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)

Purpose. The purpose of this study was to investigate the relationship between hepatic energy status and liver injury during sepsis, using transgenic mice which express creatine kinase in the liver catalyzing the phosphocreatine/creatine system. Methods. Creatine kinase transgenic mice were fed with normal rodent chow or chow containing 10% creatine for 5 days. Lipopolysaccharide (0.2 mg/kg) combined with d-galactosamine (600 mg/kg) was administered intraperitoneally. Results. Eighty percent of the creatine-fed transgenic mice had survived at 48 h post-d-galactosamine and lipopolysaccharide administration, compared with none of the normally fed transgenic mice. Hepatic phosphocreatine and ATP levels in the normally fed transgenic mice were significantly lower than those in the creatine-fed transgenic mice before and after lipopolysaccharide combined with d-galactosamine was administered. Massive hepatic hemorrhagic necrosis with apoptosis was seen in response to d-galactosamine and lipopolysaccharide in normally fed transgenic mice. These results are consistent with a significant increase in serum aminotransferase at 8 h. In contrast, there were faint necrotic changes in the liver with minimal cellular infiltration in creatine-fed transgenic mice. Conclusions. Maintenance of hepatic ATP levels protects from sepsis-induced liver injury and mortality.
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PMID:The beneficial effect of phosphocreatine accumulation in the creatine kinase transgenic mouse liver in endotoxin-induced hepatic cell death. 987 18

These serial clinical and experimental studies were designed to clarify the pathogenesis of postburn MODS. Both animal and clinical studies were performed. In animal experiments, 46 male cross-bred dogs were cannulated with Swan-Ganz catheters and 39 of them were inflicted with 50% TBSA third degree burns (7 were used as controls). The burned dogs were randomly divided into 4 groups: immediate infusion, delayed infusion, delayed fast infusion and delayed fast infusion combined with ginsenosides. All dogs were kept under constant barbiturate sedation during the whole study period. Hemodynamics, visceral MDA, mitochondrial respiratory control rate (RCR) and ADP/O ratio, ATP, succinic dehydrogenase (SDH), organ water content as well as light and electron microscopy of visceral tissues were determined. In the clinical study, 61 patients with extensive deep burns were chosen, of which 16 sustained MODS. Plasma TXB2/6-keto-PGF1alpha ratio, TNF, SOD, MDA, circulatory platelet aggregate ratio (CPAR), PGE2, interleukin-1, total organ water content and pathological observations of visceral tissues from patients who died of MODS were carried out. Results demonstrated that ischemic-reperfusion damage due to severe shock, sepsis and inhalation injury are three main causes of postburn death. All inflammatory mediators increased markedly in both animals and patients who sustained organ damage or MODS. SDH, RCR, ADP/O and ATP decreased significantly. These findings suggested that ischemic damage and systemic inflammatory response syndrome (SIRS) initiated by mediators or cytokines might be important in the pathogenesis of postburn MODS.
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PMID:Serial experimental and clinical studies on the pathogenesis of multiple organ dysfunction syndrome (MODS) in severe burns. 991 70

Insulin plays a major role in the regulation of skeletal muscle protein turnover but its mechanism of action is not fully understood, especially in vivo during catabolic states. These aspects are presently reviewed. Insulin inhibits the ATP-ubiquitin proteasome proteolytic pathway which is presumably the predominant pathway involved in the breakdown of muscle protein. Evidence of the ability of insulin to stimulate muscle protein synthesis in vivo was also presented. Many catabolic states in rats, e.g. streptozotocin diabetes, glucocorticoid excess or sepsis-induced cytokines, resulted in a decrease in insulin action on protein synthesis or degradation. The effect of catabolic factors would therefore be facilitated. In contrast, the antiproteolytic action of insulin was improved during hyperthyroidism in man and early lactation in goats. Excessive muscle protein breakdown should therefore be prevented. In other words, the anabolic hormone insulin partly controlled the 'catabolic drive'. Advances in the understanding of insulin signalling pathways and targets should provide information on the interactions between insulin action, muscle protein turnover and catabolic factors.
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PMID:Insulin action on skeletal muscle protein metabolism during catabolic states. 1022

During the last years many investigations have shown that a major catalyst within the mechanism of skeletal muscle wasting occurring under conditions like sepsis, injuries, trauma, cancer cachexia, chronic acidosis, fasting, glucocorticoid treatment, and insulinopenia is the ubiquitin-proteasome system. Evidence for this was obtained by findings that the rate of ATP-dependent protein degradation is increased, that m-RNA concentrations of several proteasome subunits and ubiquitin are increased and the amount of ubiquitin-protein conjugates is elevated under these conditions. Additionally, the enhanced protein breakdown was shown to be suppressed by proteasome inhibitors. In the present report we show that most but not all of the proteolytic activities of partially purified 20S/26S proteasomes from skeletal muscle of rats increase after induction of Diabetes mellitus. This finding suggests that part of the mechanism of acceleration of muscle protein breakdown is due to changes in proteasome activities.
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PMID:Alterations of proteasome activities in skeletal muscle tissue of diabetic rats. 1036 52

Catabolism of lean body mass (particularly muscle) occurs in sepsis and other forms of critical illness despite apparently adequate nutritional support. The determination of the optimal balance of carbohydrate and fat intake in this circumstance should be based on the resulting effect on the maintenance of lean body mass, and the nature and extent of any side effects. The general stress response involves a disruption in normal glucoregulation, in that hepatic glucose production is accelerated and the normal blood glucose lowering action of insulin is diminished. Nonetheless, the capacity to oxidize glucose once inside the cells is not impaired. Lipolysis, or the breakdown of peripheral triglycerides to free fatty acids (FFA) and glycerol, is accelerated in critical illness, to a greater extent than fat oxidation. Provision of exogenous fat maintains fat stores, but has minimal effect on the direct oxidation of plasma FFA. From the results of oxidation studies, it seems that about 5 mg kg x min of glucose can be readily oxidized, and the balance of energy will be supplied by the oxidation of fat, either endogenous or exogenous. However, an additional consideration in determining the optimal caloric substrate is that insulin is a potent anabolic hormone and stimulates muscle protein synthesis. Consequently, provision of exogenous insulin enhances retention of muscle. This procedure dictates that almost all non-protein calories be provided as carbohydrate to avoid hypoglycemia. Preliminary studies suggest this may be the optimal approach in critically ill patients. Glucose and fatty acids are the major energy substrates in the body. The oxidative metabolism of these substrates provides the ATP needed for physiological function, including protein synthesis. Over the past 20 y, development of new techniques in nutritional support have made it possible to provide large amounts of carbohydrate and fat to critically-ill patients, along with protein or amino acids. However, despite providing such patients with what should be more than adequate caloric and protein intake, critically ill patients lose lean body mass (Streat et al, 1987), largely because of persistent muscle catabolism (Sakurai et al, 1995). The general relation between energy substrate metabolism and maintenance of lean body mass has been recognized for many years (Calloway & Spector, 1954), so it is important to examine the alterations in energy substrate metabolism that occur in response to critical illness that may play a role in causing the persistent catabolism of muscle protein.
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PMID:Sepsis as a modulator of adaptation to low and high carbohydrate and low and high fat intakes. 1036 91

1. Low-dose ('renal-dose') dopamine (i.e. 1-3 micrograms/kg per min) is used widely for the treatment of acute renal failure induced by ischaemia, toxins and/or sepsis. Here we review the scientific rationale, experimental studies and clinical trials evaluating its use in these settings. 2. Renal-dose dopamine augments renal blood flow, sodium excretion and probably glomerular filtration rate in healthy humans and experimental animals and limits ATP utilization and oxygen requirements in nephron segments at risk of ischaemic injury. Renal-dose dopamine is renoprotective in several ischaemic and nephrotoxic models of acute renal failure. 3. However, most studies in humans have not demonstrated prevention of acute renal failure in high-risk patients or improved outcome in those with established acute renal failure. While the safety profile of dopamine in these settings has not been extensively defined, it is known the drug may precipitate serious cardiovascular and metabolic complications in the critically ill. Therefore, we suggest that renal-dose dopamine should not be used for selective renal vasodilatory and natriuretic actions in those patients with acute renal failure until its efficacy is established in randomized control trials. 4. Renal-dose dopamine may be most valuable when combined with agents targeting other events in acute renal failure, such as cast formation, epithelial cell injury and tubule regeneration. These recommendations should not preclude the use of dopamine for its systemic effects in heart failure and septic shock.
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PMID:Renal-dose (low-dose) dopamine for the treatment of sepsis-related and other forms of acute renal failure: ineffective and probably dangerous. 1038 50

High blood lactate concentration (hyperlactacidaemia) in trauma or sepsis is thought to indicate tissue hypoxia and anaerobic glycolysis even when blood pressure, cardiac output, and urine output are within clinically acceptable ranges. However, mechanisms of lactate generation by well-oxygenated tissues have received little attention. Within cells, oxidative and glycolytic energy production can proceed in separate, independent compartments. In skeletal muscle and other tissues, aerobic glycolysis is linked to ATP provision for the Na+-K+ pump, the activity of which is stimulated by epinephrine. In injured patients, hypokalaemia may reflect increased Na+,K+-ATPase activity. We propose that increased blood lactate often reflects increased aerobic glycolysis in skeletal muscle secondary to epinephrine-stimulated Na+,K+-ATPase activity and not anaerobic glycolysis due to hypoperfusion. The hypothesis explains why hyperlactacidaemia often neither correlates with traditional indicators of perfusion nor diminishes with increased oxygen delivery. When other variables have returned to normal, continued attempts at resuscitation based on elevated blood lactate may lead to unnecessary use of blood transfusion and inotropic agents in an effort to increase oxygen delivery and lactate clearance.
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PMID:Lactate is an unreliable indicator of tissue hypoxia in injury or sepsis. 1046 91

Changes in protein kinase A (PKA, or cAMP-dependent protein kinase) activity in the rat liver during different metabolic phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture (CLP). Experiments were divided into 3 groups: control, early sepsis, and late sepsis. Early and late sepsis refer to those animals killed at 9 and 18 h, respectively, after CLP. Hepatic PKA was extracted and partially purified by acid precipitation, ammonium sulfate fractionation, and diethylaminoethyl (DEAE)-cellulose chromatography. PKA was eluted from DEAE-cellulose column with a linear NaCl gradient. Two peaks of PKA, type I (eluted at low ionic strength) and type II (eluted at high ionic strength), were collected and their activities were determined on the basis of the rate of incorporation of [gamma-32-P]ATP into histone. The results show that during early sepsis, both type I and type II PKA activities remained unchanged. During late sepsis, type I PKA activity was decreased by 40.7-53.6%, whereas type II PKA activity was unaffected. Kinetic analysis of the data on type I PKA during the late phase of sepsis reveals that the Vmax (maximal velocity) values for ATP, cAMP, and histone were decreased by 40.7, 53.6, and 47.3%, respectively whereas the Km (substrate concentration required for half-maximal enzymatic activity) values for ATP, cAMP, and histone were unaltered. These data indicate that type I PKA was inactivated during the late hypoglycemic phase of sepsis in the rat liver. Because PKA-mediated phosphorylation plays an important role in the regulation of hepatic glucose metabolism, an inactivation of PKA may contribute to the development of hypoglycemia during the late phase of sepsis.
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PMID:Liver protein kinase A activity is decreased during the late hypoglycemic phase of sepsis. 1050 29

1. Although hepatic function is well known to deteriorate following bacterial infection, the underlying mechanisms remain poorly understood. We have previously reported that nitric oxide (NO) radical leads to a decrease in the ketone body ratio (KBR) and in ATP content due to the inhibition of mitochondrial electron transport in primary cultured rat hepatocytes. 2. To evaluate the effects of NO radical on the liver in patients with postoperative sepsis, we analysed both the stable end-product of nitric oxide radical (NOx) as well as the arterial KBR (AKBR), which reflects liver tissue NAD+/NADH. 3. Twenty patients who had undergone general abdominal surgery and who developed postoperative sepsis were divided into two groups: (i) surviving; and (ii) non-surviving. Blood samples were collected before the development of postoperative sepsis and every 3 days until the patient either died or was discharged from hospital. 4. Plasma NOx levels in seven patients who subsequently died became progressively higher than those in the 13 surviving patients over the clinical course of postoperative sepsis. 5. In the non-surviving group, the AKBR was significantly lower than in surviving patients, indicating impaired hepatic function. In contrast, plasma NOx levels in non-surviving patients were significantly higher than in surviving patients. 6. Decreases in AKBR to levels below 0.7 in non-surviving patients followed high NOx levels. Moreover, plasma NOx levels were closely correlated with the AKBR, indicating that NO radical is associated with mitochondrial dysfunction in the liver. 7. It is likely that the overproduction of NO radical plays an important role in causing fatal metabolic disorders in patients with postoperative sepsis.
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PMID:Nitric oxide production and hepatic dysfunction in patients with postoperative sepsis. 1074 47

The effect of sepsis on the ubiquitously expressed ATP-sensitive potassium (uK(ATP)-1) channel expression was measured in Sprague-Dawley rat diaphragms. Rats were treated with either 0.5 ml saline or 20 mg/Kg E. coli lipopolysaccharides and sacrificed at 3, 6, 12, 24, or 48 h later. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis showed that channel mRNA expression was increased at 3 h and continued to rise up to 48 h. Western blotting analysis showed a approximately 9-fold increase in channel protein expression 24 h after sepsis. Our results demonstrate that sepsis upregulates the uK(ATP)-1 channel.
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PMID:Induction of the ATP-sensitive potassium (uK(ATP)-1) channel by endotoxemia. 1084 76


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