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)

A 22-year-old man developed unconsciousness, severe quadriplegia and muscle atrophy, and had markedly elevated serum creatine kinase levels after using the high-dose steroid and nondepolarizing neuromuscular blocking agents during the course of sepsis and DIC. On neurological examination, he was lethargic. The patient had generalized muscle weakness and wasting, and diminished deep tendon reflexes. He weakly responsed to painful stimuli on the legs. The motor nerve conduction study demonstrated decreased CMAP (compound muscle action potential) amplitudes. Motor and sensory nerve conduction velocities and their distal latencies were normal. Muscle biopsy revealed marked muscle fiber atrophy predominantly in type 2 fibers and numerous basophilic and a few necrotic fibers. Some atrophic fibers had decreased to absent myosin adenosine triphosphatase activity in their center. Accordingly, he was diagnosed as having acute quadriplegic myopathy (AQM), which has been reported mainly in Western countries. The mechanism of muscle fiber degradation in this myopathy is still unknown. On immunohistochemical analysis to our patient, enzyme activities of various proteases such as calpain, cathepsin B, and proteasomes were increased in the sarcoplasm, especially in the atrophic fibers. We suggest that lysosomal cathepsin, nonlysosomal calpain, and ATP-ubiquitin-proteasome proteolytic pathways participate in muscle fiber degradation in AQM.
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PMID:[A case of acute quadriplegic myopathy]. 1108 98

Alterations of the ATP-dependent Ca2+ uptake in the cardiac sarcoplasmic reticulum (SR) during the 2 hemodynamically distinct phases of sepsis were investigated. Sepsis was induced by cecal ligation and puncture (CLP). Control rats were sham-operated. The SR vesicles were isolated by sucrose gradient centrifugation. The results show that the rates of ATP-dependent Ca2+ uptake in the cardiac SR were unaffected during the early hyperdynamic phase, whereas they were decreased by 41-46% (P < 0.01) during the late hypodynamic phase of sepsis. Analysis of the kinetics of Ca2+ transport indicates that during the late phase of sepsis, the Vmax values of Ca2+ pump for ATP and Ca2+ were decreased, whereas the affinities of Ca2+ pump for ATP and Ca2+ were unaffected. Magnesium stimulated, whereas vanadate inhibited the ATP-dependent Ca2+ uptake, but the Mg2+-stimulated and the vanadate-inhibited Ca2+ uptake activities were significantly lower during the late sepsis. Phosphorylation of SR by the cAMP-dependent and the calmodulin-dependent protein kinases stimulated the ATP-dependent Ca2+ uptake in the control and the early septic experiments, whereas it failed to stimulate Ca2+ uptake in the late sepsis. The extent of the phosphorylation-stimulated Ca2+ uptake activities was reduced by 65-69% (P < 0.01) during the early sepsis, and they were completely abolished during the late sepsis. These data indicate that the ATP-dependent Ca2+ uptake in cardiac SR was impaired during the late hypodynamic phase of sepsis. The impaired Ca2+ uptake during late sepsis was associated with a defective phosphorylation of SR proteins. Because the ATP-dependent Ca2+ uptake by cardiac SR plays an important role in the regulation of contraction-relaxation coupling, our findings may contribute to the understanding of the pathogenesis of altered cardiac function during the progression of sepsis.
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PMID:Calcium uptake by sarcoplasmic reticulum is impaired during the hypodynamic phase of sepsis in the rat heart. 1119 57

Myocardial function is impaired 24 h after the induction of sepsis, however, recovery of left ventricular (LV) function after 35 min of global ischemia is complete. The mechanisms by which this protection occurs are unknown. Ischemic preconditioning, another form of myocardial protection from ischemia/reperfusion (I/R) injury, has been shown to be modulated by ATP-sensitive potassium (K+ATP) channels. To investigate the role of K+ATP channels in the regulation of coronary flow (CF) and protection from I/R injury in septic rat hearts, we assessed the effects of the K+ATP channel antagonist glibenclamide (GLIB) and the agonist cromakalim (CROM) on pre- and post-ischemic CF and left ventricular developed pressure (LVDP). Although GLIB decreased pre-ischemic CF in both control and septic rat hearts, LVDP was unaffected. After I/R, CF was decreased in GLIB-treated control and septic rat hearts and LVDP was more severely depressed in control rat hearts than in septic rat hearts. CROM increased pre-ischemic CF in the septic group although LVDP was unaltered in both groups. After I/R, control rat heart CF was depressed but LVDP completely recovered. Post-ischemic CF in septic rat hearts was elevated compared with vehicle-treated septic rat hearts, but the recovery of LVDP was not improved. These results suggest that K+ATP channels modulate CF in septic rat hearts, but do not mediate cardioprotection as observed in control rat hearts.
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PMID:The role of K+ATP channels in the control of pre- and post-ischemic left ventricular developed pressure in septic rat hearts. 1129 97

Changes in Ca2+-induced Ca2+ release in cardiac sarcoplasmic reticulum (SR) during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). The 45Ca2+ release studies show that the amount of Ca2+ released from the passively and the actively loaded SR vesicles was unaffected during the early sepsis (9 h after CLP), but it was significantly decreased during the late phase (18 h after CLP) of sepsis. The [3H]ryanodine binding assays reveal that the Bmax for ryanodine binding was unaffected during the early phase, but was decreased by 32.1% during the late phase of sepsis. The affinity of ryanodine receptor for Ca2+ remained unchanged during sepsis. ATP, AMP-PCP, and caffeine stimulated binding, while MgCl2 and ruthenium red inhibited [3H]ryanodine binding in control, early sepsis, and late sepsis groups. The EC50 and IC50 values for these regulators were unaffected during the progression of sepsis. Digestion of control SR with phospholipase A2 decreased [3H]ryanodine binding and the decrease was reversible by the addition of phosphatidylcholine (PC), phosphatidylethanolamine (PE), or phosphatidylserine (PS). Addition of PC, PE, or PS to the SR isolated from septic rats stimulated [3H]ryanodine binding. These data demonstrate that Ca2+-induced Ca2+ release from cardiac SR remained relatively unaffected during the early phase, but was significantly impaired during the late phase of sepsis. The sepsis-induced impairment in SR Ca2+ release is a result of a quantitative reduction in the number of Ca2+ release channels. Furthermore, the reduction is associated with a mechanism involving a modification of membrane lipid profile in response to certain stimuli such as activation of phospholipase A2.
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PMID:Impairment of the ryanodine-sensitive calcium release channels in the cardiac sarcoplasmic reticulum and its underlying mechanism during the hypodynamic phase of sepsis. 1144 13

Poly (ADP-ribose) synthetase (PARS) is a DNA protective enzyme activated by single-strand breakage. It is suspected that exaggerated PARS activation related to biochemical stress by reactive oxygen and nitrogen species contributes to cellular injury in sepsis. The main hypothesis is that PARS activation leads to massive ATP and NAD consumption and consequent cellular energy depletion. The PARS inhibitor 3-amino-benzamide (3AB) is protective in rodents challenged with either endotoxin or intraperitoneal zymozan. The present experiment was designed to test the effect of 3AB in a more clinically relevant model of sepsis, namely polymicrobial sepsis induced by cecal ligature and puncture (CLP). Adult male Wistar rats were anesthetized, instrumented with catheters in the jugular vein and in the carotid artery, and then randomized into three groups: Sham (no laparotomy, n = 13), CLP (n = 15), and CLP/3AB (n = 18). All animals were allowed to recover and they received a continuous intravenous infusion of saline (20 mL/kg/h) and fentanyl (20 microg/kg/h). 3AB was administered to the CLP/3AB group as an intravenous bolus (10 mg/kg) followed by a continuous intravenous infusion (10 mg/kg/h). After 24 h, blood was drawn for the determination of biological indicators of organ injury. Rats were then anesthetized and biopsies of the liver were quickly frozen into liquid nitrogen for the subsequent determination of NAD and ATP levels. Further organ samples were collected for the assay of myeloperoxidase (MPO) to indicate tissue infiltration by leukocytes, and nitrotyrosine to indicate the level of biochemical stress by reactive nitrogen species. Twenty-four-hour mortality was 0/13 (Sham), 1/15 (CLP), and 5/18 (CLP/3AB; p = NS). In the surviving rats, CLP induced a clear elevation of liver enzymes, bilirubin, and pancreatic lipase, but not creatinine in the plasma, as well as a marked increase of MPO activity in liver, jejunum, and lung, but not kidney or heart. None of these variables was affected by treatment with 3AB. Furthermore, CLP did not cause depletion of NAD or ATP in the liver, nor any change in the nitrotyrosine content of any organ. These data argue against a general role of PARS activation in the pathogenesis of sepsis-induced tissue injury.
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PMID:Does the activation of poly (ADP-ribose) synthetase mediate tissue injury in the sepsis induced by cecal ligation and puncture? 1202 68

Inflammation in asthma, sepsis, transplant rejection, and many neurodegenerative diseases associates an up-regulation of NO synthesis with increased protein nitration at tyrosine. Nitration can cause protein dysfunction and is implicated in pathogenesis, but few proteins that appear nitrated in vivo have been identified. To understand how this modification impacts physiology and disease, we used a proteomic approach toward targets of protein nitration in both in vivo and cell culture inflammatory disease models. This approach identified more than 40 nitrotyrosine-immunopositive proteins, including 30 not previously identified, that became modified as a consequence of the inflammatory response. These targets include proteins involved in oxidative stress, apoptosis, ATP production, and other metabolic functions. Our approach provides a means toward obtaining a comprehensive view of the nitroproteome and promises to broaden understanding of how NO regulates cellular processes.
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PMID:Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. 1159 16

The pore-forming cytolysin of Vibrio vulnificus (VVC) causes severe hypotension and vasodilatation in vivo. Under the condition of bacterial sepsis, large amounts of nitric oxide (NO) produced by inducible NO synthase (iNOS) can contribute to host-induced tissue damage causing hypotension and septic shock. In this study, we investigated the effect of purified VVC on NO production in mouse peritoneal macrophages. VVC induced NO production in the presence of interferon-gamma. Increased NO production was not affected by polymyxin B, and heat inactivation of cytolysin abolished the NO-inducing capability. NO production was induced at the same concentration range of cytolysin for pore formation, as evidenced by the release of preloaded 2-deoxy-d-[(3)H]glucose. At the higher concentrations of cytolysin causing the depletion of cellular ATP, no NO production was observed. Increased expression of iNOS and activation of NFkappaB by VVC were confirmed by Western blotting and gel shift assay, respectively. These results suggest the role of cytolysin as an inducer of iNOS and NO production in macrophage and as a possible virulence determinant in V. vulnificus infection.
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PMID:Induction of nitric oxide synthase expression by Vibrio vulnificus cytolysin. 1179 87

Glutamine has beneficial effects on enterocytes and the immune system in sepsis, but its effects on hepatic metabolism remain unknown. The aim of the present study was to determine the effects of glutamine on hepatocyte energy metabolism under conditions of neonatal endotoxaemia. Suckling Wistar rats were injected intraperitoneally with 200 microg/kg lipopolysaccharide. Oxygen consumption was measured polarographically in hepatocytes respiring on either palmitate (0.5 mM) or palmitate plus glutamine (10 mM). Total hepatocyte oxygen consumption was similar in hepatocytes from control and endotoxic rats, but this was due to a decrease in intramitochondrial and an increase in extramitochondrial oxygen consumption in the cells from endotoxic animals. The addition of glutamine to hepatocytes from endotoxic rats restored intramitochondrial oxygen consumption to control levels. Although glutamine did not reverse the inhibition of the thermogenic proton leak observed in endotoxaemia, it significantly increased oxygen consumption due to mitochondrial ATP synthesis (P=0.03). Glutamine significantly increased the hepatocyte ATP/ADP ratio (P=0.02 compared with hepatocytes from endotoxic rats). Electron microscopy revealed morphological damage to the mitochondria of hepatocytes from endotoxic rats, and a return to a normal appearance with the addition of glutamine. We conclude that glutamine reverses the inhibition of mitochondrial metabolism that is observed in endotoxaemia. The effect is primarily at the level of ATP synthesis.
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PMID:Hepatocyte mitochondrial metabolism is inhibited in neonatal rat endotoxaemia: effects of glutamine. 1186 75

Hepatocyte injury and necrosis from many causes may result in pediatric liver disease. Influenced by other cell types in the liver, by its unique vascular arrangements, by lobular zonation, and by contributory effects of sepsis, reactive oxygen species and disordered hepatic architecture, the hepatocyte is prone to injury from exogenous toxins, from inborn errors of metabolism, from hepatotrophic viruses, and from immune mechanisms. Experimental studies on cultured hepatocytes or animal models must be interpreted with caution. Having discussed general concepts, this review describes immune mechanisms of liver injury, as seen in autoimmune hepatitis, hepatitis B and C infection, the anticonvulsant hypersensitivity syndrome, and autoimmune polyendocrinopathy. Of the monogenic disorders causing significant liver injury in childhood, alpha-1 antitrypsin deficiency and Niemann-Pick C disease demonstrate the effect of endoplasmic or endosomal retention of macromolecules. Tyrosinemia illustrates how understanding the biochemical defect leads to understanding cell injury, extrahepatic porphyric effects, oncogenesis, pharmacological intervention, and possible stem cell therapy. Pathogenesis of cirrhosis in galactosemia remains incompletely understood. In hereditary fructose intolerance, phosphate sequestration causes ATP depletion. Recent information about mitochondrial disease, NASH, disorders of glycosylation, Wilson's disease, and the progressive familial intrahepatic cholestases is discussed.
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PMID:Mechanisms of liver injury relevant to pediatric hepatology. 1189 Feb 7

The present study was designed to test the hypothesis that induction of chronic peritoneal sepsis in rats would produce a more severe calcium paradox-mediated myocardial injury in isolated heart preparation than is seen in normal hearts, and that this would be inhibited by sucrose as in normal hearts. Male Sprague-Dawley rats were made septic using 200 mg of cecal material (obtained from a donor rat) suspended in 5 mL of 5% dextrose in sterile water D5 W/kg. In septic animals, the cecal material was injected in the peritoneum, while sham-septic animals received only D5 W/kg (5 mL/kg). A third group consisting of normal rats (no surgery) group was also included. Hearts were harvested from all three groups and were subjected to a calcium paradox-mediated injury in an isolated heart preparation. Hearts were perfused with Krebs-Henseleit (KH) medium and were allowed to stabilize, followed by a perfusion with Ca2+-free KH for 10 min. After this 10-min Ca2+-free KH perfusion, rats were reperfused with KH medium for 60 min. Ca2+-free KH medium was used in control experiments, while sucrose experiments were conducted with the same medium except that 150 mM sucrose replaced 75 mM NaCl. A marked decrease in ATP and phosphocreatine occurred during Ca2+ reperfusion in all hearts in absence of sucrose. In the presence of the disaccharide, no change in high-energy phosphate (HEP) levels was observed in normal hearts, while lower ATP concentrations were seen in sham and septic hearts. Thus, sucrose did not inhibit cellular injury in sham and septic hearts as it did in normal hearts, and this might be due to a smaller HEP availability. Control studies with normal, sham, and septic hearts exhibited cessation of contractions in the absence of Ca2+, and appearance of large amounts of cytosolic protein in the effluent perfusate during Ca2+ reperfusion. With normal hearts, perfusion with sucrose caused a 96% inhibition of the total creatine kinase (CK) release observed in control experiments. With sham hearts, 32% of CK release was inhibited by sucrose, while 68% of the CK release was attributed to stress associated with surgery performed in the sham-septic group. In septic hearts, only 8% of the CK release was inhibited by sucrose, suggesting that more severe myocardial injury occurs when septic hearts are subjected to a calcium paradox as compared to other groups. It is evident that sucrose can inhibit a small fraction of the CK release from septic hearts during the calcium paradox as compared to the large CK loss associated with sham sepsis. We have concluded that induction of sepsis made the heart more susceptible to a calcium paradox-mediated myocardial injury.
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PMID:Induction of peritoneal sepsis increases the susceptibility of isolated hearts to a calcium paradox-mediated injury. 1190 Mar 37


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