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)

Muscle catabolism during sepsis is mainly caused by myofibrillar protein breakdown. The mechanism of this metabolic response is not known. We tested the hypothesis that increased protein breakdown in the extensor digitorum longus (EDL) muscle of septic rats is caused by increased activity of the so-called myofibrillar proteinase, which is a nonlysosomal proteolytic enzyme, and cathepsin B, which is a lysosomal proteinase. Sepsis, induced in male Sprague-Dawley rats (50 to 60 g) by cecal ligation and puncture (CLP), resulted in an approximately 50% increase in myofibrillar proteinase activity and an approximately 30% increase in cathepsin B activity. Concomitantly, both total and myofibrillar protein breakdown rates, measured as release of tyrosine and 3-methylhistidine (3-MH), respectively, by incubated EDL muscles, were substantially elevated. Treatment of septic rats with the mast cell degranulating compound 48/80 or the lysosomal protease inhibitor leupeptin significantly reduced myofibrillar proteinase and cathepsin B activities, but did not affect protein breakdown rates. The results suggest that increased protein breakdown in septic skeletal muscle is associated with, but not caused by, myofibrillar proteinase or cathepsin B activity. The data also support the concept of a mast cell origin of the myofibrillar proteinase activity, but do not suggest an obligatory involvement of mast cell proteinase in increased protein degradation during sepsis.
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PMID:Myofibrillar proteinase, cathepsin B, and protein breakdown rates in skeletal muscle from septic rats. 200 44

Using fluorogenic substrates and the specific inhibitor E-64, cysteine proteinase (CP) activity was measured in blood plasma of healthy controls (mean = 35.0 mU/l) and patients with cancer and severe septic shock. Whereas moderately elevated activity was observed in some kinds of cancer (mean = 63.9 mU/l), 10-fold increased CP activity was found in septic shock. The plasma CP activity of sepsis patients paralleled the immunologically determined concentration of elastase-alpha 1-proteinase inhibitor complex. On the basis of its substrate specificity and its Michaelis constant for Z-Phe-Arg-NMec the plasma CP was identified as cathepsin B or a cathepsin B-like proteinase (CBP). Kinetic studies revealed that dilution and competition with substrate effects reversible dissociation of CBP from complexes with plasma inhibitors that are most probably the kininogens. The dissociation of CBP was confirmed by gel chromatographic fractionation of the plasma proteins. The results suggest that active CBP can easily dissociate from its plasma inhibitor complexes in vivo and may be involved in pathogenetic extracellular proteolysis.
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PMID:Enzymatically active cathepsin B dissociating from its inhibitor complexes is elevated in blood plasma of patients with septic shock and some malignant tumors. 320 66

Protein synthesis and degradation are particularly sensitive to malnutrition and catabolic states. Intracellular protein degradation is determined by the conformation, molecular weight, isoelectric point, and carbohydrate content of the proteins. ATP-stimulated endoproteases appear to catalyse the rate-limiting steps. In the liver, proteolysis is reduced by amino acids and/or insulin, whereas glucagon stimulates protein degradation, probably due to depletion of intracellular gluconeogenic amino acids. In the muscle, protein degradation is promoted by interleukin-1 and inhibited by Ep-475, which specifically inactivates cathepsin B,H, and L. Myofibrillar alkaline proteinase activity increases postoperatively and in patients suffering from malignant tumors, whereas normal proteinase values were observed in these patients following total parenteral nutrition. Increased alkaline proteinase activity is also observed in diabetes mellitus and is normalized by insulin. Extracellular proteolysis has been reported in patients with hypercatabolic acute renal failure and in patients with sepsis or acute pancreatitis. Plasma fractions obtained from hypercatabolic patients with postoperative acute renal failure were proteolytic. Plasma proteinase activity decreases during hemodialysis due to elimination of a metallo-proteinase. Plasma alpha 2-macroglobulin decreases in patients with acute renal failure and also during acute pancreatitis. Proteolytic degradation of parathyroid hormone by sera obtained from patients with acute pancreatitis has been observed. Also, there is a decrease of high molecular weight kininogen during experimental acute pancreatitis. Granulocyte elastase increases postoperatively, mainly in patients with sepsis. Sepsis also causes increased proteolytic activity in the urine. In conclusion, intracellular protein degradation can supply important precursors for hepatic and renal gluconeogenesis during malnutrition.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proteinases in catabolism and malnutrition. 331

The mechanisms of accelerated skeletal muscle protein degradation during sepsis have not been fully elucidated. Activity of the lysosomal protease cathepsin B is increased in skeletal muscle during various catabolic states other than sepsis. In the present study the protein degradation rate and cathepsin B activity were determined in extensor digitorum longus and soleus muscles from nonseptic and septic rats. The protein degradation rate during incubation in vitro with or without the cathepsin B inhibitor leupeptin was also determined. Both protein degradation and cathepsin B activity were increased in muscles from septic rats. Incubation with leupeptin reduced, but did not normalize, the protein degradation rate in both extensor digitorum longus and soleus muscles from septic animals. These studies suggest that increased cathepsin B activity contributes to the accelerated muscle proteolysis seen during sepsis and that proteases other than cathepsin B are also involved.
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PMID:Evidence that cathepsin B contributes to skeletal muscle protein breakdown during sepsis. 334 5

The roles of prostaglandins and lysosomal proteases in accelerated skeletal muscle proteolysis during sepsis are not yet fully understood. In this study rats received intraperitoneal injections of the prostaglandin synthesis inhibitor indomethacin (IND, 5.0 mg/kg), the lysosomal cathepsin B inhibitor leupeptin (LEU, 2.5 mg/kg), or normal saline 2 hr before cecal ligation and puncture (a model of intraabdominal sepsis) or sham-operation. The injections were repeated every 6 hr for a total of four doses. Sixteen hours after operation, intact extensor digitorum longus (EDL) muscles were harvested and cathepsin B activity was measured in one muscle. The contralateral muscle was incubated in oxygenated Krebs-Henseleit bicarbonate buffer containing glucose (10 mM) and cycloheximide (0.5 mM), and protein degradation rate was determined as the release of tyrosine into the incubation medium. Both muscle cathepsin B activity and protein degradation rate were higher in septic than in sham-operated rats. Treatment with IND or LEU significantly reduced the elevated cathepsin B activity in septic muscles, but failed to significantly alter muscle proteolysis. In nonseptic muscle, both cathepsin B activity and protein degradation rate were unaffected by the different types of treatment. The results suggest that although prostaglandins may influence muscle lysosomal protease activity, neither prostaglandins nor the lysosomal protease cathepsin B appear to be major regulators of accelerated muscle protein breakdown during sepsis.
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PMID:Effects of indomethacin and leupeptin on muscle cathepsin B activity and protein degradation during sepsis. 339 87

Systemic infection with Streptococcus pneumoniae produced atrophy, decreased twitch and tetanic tension, and altered intracellular electrolyte composition in rat skeletal muscle. Cathepsin B activity was selectively elevated early in the course of illness. Luepeptin, a cathepsin B inhibitor, and indomethacin, a prostaglandin synthesis inhibitor, prevented muscle atrophy and impaired contractility. Indomethacin, but not leupeptin, prevented the intracellular electrolyte changes. Acetaminophen reduced fever but did not prevent muscle atrophy, impaired contractility, or altered intracellular electrolytes. Muscle wasting and impaired contractility associated with sepsis may involve selective prostaglandin stimulation of cathepsin B activity. Intracellular electrolyte changes may involve prostaglandin synthesis but do not require cathepsin B activation.
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PMID:Inhibitors of prostaglandin synthesis or cathepsin B prevent muscle wasting due to sepsis in the rat. 671 47

1. A cell culture system of C2C12 myotubes was established as a model of the muscle. With the aid of this model, the half-lives of intracellular proteins as well as the activities and mRNA levels of proteasomes (26S and 20S) and cathepsins (B, L, and H) were examined in the presence of various amounts of cytokines. 2. It was found that 100 units/ml recombinant human interleukin-6 somewhat shortened the half-life of long-lived proteins to 23.79 +/- 1.55 h (control: 25.60 +/- 1.87 h). When 1% fetal bovine serum contained in the culture medium was replaced by 0.5 mg/ml bovine serum albumin, interleukin-6 was more effective since 10 units/ml of interleukin-6 shortened the half-life to 19.09 +/- 2.87 h (control: 22.26 +/- 321 h). Interleukin-6 (100 units/ml) increased the activity of 26S proteasome by 31.5%, of cathepsin B by 53.5% and of cathepsin B+L by 21.3%. These increases occurred in association with an increase in their transcription. 3. On the other hand, 1000 units/ml of recombinant human tumour necrosis factor alpha prolonged the half-life of long-lived proteins while reducing the protease activities of 20S proteasome (-27.1%), cathepsins B (-64.6%) and B+L (-54.9%). 4. These results suggest that interleukin-6 induces degradation of long-lived intracellular proteins by activating both the non-lysosomal (proteasomes) and lysosomal (cathepsins) proteolytic pathways. It is therefore concluded that interleukin-6 is a candidate for a proteolysis-inducing factor in myotubes and may play an important role in the progression of muscle degradation in systemic inflammatory responses induced by sepsis or severe injury.
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PMID:Interleukin-6 induces proteolysis by activating intracellular proteases (cathepsins B and L, proteasome) in C2C12 myotubes. 749 44

We studied the alterations in skeletal muscle protein breakdown in long lasting sepsis using a rat model that reproduces a sustained and reversible catabolic state, as observed in humans. Rats were injected intravenously with live Escherichia coli; control rats were pair-fed to the intake of infected rats. Rats were studied in an acute septic phase (day 2 postinfection), in a chronic septic phase (day 6), and in a late septic phase (day 10). The importance of the lysosomal, Ca2+ -dependent, and ubiquitin-proteasome proteolytic processes was investigated using proteolytic inhibitors in incubated epitrochlearis muscles and by measuring mRNA levels for critical components of these pathways. Protein breakdown was elevated during the acute and chronic septic phases (when significant muscle wasting occurred) and returned to control values in the late septic phase (when wasting was stopped). A nonlysosomal and Ca2+ -independent process accounted for the enhanced proteolysis, and only mRNA levels for ubiquitin and subunits of the 20 S proteasome, the proteolytic core of the 26 S proteasome that degrades ubiquitin conjugates, paralleled the increased and decreased rates of proteolysis throughout. However, increased mRNA levels for the 14-kD ubiquitin conjugating enzyme E2, involved in substrate ubiquitylation, and for cathepsin B and m-calpain were observed in chronic sepsis. These data clearly support a major role for the ubiquitin-proteasome dependent proteolytic process during sepsis but also suggest that the activation of lysosomal and Ca2+ -dependent proteolysis may be important in the chronic phase.
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PMID:Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways. 860 25

To evaluate the effects of sepsis on the exocrine pancreas, we studied (1) serum amylase levels, pancreatic water and trypsin content; (2) pancreatic histological changes; (3) pancreatic subcellular distribution of lysosomal enzyme in the acinar cells; and (4) protective effects of a new synthetic protease inhibitor, FUT-187 against the pancreatic injuries in sepsis of rats induced by cecal ligation and puncture. Elevated serum amylase levels, increased pancreatic water and trypsin content, were observed in rats with fecal peritonitis induced by cecal ligation and puncture. Subcellular redistribution of lysosomal enzyme, cathepsin B, activity from the lysosomal fraction to the zymogen fraction was also observed. FUT-187 was found to significantly prevent these pancreatic injuries induced by fecal peritonitis. These results indicate that the exocrine pancreas is injured during sepsis, and that some unknown protease activities, which are present during sepsis and are susceptible to the inhibition of FUT-187, seem to play an important role in the pathogenesis of the pancreatic injuries induced by fecal peritonitis. These results also indicate the important pathological role of lysosomal enzymes in the pancreatic injuries induced by sepsis.
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PMID:Pancreatic injuries in rats with fecal peritonitis: protective effect of a new synthetic protease inhibitor, sepinostat mesilate (FUT-187). 865 99

This study assessed sepsis-induced changes in the contents of calpain and cathepsin B in rat soleus muscle. Sepsis was induced in rats by intra-abdominally implanting fecal pellets containing Escherichia coil and Bacteroides fragilis. Intact soleus muscles were isolated from non-operated control rats, and from rats sacrificed 1 and 2 days after they were implanted with bacteria-free (sterile implanted) or bacteria-laden (septic implanted) pellets. Western blot analyses of muscle homogenates were performed to identify and quantitate these proteinases using specific antibodies. No significant differences in cathepsin B contents were observed between the septic and nonseptic animals on days 1 and 2, post-implantation. Among the three distinct bands recognized by anti-calpain, two prominent bands of 80 and 76 kDa, representing calpain subunits, did not seem to be altered in septic rats compared to the nonseptic groups. The content of the 45-kDa subunit decreased in both the septic and sterile groups compared with non-operated control. These results along with our previous observations suggest that although Gram-negative sepsis does not appear to have an effect on Ca2(+)-insensitive lysosomal cathepsin B content or activity, it upregulates the activity of the Ca2(+)-dependent calpain but not its content in the skeletal muscle during sepsis.
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PMID:Ca2(+)-dependent and Ca2(+)-independent proteinase contents in the skeletal muscle in septic rats. 872 83


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