Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
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.
 ...
PMID:Analysis of circulating phagocyte activity measured by whole blood luminescence: correlations with clinical status. 799 86

A new method for ascites recirculation, consisting of a cellulose diacetate filter to remove substances with molecular weight > or = 300,000, cell debris and bacteria, followed by the concentration of ascitic fluid prior to i.v. infusion, was used 24 times in 19 patients with cirrhosis and massive or refractory ascites. The amount of ascites removed was 7.67 +/- 0.49 l, which was reduced to 407 +/- 37 ml. The procedure took 367 +/- 22 min to complete. No statistically significant changes in liver function tests, coagulative parameters, platelet count or natremia were found. The activity of coagulation and fibrinolytic systems was further assessed in six patients. No changes suggesting an activation of intravascular coagulation and/or primary fibrinolysis were disclosed. An asymptomatic fall in mean arterial pressure (from 88.6 +/- 2.6 to 80.3 +/- 3.0 mmHg; p = 0.02) occurred after paracentesis and was still present 48 h after ascites reinfusion. Plasma renin activity significantly decreased at the end of the procedure, but was not associated with a proportional reduction of plasma aldosterone concentrations. Both variables returned to baseline values 48 h later. A significant increase in the glomerular filtration rate occurred just after the end of the procedure (from 50.4 +/- 9.1 to 73.1 +/- 23.5 ml/min; p < 0.05) and subsided 48 h later. In contrast, no significant changes in diuresis and renal sodium excretion were found. Complications due to volume overload and sepsis did not occur; in one case, spontaneous bacterial peritonitis developed 3 days after the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Ascites apheresis, concentration and reinfusion for the treatment of massive or refractory ascites in cirrhosis. 800 9

A recombinant endotoxin-neutralizing protein (ENP) from Limulus polyphemus and a monoclonal IgM anti-lipid A antibody (HA-1A) were compared in a rat model of Escherichia coli sepsis. One hour after intraperitoneal challenge with 10(6) cfu of E. coli O18ac K1, animals were sensitized to endotoxin with lead acetate and treated with ENP, HA-1A, or saline, followed by ceftriaxone and gentamicin. Before treatment, 95% of rats had high-grade bacteremia and high serum endotoxin concentrations, which were similar in all treatment groups (P > .60). One hour after treatment, there was no bacterial growth in any blood sample, and endotoxin concentrations were significantly lower in the ENP group than in the HA-1A and saline groups (P < .01). At 24 h after challenge, survival in the ENP group was significantly higher than in the HA-1A saline group (P < .001). ENP improved survival in a rat model of E. coli sepsis with high mortality despite effective antibiotic therapy.
 ...
PMID:Comparison of a recombinant endotoxin-neutralizing protein with a human monoclonal antibody to endotoxin for the treatment of Escherichia coli sepsis in rats. 807 21

Interleukin-8 (IL-8), a neutrophil chemoattractant and activating cytokine, has been implicated as a proinflammatory mediator in gram-negative sepsis. In vitro data support the notion of IL-8 as an endothelial adherence inhibitor. To evaluate this issue, we infused six volunteers with reference endotoxin and measured plasma levels of IL-8, neutrophil tumor necrosis factor alpha (TNF-alpha) receptors, TNF-alpha-induced adherence to fibronectin, and neutrophil chemotaxis to IL-8 and other attractants. We found that, at 3 h postinfusion, IL-8 but not TNF-alpha plasma levels were elevated. Neutrophils had shed L-selectin (mean channel fluorescence decrease, 79 +/- 9 to 49 +/- 7; P = 0.0625) and TNF-alpha receptors (decrease in number of receptors per cell, 1,596 +/- 340 to 574 +/- 93; P = 0.004). Cells were chemotactically desensitized to IL-8. TNF-alpha-induced adherence to fibronectin was suppressed from 69% +/- 5% of the phorbol myristate acetate response to 38% +/- 7% (P = 0.0154). These findings support the notion that release of IL-8 into the vascular space may be an in vivo mechanism for suppression of neutrophil accumulation at extravascular sites. L-Selectin loss would reduce the ability of neutrophils to adhere to activated endothelial cells. The specific loss of migratory response to IL-8 would impair neutrophil delivery to areas where IL-8 was the predominant chemoattractant. Loss of TNF-alpha-induced adherence to fibronectin would blunt those responses, including production of oxidants, capacitated by adherence.
 ...
PMID:Alterations of neutrophil responses to tumor necrosis factor alpha and interleukin-8 following human endotoxemia. 811 67

Activation of neutrophils by various inflammatory stimuli has been shown to play a pivotal role in septic and posttraumatic tissue injury. To further elucidate the mechanisms modulating the oxidative metabolism, we assessed superoxide production induced by N-formylmethionyl-leucyl-phenylalanine (FMLP) and phorbol myristate acetate and the expression of FMLP receptors of human neutrophils on several days during sepsis and after trauma. Neutrophils of septic patients isolated on days 0-4 after the diagnosis of sepsis showed a significant, more than twofold increase in specific binding of [3H]FMLP at 1, 120, and 240 nM. Scatchard plot analyses revealed that this increase in specific binding was due to an increase in the number of low- and high-affinity FMLP receptors with no changes in receptor affinity. On days 5-10 after the onset of sepsis the up-regulation of FMLP receptors on circulating neutrophils was followed by receptor down-regulation. Likewise, neutrophils from patients with trauma that was not complicated by sepsis bound significantly more [3H]FMLP than neutrophils from volunteers. However, the increase in FMLP receptors was less than that in septic neutrophils and returned earlier to normal. In accordance with the up-regulation of FMLP receptors, neutrophils obtained from patients with sepsis or after trauma on days 1-4 and days 1-2, respectively, produced significantly more superoxide anion upon stimulation with FMLP. However, after stimulation with phorbol myristate acetate, a receptor-independent activator of protein kinase C, these cells released less superoxide anion than controls.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Increased fMet-Leu-Phe receptor expression and altered superoxide production of neutrophil granulocytes in septic and posttraumatic patients. 813 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>