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)

Interleukin-11 (IL-11), a newly-identified cytokine produced by stromal cells, elevates platelet counts in neonatal rats in vivo and synergizes in vitro with IL-3 in supporting murine megakaryocyte colony formation and stimulating hematopoietic stem cells. Megakaryocytopoiesis is also enhanced by other colony-stimulating factors (CSFs), including IL-3, IL-6, and Steel factor (SLF). Dysregulation of neonatal thrombopoiesis predisposes newborns to develop thrombocytopenia during sepsis, despite increased circulating pools of committed thrombopoietic progenitors in newborn cord blood compared with adult. We previously reported reduced expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte-colony-stimulating factor (G-CSF), and IL-3 from stimulated cord mononuclear cells, but increased expression of SLF in human umbilical vein endothelial cells (HUVEC). Therefore, we hypothesized that IL-3, IL-6, and SLF might modulate megakaryocytopoiesis by inducing IL-11 expression, and newborns might express altered levels of IL-11 mRNA expression during activated conditions, contributing to the difference in circulating colony-forming unit-megakaryocyte (CFU-Meg) cord and adult blood. Phorbol myristate acetate (PMA) induced a twofold greater increase in IL-11 mRNA expression in neonatal fibroblasts (NFb) compared with adult fibroblasts (AFb), and a 3.6-fold greater increase in HUVEC than human adult aorta endothelial cells (HAEC) by Northern blot analysis. PMA also induced a threefold greater increase in IL-11 protein production in NFb than AFb. Physiologic agonists IL-1 alpha, transforming growth factor-beta 1 (TGF-beta 1), and TGF-beta 2 triggered upregulation of IL-11 mRNA expression in both NFb and AFb. However, IL-3, IL-6, PIXY321 (a GM-CSF-IL-3 fusion protein), and SLF failed to upregulate IL-11 mRNA expression from the basal level, while macrophage-colony stimulating factor (M-CSF) mRNA was significantly induced. These data suggest that the hematopoietic effect of IL-6, SLF, and IL-3 on megakaryocytopoiesis is probably not mediated by secondary IL-11 mRNA expression. Similarly, inflammatory agonists IL-1 beta, lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) alone did not upregulate IL-11 expression from the basal level in endothelial cells, whereas intracellular adhesion molecule-1 (ICAM-1) and endothelial leukocyte adhesion molecule-1 were strongly induced. Minimal basal IL-11 expression was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in NFb, AFb, HUVEC and HAEC. The quantitative RT-PCR assay also verified that IL-1 beta and TNF-alpha-stimulated HUVEC and HAEC, and IL-3- and IL-6-stimulated NFb and AFb only expressed minimal levels of IL-11 mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of interleukin-11 protein and mRNA expression in neonatal and adult fibroblasts and endothelial cells. 752 67

The benefits of nitric oxide synthase (NOS) inhibitors in the treatment of endotoxemia or sepsis presumably arise from inhibition of the type II (inducible) NOS. However, inasmuch as the effect of these inhibitors on NOS function in vivo is rarely assessed, NOS activity was evaluated in rats and mice by measuring changes in plasma nitrite and nitrate concentrations ([NOx]) after administration of lipopolysaccharide (LPS). In both species, [NOx] peaked at 20 hr, returning to base line by 48 to 72 hr. The ED50 values (dose that elicited a 50% inhibition of the LPS-dependent increase in [NOx] 6 hr after LPS administration) for L-NG-monomethylarginine acetate, L-NG-nitroarginine methyl ester and aminoguanidine (administered 3 hr after LPS) were 34, 21 and 19 mg/kg in the rat and 32, 5 and 4 mg/kg in the mouse. These compounds also decreased the survival of LPS-challenged animals, which in the case of L-NG-nitroarginine methyl ester was reversed by L-arginine. Dexamethasone (which prevents the induction of type II NOS) also inhibited the LPS-dependent increase in [NOx] with ED50 values of 0.05 mg/kg (rat) and 1 mg/kg (mouse), but did not lead to decreased survival. Thus, inhibition of the type I (neuronal) or type III (endothelial) NOS, rather than the type II isoform, may be a possible mechanism for the animal mortality. These models provide a simple and reproducible means for assessing the in vivo inhibition of type II NOS by various compounds.
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PMID:Lipopolysaccharide-induced changes in plasma nitrite and nitrate concentrations in rats and mice: pharmacological evaluation of nitric oxide synthase inhibitors. 753 50

To investigate the mechanism of sepsis-associated hyperbilirubinemia we have studied hepatocanalicular transport of organic anions in a rat model of endotoxemia. Rats were injected intravenously with lipopolysaccharides (LPS), and at different times after injection, canalicular transport of 2,4-dinitrophenyl-S-glutathione (GS-DNP), as a model organic anion, was measured in perfused livers and isolated hepatocytes. In isolated liver perfusion experiments the initial biliary GS-DNP secretion rate was found to be significantly decreased 18 h after injection with 2 mg/kg LPS. In isolated hepatocytes from these rats, GS-DNP efflux rate was also significantly decreased (193.0 +/- 67 and 448.3 +/- 53 nmol.min-1.g dry wt-1 in endotoxemic and normal hepatocytes, respectively). Inhibition of GS-DNP effluxin isolated endotoxemic hepatocytes was dose dependent and reached a maximum with 0.25 mg/kg LPS. Inhibition was maximal at 12 h after LPS injection. Transport activity gradually returned to normal in 4-5 days after endotoxemia was induced. Dexamethasone pretreatment partially reversed the inhibition of GS-DNP transport in isolated endotoxemic hepatocytes. The phorbol ester phorbol 12-myristate 13-acetate increased GS-DNP efflux by 73 +/- 16 and 24 +/- 8% in endotoxemic and control hepatocytes, respectively, but could not restore the transport activity of endotoxemic hepatocytes to control levels. These results show that canalicular organic anion transport is decreased in the endotoxemic liver; this may play a role in the frequently observed hyperbilirubinemia during sepsis.
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PMID:Impaired hepatocanalicular organic anion transport in endotoxemic rats. 757 54

Tissue factor (TF), a 46-kD glycoprotein receptor for coagulation factors VII and VIIa, is expressed on the surface of endothelial cells in response to a variety of agonists and is thought to play an important role in initiating the thrombosis associated with inflammation during infection, sepsis, and organ transplant rejection. The induction of TF activity by lipopolysaccharide (LPS) is regulated, at least partially, at a transcriptional level and an LPS response element containing two activator protein-1 sites and a nuclear factor-kappa B (NF kappa B)-like site has been localized to the 5' flanking region of the TF gene by transfection studies of TF promoter/reporter gene constructs. We have examined the effect of pyrrolidine dithiocarbamate (PDTC), a specific inhibitor of the NF kappa B pathway on the expression of the endogenous TF gene in human umbilical vein endothelial cells (HUVEC). Preincubation of HUVEC for 60 minutes with PDTC inhibited LPS induction of TF activity on the cell surface in a dose-dependent manner, with 50% inhibition occurring at 10 mumol/L PDTC and 100% inhibition at higher concentrations (> or = 100 mumol/L). Furthermore, PDTC inhibited TF expression in response to tumor necrosis factor-alpha, interleukin-1 beta, and phorbol 12-myristate 13-acetate. The effect of PDTC was at the mRNA level, as seen by the complete abrogation of the large increase in TF mRNA observed in LPS-treated HUVEC. These results suggest that endothelial cell activation by diverse agonists initiates intracellular signaling events that converge upon a common pathway involving NF kappa B and, furthermore, that NF kappa B activation is an obligatory step induction of TF.
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PMID:Pyrrolidine dithiocarbamate abrogates tissue factor (TF) expression by endothelial cells: evidence implicating nuclear factor-kappa B in TF induction by diverse agonists. 760 83

Ninety minutes after i.v. injection of Escherichia coli lipopolysaccharide (LPS) (1 mg/kg) into rats, phorbol 12-myristate 13-acetate (PMA)-stimulated superoxide anion (O2-) secretion was enhanced in suspensions of in vivo LPS-treated alveolar macrophages (AM phi) when compared with saline (SAL)-treated AM phi. The purpose of this investigation was to dissect the in vitro mechanism of PMA-stimulated O2- generation in both LPS and SAL-treated rat AM phi, with a panel of inhibitors of protein kinase C (PKC), protein serine-threonine phosphatase(s) (PSP), protein tyrosine kinase(s) (PTK) and phosphatase(s) (PTP), phospholipase A2 (PLA2), cyclooxygenase (CO) and 5-lipoxygenase (5-LO). The following agents blocked PMA-stimulated O2- generation in both LPS- and SAL-treated AM phi (expressed as percentage of control): 1) PKC inhibitors: staurosporine: 100 nM, 7.0% (LPS) and 5.6% (SAL); sphingosine: 10 microM, 21% (LPS) and 10.5% (SAL); 2) PTK inhibitor: genistein: 100 microM, 44% (LPS) and 31% (SAL); 3) PTP inhibitors: phenylarsine oxide, 10 microM, 12.1% (LPS) and 18% (SAL); diamide, 1000 microM, 10.1% (LPS) and 10.5% (SAL); and 4) PLA2 inhibitors: manoalide: 1 microM, 29.3% (LPS) and 5.2% (SAL); scalaradial: 1 microM, 7.7% (LPS) and 7.1% (SAL); and WAY 125,984: 10 microM, 17.1% (LPS) and 14.5% (SAL). In addition, it was observed that exogenously added arachidonic acid (AA)-stimulated O2- generation in a time- and dose-dependent manner in both LPS and SAL-treated AM phi. The following inhibitors enhanced or did not affect PMA-stimulated O2- generation in LPS- and SAL-treated AM phi (expressed as percentage of of control): 1) PSP inhibitors: okadaic acid: 0.5 microM, 117% (LPS) and 153% (SAL); calyculin A: 1 microM, 112% (LPS) and 101% (SAL); 2) CO and 5-LO inhibitors: indomethacin: 10 microM, 107% (LPS) and 90% (SAL); WY 50, 295: 1 microM, 99% (LPS) and 103% (SAL); and 3) the PTP inhibitor orthovanadate upon prolonged preincubation. In both in vivo LPS- or SAL-primed AM phi, PMA-stimulated O2- generation appears to be modulated by PKC, PLA2, AA, PTK, PTP and PSP. No modulatory role was evident for either CO or 5-LO metabolites. These findings might bear on the design of therapeutic approaches for the modulation of O2- release by AM phi in the early stages of sepsis and adult respiratory distress syndrome.
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PMID:Modulation of superoxide generation in in vivo lipopolysaccharide-primed rat alveolar macrophages by arachidonic acid and inhibitors of protein kinase C, phospholipase A2, protein serine-threonine phosphatase(s), protein tyrosine kinase(s) and phosphatase(s). 761 27

Human Mono Mac 6 cells exhibit characteristics of mature blood monocytes. Treatment of these cells with human recombinant human tumor necrosis factor (TNF) resulted in an increase in phagocytosis and phorbol myristate acetate-stimulated superoxide anion production at 12 h and growth retardation occurring at 24 h. Moreover, TNF induced a moderate increase of CD14 surface antigen expression, used as a phenotypic marker of monocyte/macrophage differentiation. Platelet-activating factor (PAF) stimulated a rapid rise in cytosolic free Ca++ ([Ca++]i) of 308 +/- 93 nM in TNF-treated cells compared to untreated cells (33 +/- 8 nM, n = 4). The effect of TNF was dose and time dependent, evident after 12 h and maximal at 48 h. The enhanced PAF-induced [Ca++]i rise was inhibited by the PAF receptor antagonist L-659,989 and EGTA, indicating receptor-dependent Ca++ influx. Furthermore, L-659,989 and PAF inhibited specific 3H-labeled PAF binding in TNF-treated, but not in untreated cells. Consistently, PAF stimulated arachidonic acid release only in TNF-treated cells. Preincubation of cells with anti-TNF monoclonal antibodies abolished TNF-induced effects, but failed to block lipopolysaccharide (LPS) effects. Distinct mechanisms of action by LPS were reflected by the different ability to induce surface antigen expression. In conclusion, the enhancement of PAF responses by TNF, associated with functional characteristics of differentiation in Mono Mac 6 cells, may represent a specific mechanism of cooperative interaction between PAF and TNF in inflammation, sepsis, immunoregulation and atherogenesis.
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PMID:Tumor necrosis factor induces enhanced responses to platelet-activating factor and differentiation in human monocytic Mono Mac 6 cells. 768 99

The purpose of this study was to develop a bedside assay based on the in vitro glycolysis of a whole blood sample that could detect primed neutrophils (PMNs). A mathematical index of the PMN response to exogenous stimulation with phorbol myristate 13-acetate (PMA), called the Delta value, was derived by comparing the increase in glycolysis for paired blood samples with and without PMA to that expected from normal subjects. Delta values for systemic inflammatory response syndrome/sepsis patients (9.09 +/- 7.61) (N = 36) were significantly higher than normal controls (2.02 +/- 1.76) (N = 51), nonsepsis ICU patients (3.81 +/- 2.80) (N = 14) and patients in septic shock (2.33 +/- 3.04) (N = 10) (p < .05). Delta values were consistently reflected in parallel measurements of increased reactive oxygen species production by neutrophils detected cytofluorometrically. PMN priming can be simply and rapidly detected by an assay based on the numbers of PMNs and erythrocytes and the measured rates of in vitro glycolysis of paired whole blood samples with and without PMA.
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PMID:In vitro glycolysis of whole blood can detect primed neutrophils in septic ICU patients. 774 43

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

Endotoxin-induced cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF) are thought to contribute to the proinflammatory effects of endotoxin in gram-negative infections. Using a conscious rat model of sepsis, induced by intravenous challenge with LD95 doses of endotoxin (n = 24) or live Escherichia coli (E. coli) (n = 24), we examined frozen sections of kidney at various intervals for evidence of IL-1 alpha and TNF alpha expression. A transient glomerular endothelial IL-1 alpha expression was demonstrated at 30 and 90 min after initiation of the sepsis in both endotoxin and E. coli-treated animals using immunohistochemistry. The endothelial IL-1 alpha expression as determined by immunohistochemistry occurred at the same time as IL-1 alpha mRNA expression, as determined by Northern blot analysis. The glomerular endothelial IL-1 alpha expression coincided with a slight but significant increase in the number of the glomerular polymorphonuclear leukocytes as identified by naphthol AS-D chloroacetate esterase enzyme histochemical reaction. Glomerular endothelial IL-1 alpha expression was virtually absent by 180 and 360 min. No TNF alpha expression was detected in the renal tissues at any time interval. Neither alpha-naphthyl acetate esterase-positive nor acid phosphatase-positive monocytes/macrophages were identified in the glomeruli. Our findings provide direct in vivo evidence that the IL-1 alpha gene product is expressed locally in the kidney by glomerular endothelial cells in this septic rat model.
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PMID:Renal interleukin-1 expression during endotoxemia and gram-negative septicemia in conscious rats. 785 Sep 31

The present study was undertaken to determine if measurement and analysis of phagocyte function are useful for diagnosis and staging of infection. Circulating phagocyte activity was measured in healthy volunteers and sequentially in patients with acute infections of different types and severity, including those with diabetes mellitus or human immunodeficiency virus (HIV) infection. Using an automated luminescence system, these phagocyte functions were measured in whole blood: basal and phorbol 12-myristate 13-acetate (PMA)-stimulated oxidase activity, basal and PMA-stimulated simple dioxygenation (e.g., oxidase-driven haloperoxidase activity), and circulating and primed opsonin receptor-dependent dioxygenation. Multiple discriminant analysis of these data showed significant differences between healthy controls, diabetic patients, HIV-positive subjects, and patients with pneumonia or sepsis syndromes. Longitudinally, circulating phagocyte function correlated with clinical condition, severity of infection, and outcome. This methodology provides rapid, objective, and sensitive diagnostic and monitoring information for patients with infections.
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PMID:Analysis of circulating phagocyte activity measured by whole blood luminescence: correlations with clinical status. 799 86


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