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)

Cytotoxic necrotizing factor type 2 (CNF2) produced by Escherichia coli strains isolated from intestinal and extraintestinal infections is a dermonecrotic toxin of 110 kDa. We cloned the CNF2 gene from a large plasmid carried by an Escherichia coli strain isolated from a lamb with septicemia. Hydropathy analysis of the deduced amino acid sequence revealed a largely hydrophilic protein with two potential hydrophobic transmembrane domains. The N-terminal half of CNF2 showed striking homology (27% identity and 80% conserved residues) to the N-terminal portion of Pasteurella multocida toxin. Methylamine protection experiments and immunofluorescence studies suggested that CNF2 enters the cytosol of the target cell through an acidic compartment and induces the reorganization of actin into stress fibers. Since the formation of stress fibers in eukaryotic cells involves Rho proteins, we radiolabeled these small GTP-binding proteins from CNF2-treated and control cells with a Rho-specific ADP-ribosyltransferase. The [32P]ADP-ribosylated Rho proteins from CNF2-treated cells migrated slightly more slowly in SDS/PAGE than did the labeled proteins from the control cells. This shift in mobility of Rho proteins in SDS/PAGE was also observed when CNF2 and the RhoA protein were coexpressed in E. coli. We propose that Rho proteins are the targets of CNF2 in mammalian cells.
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PMID:Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. 817 Sep 93

Diminished availability of oxygen at the cellular level might account for organ dysfunction in sepsis. Although the classical forms of tissue hypoxia due to hypoxemia, anemia, or inadequate perfusion all might be important under some conditions, it seems increasingly likely that a fourth mechanism, namely cytopathic hypoxia, might play a role as well. The term cytopathic hypoxia is used to denote diminished production of adenosine triphosphate (ATP) despite normal (or even supranormal) PO2 values in the vicinity of mitochondria within cells. At least in theory, cytopathic hypoxia could be a consequence of several different (but mutually compatible) pathogenic mechanisms, including diminished delivery of a key substrate (e.g., pyruvate) into the mitochondrial tricarboxylic acid (TCA) cycle, inhibition of key mitochondrial enzymes involved in either the TCA cycle or the electron transport chain, activation of the enzyme, poly-(ADP)-ribosylpolymerase (PARP), or collapse of the protonic gradient across the inner mitochondrial membrane leading to uncoupling of oxidation (of NADH and FADH) from phosphorylation of ADP to form ATP. Tantalizing, but limited, data support the view that cytopathic hypoxia occurs in both animals and patients with sepsis or endotoxemia.
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PMID:Cytopathic hypoxia in sepsis. 924 46

Burn patients suffer a break in the physical barrier (skin), which, when combined with their generalized state of immunodeficiency, creates an open window for opportunistic infections, mainly with Pseudomonas aeruginosa. Infection of the burn wound has always been a major factor in retardation of wound healing, and sepsis remains the leading cause of death in burn patients. Because studies have shown that topical treatment with antiexotoxin A (ETA) antibodies significantly increases survival in rats infected with toxin-producing strains of P. aeruginosa, we examined 11 synthetic peptides encompassing 12 to 45 amino acid (aa) residues, representing what were predicted by computer analysis to be the most hydrophilic and antigenic regions of ETA. These synthetic peptides were injected into rabbits for antibody production. Different groups of rabbits were immunized with a combination of peptides, with each combination representing one of the three distinct domains of ETA. Animals immunized with various peptide combinations produced peptide-specific antibodies that exhibited cross-reactivity to ETA. Two major epitopes were identified on the ETA molecule by experiments with peptide-specific antibodies in enzyme-linked immunosorbent assay and immunoprecipitation. One of these epitopes was located in the translocation domain (II) (aa 297 to 310), while the other was mapped to the last 13 aa residues at the carboxy-terminal end of the enzymatic domain (III) (aa 626 to 638). Of these two regions, the epitope in the enzymatic domain induced a much higher level of neutralizing antibodies that abrogated the cytotoxic activity of ETA in vitro. Antibodies to this epitope blocked the ADP-ribosyltransferase activity of ETA and appeared to interfere with binding of the substrate elongation factor 2 to the enzymatic active site of the ETA molecule. We conclude that polyclonal, as well as monoclonal, antibodies to short peptides, representing small regions of ETA, may have therapeutic potential in passive immunization or topical treatment of burn patients infected with toxin-producing strains of P. aeruginosa.
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PMID:Generation of neutralizing antipeptide antibodies to the enzymatic domain of Pseudomonas aeruginosa exotoxin A. 957 4

The present study investigates the relationship between the PKC-alpha and hepatic apoptosis during sepsis. Cecal ligation and puncture- (CLP) induced animal model of polymicrobial sepsis was used, with early and late sepsis referring to those animals sacrificed at 9 and 18 h, respectively, after CLP. The expressions of PKCalpha and Bcl-2 family proteins as well as poly(ADP-ribose) polymerase (PARP) cleavage were quantified to evaluate the possible factors involved in the hepatic cell death during sepsis. The apoptosis of hepatocytes under septic condition or hepatocytes treated with PKCalpha antisense was evaluated by gel electrophoresis and/or flow cytometry after Annexin-V-Fluos and propidium iodide staining. The results indicated that (1) the protein expression of membrane-associated PKCalpha was decreased at early (P < 0.05) and late (P < 0.01) sepsis; (2) the protein expressions of Bcl-2 and Bcl-xL were decreased, whereas Bax expression was increased at late sepsis; (3) the percentage of PARP cleavage was increased at early (P < 0.05) and late (P < 0.01) sepsis; (4) severe DNA fragmentation was observed at late sepsis; (5) the apoptotic cell population was increased at early and late sepsis; and (6) the percentage of apoptotic cell population in PKCalpha antisense-treated cells was significantly higher than that in untreated cells. These results suggest that inactivation of PKCalpha may play an important role in modulating hepatic apoptosis during sepsis and the apoptosis is closely associated with the alterations of Bcl-2 family proteins.
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PMID:The decrease of PKCalpha is associated with hepatic apoptosis at early and late phases of polymicrobial sepsis. 1122 Jun 41

Several lines of evidence indicate that cellular energetics are deranged in sepsis, not by inadequate tissue perfusion but rather by impaired mitochondrial respiration; that is, organ dysfunction in sepsis may result from cytopathic hypoxia. If this concept is correct, the therapeutic implications are enormous. Efforts to improve outcome in septic patients by monitoring and manipulating cardiac output, systemic oxygen (DO2), and regional blood flow are doomed to failure. Instead, the focus should be on developing pharmacologic strategies (e.g., isoform-selective iNOS or PARP inhibitors) to restore normal mitochondrial function and cellular energetics.
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PMID:Cytopathic hypoxia. Is oxygen use impaired in sepsis as a result of an acquired intrinsic derangement in cellular respiration? 1191 Jul 29

Accumulating data support the view that sepsis is associated with an acquired intrinsic derangement in the ability of cells to consume O(2), a phenomenon that has been termed "cytopathic hypoxia." We sought to use an in vitro "reductionist" model system using cultured cells stimulated with proinflammatory cytokines to test the hypothesis that cytopathic hypoxia is mediated, at least in part, by depletion of intracellular levels of NAD(+)/NADH secondary to activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP). We measured O(2) consumption by Caco-2 enterocytes growing on microcarrier beads after cells were incubated for 24 h under control conditions or with cytomix, a mixture of tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma. Immunostimulated cells consumed O(2) at about one-half the rate of control cells, but this effect was largely prevented if any one of the following pharmacological agents was present during the period of incubation with cytomix: 4,5-dihydroxy-1,3-benzene disulfonic acid, a superoxide radical anion scavenger; 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide, a nitric oxide scavenger; 5,10,15,20- tetrakis-[4-sulfonatophenyl]-porphyrinato-iron[III], a peroxynitrite (ONOO(-)) decomposition catalyst; urate, an ONOO(-) scavenger; 3-aminobenzamide, a PARP inhibitor; or N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide HCl, a chemically dissimilar and more potent PARP inhibitor. The decrease in O(2) uptake induced by cytomix was associated with decreased cellular levels of NAD(+)/NADH. The decrease in cellular NAD(+)/NADH content and the decrease in O(2) uptake induced by cytomix were completely abrogated if liposome-encapsulated NAD(+) was added to the cultures during immunostimulation. Empty liposomes also increased O(2) uptake by immunostimulated Caco-2 cells, but much less effectively than liposomes containing NAD(+). These data are consistent with the view that enterocytes exposed to proinflammatory cytokines consume less O(2) due to NAD(+)/NADH depletion secondary to activation of PARP by ONOO(-) or other oxidants.
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PMID:Liposomal NAD(+) prevents diminished O(2) consumption by immunostimulated Caco-2 cells. 1194 74

Sepsis is associated with a widespread production of proinflammatory cytokines and various oxidant species. Activation of the enzyme poly(ADP-ribose) polymerase (PARP) has been shown to contribute to cell necrosis and organ failure in various diseases associated with inflammation and reperfusion injury. The aim of the current study was to elucidate the role of PARP activation in the multiple organ dysfunction complicating sepsis in a murine model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). Mice genetically deficient in PARP (PARP-/-) and their wild-type littermates (PARP+/+) were subjected to CLP. After 12 and 24 h, the proinflammatory cytokines TNF-alpha and IL-6, as well as the anti-inflammatory cytokine IL-10, and nitrite/nitrate were measured in plasma samples. Organs were harvested for the measurement of myeloperoxidase (MPO) and malondialdehyde (MDA) levels, and immunohistochemical staining for nitrotyrosine and poly(ADP ribose) was performed in gut sections. PARP-/- mice, and their wild-type littermate showed a similar time-dependent increase in plasma nitrite/nitrate and in gut and lung MDA content, as well as the presence of nitrotyrosine in the gut. In contrast to wild-type mice showing a PARP activation in the gut, PARP-/- mice had no staining for poly(ADP ribose). PARP-/- mice had significantly lower plasma levels of TNF-alpha, IL-6, and IL-10, and they exhibited a reduced degree of organ inflammation, indicated by decreased MPO activity in the gut and lung. These effects were associated with a significant improvement in the survival of CLP in PARP-/- mice. Thus, PARP activation has an important role in systemic inflammation and organ damage in the present model of polymicrobial septic shock.
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PMID:Resistance to acute septic peritonitis in poly(ADP-ribose) polymerase-1-deficient mice. 1195 28

Falciparum malaria is a complex disease with no simple explanation, affecting organs where the parasite is rare as well as those organs where it is more common. We continue to argue that it can best be understood in terms of excessive stimulation of normally useful pathways mediated by inflammatory cytokines, the prototype being tumor necrosis factor (TNF). These pathways involve downstream mediators, such as nitric oxide (NO) that the host normally uses to control parasites, but which, when uncontrolled, have bioenergetic failure of patient tissues as their predictable end point. Falciparum malaria is no different from many other infectious diseases that are clinically confused with it. The sequestration of parasitized red blood cells, prominent in some tissues but absent in others with equal functional loss, exacerbates, but does not change, these overriding principles. Recent opportunities to stain a wide range of tissues from African pediatric cases of falciparum malaria and sepsis for the inducible NO synthase (iNOS) and migration inhibitory factor (MIF) have strengthened these arguments considerably. The recent demonstration of bioenergetic failure in tissue removed from sepsis patients being able to predict a fatal outcome fulfils a prediction of these principles, and it is plausible that this will be demonstrable in severe falciparum malaria. Understanding the disease caused by falciparum malaria at a molecular level requires an appreciation of the universality of poly(ADP-ribose) polymerase-1 (PARP-1) and Na(+)/K(+)-ATPase and the protean effects of activation by inflammation of the former that include inactivation of the latter.
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PMID:The pathophysiology of falciparum malaria. 1288 13

The hemostatic system is severely disturbed during endotoxemia, leading to a hypercoagulable state. However, it remains uncertain to what extent hypercoagulability is the critical factor in determining the clinical course rather than just the consequence of a severe systemic inflammatory response. To answer this question, we evaluated the evolution of hemostatic and inflammatory markers, as well as histological features, in mice sensitive and resistant to two models of endotoxemia: lipopolysaccharide-injection and cecal ligation puncture. Genetic (knockout mice) and pharmacological (PJ34) blockade of the nuclear enzyme PARP-1 was used to achieve resistance to the endotoxemia. In both models, endotoxemia resulted in antithrombin deficiency, decreased platelets, and fibrin deposition in organs, which were similar in all groups of mice. By contrast, proinflammatory mediators, inflammatory cell infiltration (especially that mediated by mononuclear cells), and organ degeneration were more intense in sensitive animals. Further studies supported a negative role for the triggering of the coagulation cascade in the mortality associated with the endotoxic shock. Hirudin had a minor effect on cell infiltration and organ damage, despite causing a potent inhibition of fibrin deposition. On the other hand, a sublethal dose of lipopolysaccharide yielded significant fibrin deposition but weak activation of the inflammatory response. Our results suggest that activation of coagulation by endotoxemia is severe and independent of the inflammatory response. However, such activation may act with fibrin deposition to have a minor influence on survival in sepsis.
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PMID:Role of lipopolysaccharide and cecal ligation and puncture on blood coagulation and inflammation in sensitive and resistant mice models. 1579 89

Reactive oxygen and nitrogen species, particularly peroxynitrite, are potent inducers of tissue damage during systemic inflammatory response and circulatory shock. Recent evidence indicates that the toxicity of these species largely depends on their ability to trigger activation of the nuclear enzyme poly(adenosine 5'-diphosphate ribose) polymerase-1 (PARP-1). Following excessive activation, PARP-1 depletes the intracellular stores of its substrate, nicotinamide adenine dinucleotide, thus slowing glycolysis, generation of high energy phosphates, and mitochondrial electron transport. Consequently, the severe metabolic crisis induced by PARP-1 activation results in acute cell dysfunction and necrotic cell death. In addition, activation of PARP-1 plays an important role in the upregulation of inflammatory cascades via a functional association with mitogen-activated protein kinases and several transcription factors, such as nuclear factor kappa B, resulting in augmented expression of pro-inflammatory cytokines, chemokines, adhesion molecules, and enzymes. In severe sepsis and hemorrhage, PARP-1 activation has emerged as one of the central mechanisms of systemic inflammation, endothelial dysfunction, peripheral vascular failure, and reduction of cardiac contractility. Innovative therapeutic strategies based on the pharmacological inhibition of PARP-1 catalytic activity might provide benefits by preventing tissue injury, organ dysfunction, and lethality associated with these conditions.
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PMID:Role of nitrosative stress and activation of poly(ADP-ribose) polymerase-1 in cardiovascular failure associated with septic and hemorrhagic shock. 1602 25


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