the same as those in controls. In both DIC and control rats, the total release of Tyr and proteasome activity were greater in SOL than in EDL muscles. These results suggest that reutilization of Tyr, reflecting protein synthesis, is suppressed in DIC and that the red slow muscle is more active in nonfibrillar proteolysis than the white fast muscle.
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PMID:Modulation of muscle protein metabolism in disseminated intravascular coagulation. 764 9

The effects of administering total parenteral nutrition (TPN) supplemented with the dipeptide of L-alanyl-L-glutamine (Ala-Gln) on gut structure, barrier function, and protein metabolism were investigated in septic rats. Sepsis was induced by the continuous intraperitoneal administration of endotoxin via a miniosmotic pump. Twenty-three rats were divided into two groups and fed parenterally for 5 days. The Ala-Gln group (n = 11) received a conventional TPN solution supplemented with 2% Ala-Gln, whereas the control group (n = 12) received conventional TPN solution alone. One rat in each group died of endotoxemia. The groups showed similar nitrogen balance, urinary excretion of 3-methylhistidine, and plasma concentration of endotoxin in the portal vein. The groups showed similar incidence of bacterial translocation from the gut to the mesenteric lymph nodes. The intestinal mucosal weight and villous height were significantly greater in the Ala-Gln group than in the control group. Pathological derangement of the mucosal structure was more marked in the control group than in the Ala-Gln group. These results suggest that TPN supplemented with Ala-Gln preserves the gut structure without decreasing the nitrogen balance under septic conditions.
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PMID:Total parenteral nutrition supplemented with L-alanyl-L-glutamine and gut structure and protein metabolism in septic rats. 791 76

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

1. The role of interleukin-1 (IL-1) in sepsis-induced muscle proteolysis was assessed by treating septic rats with recombinant IL-1 receptor antagonist (rIL-1ra). 2. In initial experiments, we tested the effectiveness of IL-1ra in preventing muscle proteolysis induced by administration of IL-1. 3. When normal rats were treated with rIL-1 alpha (three intraperitoneal doses of 100 micrograms/kg body weight each over 16 hr), total and myofibrillar muscle protein breakdown rates, measured as release of tyrosine and 3-methylhistidine, respectively, by incubated extensor digitorum longus muscles, were significantly increased. 4. This metabolic response to IL-1 alpha was completely abolished by rIL-1ra, administered as three intraperitoneal doses of 3 mg/kg body weight each over 16 hr. 5. In subsequent experiments, sepsis was induced in rats by cecal ligation and puncture (CLP); non-septic rats were sham-operated. 6. Treatment of septic rats over 16 hr with a total dose of 25 mg/kg body weight of rIL-1ra reduced, but did not normalize, the increased muscle protein breakdown rates seen during sepsis. 7. When the dose of rIL-1ra was more than doubled and given as a constant infusion at a rate of 4.2 mg/kg body weight/hr for 16 hr, the increased rate of muscle proteolysis in septic rats was normalized. 8. The present study offers the first direct evidence that IL-1 is involved in the regulation of muscle proteolysis during sepsis.
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PMID:Reduced muscle protein breakdown in septic rats following treatment with interleukin-1 receptor antagonist. 806 18

Plasma levels of interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF alpha), interleukin 6 (IL-6), and markers of protein metabolism were determined in 12 burn patients throughout the healing period (day 2 to 21 post-injury) to determine the pattern of variations in plasma cytokine concentration. To establish the relationship between cytokine production and the nutritional status a wide range of severity standpoints (burn surface area ranging from 9% to 82%) was chosen. Interleukin 6 levels were increased in all patients throughout the study period; maximum concentrations (615 +/- 198 pg/mL) were reached on day 4 and correlated (p < 0.01) with the extent of burn injury. Tumor necrosis factor alpha levels were also elevated; they were significantly higher on day 7 in the patients who developed sepsis than in the other patients (67 +/- 21 pg/mL vs. 20 +/- 7 pg/mL; p < 0.05) but did not correlate with the extent of burn injury. Interleukin 1 beta was rarely detected. Cortisolemia on day 7 was inversely correlated with levels of TNF alpha but not with those of IL-6. Interleukin 6 levels correlated positively with protein turnover (phenylalaninemia) and catabolism (3-methylhistidine/creatinine ratio) and negatively with levels of fibronectin and transthyretin. Our data indicate that the systemic cytokine response to burn injury is mainly represented by IL-6. These data also support the hypothesis that IL-6 is a key mediator of the variations in protein metabolism following burn injury.
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PMID:Cytokine response to burn injury: relationship with protein metabolism. 818 61

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

Previous studies provided evidence that sepsis-induced muscle proteolysis in experimental animals is caused by increased ubiquitin-proteasome-dependent protein breakdown. It is not known if a similar mechanism accounts for muscle proteolysis in patients with sepsis. We determined mRNA levels for ubiquitin and the 20 S proteasome subunit HC3 by Northern blot analysis in muscle tissue from septic (n = 7) and non-septic (n = 11) patients. Plasma and muscle amino acid concentrations and concentrations in urine of 3-methylhistidine (3-MH), creatinine, and cortisol were measured at the time of surgery to assess the catabolic state of the patients. A three- to fourfold increase in mRNA levels for ubiquitin and HC3 was noted in muscle tissue from the septic patients concomitant with increased muscle levels of phenylalanine and 3-MH and reduced levels of glutamine. Total plasma amino acids were decreased by approximately 30% in the septic patients. The 3-MH/creatinine ratio in urine was almost doubled in septic patients. The cortisol levels in urine were higher in septic than in control patients but this difference did not reach statistical significance. The results suggest that sepsis is associated with increased mRNAs of the ubiquitin-proteasome pathway in human skeletal muscle.
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PMID:Sepsis is associated with increased mRNAs of the ubiquitin-proteasome proteolytic pathway in human skeletal muscle. 900 83

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

The efficacy of ornithine alpha-ketoglutarate (OKG) in preventing bacterial translocation and dissemination, metabolic disorders and changes in mucosal enzyme activities was assessed in a model of bacterial translocation in rats. Antibiotic decontamination was performed 4 d before intragastric inoculation with an Escherichia coli strain (10(10) bacteria/kg body). Two days later, the rats were given either a lipopolysaccharide (LPS) 0127:B8 or a saline injection and were deprived of food for 24 h. Enteral nutrition, [Osmolite, 880 kJ/(kg. d)] supplemented with either OKG (LPS + OKG) or glycine (Saline + Gly or LPS + Gly), was then given for 2 d. Urinary total nitrogen losses and 3-methylhistidine excretion were determined daily. On killing at d 3, bacterial translocation to the mesenteric lymph nodes (MLN) and dissemination to the spleen and liver were evaluated, jejunal mucosa enzyme activities were assayed and tissue free amino acids in muscles were measured. Endotoxin induced translocation from the gut lumen to the MLN in all groups, whereas dissemination occurred only in LPS-treated rats. OKG significantly reduced dissemination of the bacteria in the spleen. 3-Methylhistidine excretion was greater in the LPS + Gly group (+25%, P: < 0.05) than in either the LPS + OKG or Saline + Gly group. The group fed the OKG-enriched diet had higher muscular glutamine, ornithine and arginine concentrations than did the Gly-supplemented groups (P: < 0.05). Intestinal sucrase and aminopeptidase activities were higher in the LPS + OKG group than in the LPS + Gly group (-30%, P: < 0.05). OKG supplementation limits bacterial dissemination and metabolic changes after injury in rats and thus may be useful in the prevention of gut-derived sepsis in critically ill patients.
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PMID:Bacterial dissemination and metabolic changes in rats induced by endotoxemia following intestinal E. coli overgrowth are reduced by ornithine alpha-ketoglutarate administration. 1111 Aug 43

The effects of dantrolene on serum TNFalpha and corticosterone levels and on muscle calcium, calpain gene expression, and protein breakdown were studied in rats with abdominal sepsis induced by cecal ligation and puncture. Treatment of rats with 10 mg/kg of dantrolene 2 h before and 8 h after induction of sepsis reduced serum TNFalpha and corticosterone, muscle calcium levels, mRNA levels for m- and mu-calpain, and the muscle specific calpain p94, as well as total and myofibrillar protein breakdown rates, determined as release of tyrosine and 3-methylhistidine, respectively, from incubated extensor digitorum longus muscles. The results support the concept that increased calcium concentrations may be an important mechanism of sepsis-induced muscle protein breakdown. The data also indicate that other mechanisms, in addition to reduced muscle calcium concentrations such as decreased levels of TNFalpha and glucocorticoids, may contribute to the anti-catabolic effects of dantrolene during sepsis. The observations are important from a clinical standpoint because they suggest that the catabolic response in skeletal muscle during sepsis may be prevented by treatment with a calcium antagonist.
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PMID:Dantrolene reduces serum TNFalpha and corticosterone levels and muscle calcium, calpain gene expression, and protein breakdown in septic rats. 1123 3


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