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)

Modification in the enzymatic complement and lipogenic functions of rat liver endoplasmic reticulum (ER) were shown to occur during pneumococcal sepsis. Glucose-6-phosphatase, 5'nucleotidase, esterase, and NADPH cytochrome C reductase decreased in activity by as much as 50% with respect to controls. Hydroxymethylglutaryl-CoA and NADH cytochrome C reductases were increased 6-and 2-fold, respectively. Alkaline phosphatase and inosine-5'-diphosphatase did not differ with respect to fasted controls. The lipogenic capacity of the ER was shown to be enhanced. In vitro [14C]acetate incorporation into cholesterol and other lipids by hepatocytes isolated from infected rats was increased 2-to 10-fold. It is concluded that the flow of acetyl-CoA in liver cell of Streptococcus pneumoniae-infected rats is toward lipogenesis rather than ketogenesis.
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PMID:Effects of pneumococcal infection on rat liver microsomal enzymes and lipogenesis by isolated hepatocytes. 1 31

Primed neutrophils may contribute to endothelial and end-organ damage after burn injury because of increased endothelial adherence and enhanced toxic oxygen metabolite generation in response to a "second insult" such as bacterial sepsis. The purposes of this study were to determine: (1) whether serum from patients with thermal injury causes priming of the neutrophil NADPH:O2 oxidoreductase, (2) whether time after burn (early vs late) influences neutrophil priming, and (3) whether priming could be attenuated by a specific platelet-activating factor antagonist, WEB2170. Normal human neutrophils were incubated with 10% sera that was obtained from healthy adult controls (normal human sera) and with 10% sera from patients with greater than 30% total body surface area burns, which was collected early (early postburn sera) (i.e., between 12 and 48 hours after burn) or late (late postburn sera) (5 to 15 days, after burn). Priming of the neutrophil oxidase was tested for by measurement of the generation of superoxide anion after a stimulus of 10(-6) mol/L formyl-methionine-leucine-phenylalanine (fMLP). In separate experiments, neutrophils were pretreated with WEB2170 before serum incubation and fMLP stimulation to block any priming that may be mediated by platelet-activating factor. All sera caused an increased rate of superoxide anion production in response to fMLP and thus "primed" the neutrophil NADPH:O2 oxidoreductase. Greater priming occurred after incubation with late postburn sera than with other sera. WEB2170 completely inhibited priming by normal human sera and early postburn sera and partially inhibited priming by late postburn sera.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:WEB2170, a specific platelet-activating factor antagonist, attenuates neutrophil priming by human serum after clinical burn injury: the 1991 Moyer Award. 166 Dec 87

A 52 yr old Caucasian female (F. E.) had hemolytic anemia, a leukemoid reaction, and fatal sepsis due to Escherichia coli. Her leukocytes ingested bacteria normally but did not kill catalase positive Staphylococcus aureus, Escherichia coli, and Serratia marcescens. An H(2)O(2)-producing bacterium, Streptococcus faecalis, was killed normally. Granule myeloperoxidase, acid and alkaline phosphatase, and beta glucuronidase activities were normal, and these enzymes shifted normally to the phagocyte vacuole (light and electron microscopy). Intravacuolar reduction of nitroblue tetrazolium did not occur. Moreover, only minimal quantities of H(2)O(2) were generated, and the hexose monophosphate shunt (HMPS) was not stimulated during phagocytosis. These observations suggested the diagnosis of chronic granulomatous disease. However, in contrast to control and chronic granulomatous disease leukocytes, glucose-6-phosphate dehydrogenase activity was completely absent in F. E. leukocytes whereas NADH oxidase and NADPH oxidase activities were both normal. Unlike chronic granulomatous disease, methylene blue did not stimulate the hexose monophosphate shunt in F. E. cells. Thus, F. E. and chronic granulomatous disease leukocytes appear to share certain metabolic and bactericidal defects, but the metabolic basis of the abnormality differs. Chronic granulomatous disease cells lack oxidase activity which produces H(2)O(2); F. E. cells had normal levels of oxidase activity but failed to produce NADPH due to complete glucose-6-phosphate dehydrogenase deficiency. These data indicate that a complete absence of leukocyte glucose-6-phosphate dehydrogenase with defective hexose monophosphate shunt activity is associated with low H(2)O(2) production and inadequate bactericidal activity, and further suggest an important role for NADPH in the production of H(2)O(2) in human granulocytes.
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PMID:Complete deficiency of leukocyte glucose-6-phosphate dehydrogenase with defective bactericidal activity. 440 Dec 71

1. Male Sprague-Dawley or Wistar rats were injected with bacterial lipopolysaccharide (LPS; 5 mg kg-1, i.p.) and killed after 1, 3, 6, 15, and 24 h. The brains, mesenteries, spleens, lungs, livers, kidneys, hearts, aortae and diaphragms were removed and frozen immediately. Control rats were injected with sterile saline and killed after 6 h. 2. The organs were homogenized in a semi-frozen state and NO synthase (NOS) activity measured in tissues from both LPS-treated and saline-treated groups by the ability of homogenates to convert [3H]-L-arginine to [3H]-L-citrulline in a NADPH-dependent manner. 3. The NOS activity in all organs taken from control animals was found to be calcium-dependent, with the highest activity being in the brain. After LPS-treatment an induced calcium-independent NOS was detected in all tissues tested, with the exception of the brain. The spleen, lung, mesentery and liver had the highest amounts of LPS-induced NOS activity. No induction of calcium-dependent NOS was detected. 4. Induction of NOS was maximum 6 h after administration of LPS and had returned to control levels in 24 h. 5. The constitutive NOS in brain and mesentery and the LPS-induced activities in the spleen, lung, liver and mesentery were inhibited by NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME) according to concentration. The IC50 for L-NAME was 2.5 microM against the constitutive NOS from brain, and 20-25 microM against the inducible NOS. For L-NMMA the IC50 was 20-25 microM against either NOS isoform. 7. The vascular responses to endothelin-I (ET-1), the thromboxane A2-mimetic 11 alpha,9 alpha-epoxymethanoprostaglandin F2alpha (U46619), phenylephrine (PE) or 5-hydroxytryptamine (5-HT) were measured in the simultaneously perfused arterial and venous mesenteric vascular beds from both control and LPS-treated(6 h) rats. Vasoconstrictor responses to all agonists tested were unaffected by LPS treatment. In the presence of L-NAME (100 microM) vasoconstrictor responses were potentiated in both the arterial and venous portion of the mesenteric beds from both control and LPS-treated rats. The potentiation of responses to U46619 was significantly greater in beds from LPS-treated rats.8. Injection of LPS i.p. is associated with induction of NOS in all organs tested, except for the brain. In the mesentery this is not accompanied by a hyporesponsiveness to constrictor agents suggesting an increased sensitivity, particularly to U46619. This may explain the poor perfusion and tissue damage in the splanchnic circulation associated with sepsis.
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PMID:Induction by endotoxin of nitric oxide synthase in the rat mesentery: lack of effect on action of vasoconstrictors. 768 6

Both hyperactivity and hypoactivity of neutrophils (PMNs) have been implicated in the pathogenesis of postinjury multiple organ failure. In this paper, the cellular and molecular mechanisms involved in the regulation of PMN O2- production are reviewed. In addition, relevant research laboratory techniques for measuring both intracellular and extracellular O2- release are outlined. In a pilot study PMN O2- release in response to a battery of PMN agonists was determined, and four functional states of the NADPH were defined: resting, primed, activated, and unresponsive. PMNs from normal adult volunteers are in the resting state. In contrast, PMNs from patients with severe torso trauma are primed and activated in the first 24 h postinjury, but, after 48 h, become unresponsive to both receptor-dependent (platelet activating factor and N-formyl-methyl-leucyl-phenylalanine) and receptor-independent (phorbol 12-myristate 13-acetate) activation. The ability to identify at-risk patients and provide a rationale for ameliorating PMN-mediated tissue injury in patients with hyperinflammation syndromes are discussed. In addition, the importance of identifying patients with PMNs that are unresponsive, and the necessity for increasing PMN function in these patients in order to reduce the risk of sepsis, are also discussed.
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PMID:Postinjury neutrophil priming and activation states: therapeutic challenges. 777 93

We examined changes in the enzyme activities and metabolites related to hepatic fatty acid synthesis in fasted rats with sepsis produced by cecal ligation and puncture. Sepsis stimulated the in vivo incorporation of tritiated water into hepatic fatty acids and nonsaponifiable lipids. The activities of acetyl-CoA carboxylase, ATP-citrate lyase, and NADPH-generating enzymes (glucose-6-phosphate dehydrogenase and malic enzyme), the tissue levels of citrate and malonyl-CoA, and the dephosphorylation of carboxylase were increased in the livers of fasted septic rats compared with fasted sham-operated control rats. These results indicate that sepsis stimulated hepatic lipogenesis and sterologenesis in fasting rats. Furthermore, sepsis reduced the specific activity of hepatic mitochondrial carnitine palmitoyltransferase and raised that of glycerophosphate acyltransferase, suggesting an increased diversion of cytosolic acyl-CoA towards esterification. These intrahepatic metabolic changes strongly suggest that sepsis causes anabolic action on hepatic lipid metabolism.
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PMID:Accelerated hepatic lipid synthesis in fasted septic rats. 809 11

During the last decade, a multitude of experimental arguments have led to the concept that EDRF is nitric oxide (NO), a messenger not only involved in the control of vasomotor tone but also in vascular homeostasis, neuronal and immunological functions. Regardless of its origin, endogenous NO is produced through the conversion of L-arginine to L-citrulline by NO-synthase (NOS) from which several isoforms have recently been isolated, purified and cloned. NOS-type I (isolated from brain) and type III (isolated from endothelial cells) are termed "constitutive-NOS" and produce picomolar levels of NO from which only a small fraction elicits physiological responses. These isoforms are regulated by Ca(2+)-calmodulin with NADPH, FAD/FMN and tetrahydrobiopterin as co-factors and reveal a high degree of homology with the amino-acid sequence of cytochrome P450 reductase within the C-terminal domain. Functionally, neuronal-NOS type I is important in neurotransmission (modulation of NMDA receptor), the central control of vascular homeostasis and possibly learning and memory. In the peripheral nervous system, NOS appears to be linked to nonadrenergic noncholinergic (NANC) neuronal pathways. Endothelial-NOS type III is essential for the control of vascular tone in response to the release of endogenous mediators, although shear stress is the major trigger of endothelial-NOS activity under physiological conditions. NOS-type III also contributes to the prevention of abnormal platelet aggregation. NOS-types II and IV (isolated from macrophages) are Ca(2+)-calmodulin independent and are termed "inducible-NOS" since their activation is only promoted under pathophysiological situations where macrophages exert cytotoxic effects in response to cytokines. In contrast with NOS-types I and III, activation of NOS-type II in these cells induces the formation of nanomolar levels of NO which act as a defense mechanism of the immune system. Dysfunctions of the L-arginine-NO pathway have been characterized in multiple diseases (atherosclerosis, hypertension, diabetes, sepsis, cerebral ischemia, etc) and the design of more selective activators/inhibitors of NOS isoforms is a new challenge for the understanding of their pathophysiology and treatment.
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PMID:Nitric oxide: an ubiquitous messenger. 829 80

Our previous studies have shown that rat pulmonary microvascular smooth muscle cells (RPMSMC) upregulate inducible nitric oxide synthase (iNOS) and produce nitric oxide (NO) when treated with interleukin-1 beta (IL-1 beta). We now report that an additional effect of IL-1 beta stimulation in RPMSMC is an increase in production of superoxide (O2-) that results in the formation of peroxynitrite (ONOO-). IL-1 beta produced a rapid (within 1 h) concentration-dependent increase in O2-, as detected by ferricytochrome c reduction and lucigenin-enhanced chemiluminescence. O2- production was sensitive to quinacrine and diphenyliodinium, suggesting that NADH and NADPH oxidoreductases were responsible. After induction of iNOS and production of iNOS-derived NO, ONOO- was detected by luminol-enhanced chemiluminescence and was found to cause lipid peroxidation and to form nitrotyrosine in the cytoskeleton, detected by immunostaining. Cell viability, however, appeared to be unaffected. IL-1 beta-mediated induction of RPMSMC-derived ONOO- may have significant effects on pulmonary vascular function in sepsis and inflammatory states.
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PMID:IL-1 beta stimulates superoxide and delayed peroxynitrite production by pulmonary vascular smooth muscle cells. 899 63

Hydrogen peroxide (H2O2) pretreatment of human neutrophils results in a suppression of the superoxide anion (O2) production in response to surface-acting stimulants such as lipopolysaccharide (LPS) and opsonized zymosan. This effect was not observed when phorbol myristate acetate (PMA), formyl-methionyl-leucyl-phenylalanine (fMLP) or tumor necrosis factor alpha (TNF alpha) were used as a stimuli. Since the response to PMA and other stimuli was unimpaired by preincubation with H2O2, we assume that the H2O2 modulated O2 production is probably due to alteration of the LPS receptor conformation rather than effecting directly NADPH-oxidase. The balance of reactive oxygen species (ROS) produced by neutrophils in the state of sepsis may thus be autoregulated by negative feedback phenomena of locally produced H202.
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PMID:Hydrogen peroxide modulation of the superoxide anion production by stimulated neutrophils. 954 2

Severe muscle wasting is a characteristic feature of sepsis. We have previously established that the rate of protein synthesis in muscles composed of fast-twitch fibers is severely diminished in response to sepsis. The present studies investigate the biochemical reactions responsible for the decreased rate of protein synthesis using gastrocnemius from control and septic rats perfused in situ. Analysis of free ribosomal subunits indicated peptide-chain initiation was impaired by infection. To characterize biochemical reactions in the pathway of peptide-chain initiation affected, the effect of sepsis on the incorporation of initiator [35S]methionyl-tRNA (met-tRNA(imet)) into the 40S initiation complex was examined. Sepsis caused a 65% decrease in the binding of radiolabelled met-tRNA(imet) to the 40S initiation complex compared with controls. The binding of met-tRNA(met) to the 40S ribosome is regulated by eukaryotic initiation factor eIF-2B, whose activity can be modulated in part by the redox state of pyridine dinucleotides. The mean cytoplasmic NADH/NAD+ ratio was increased 2 fold in sepsis, while the NADPH/NADP+ ratio was unchanged. These findings identify the formation of the 40S initiation complex as a defect in the protein synthesis machinery during sepsis. The decreased formation of the 40S initiation complex in muscle could not be explained by changes in the cytoplasmic redox state.
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PMID:Reduced 40S initiation complex formation in skeletal muscle during sepsis. 954 85


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