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)

TNF is produced by monocytes/macrophages in response to endotoxin, which may lead to septic shock. TNF stimulates neutrophil adherence, degranulation, and superoxide production, but inhibits neutrophil migration. A mitigating anti-inflammatory effect can be experimentally induced in septic shock by TNF blockers, such as pentoxifylline, and is also suggested for treatment with hrG-CSF. With regard to the combination of pentoxifylline and hrG-CSF, the purpose of this investigation was to explore whether and in what way the effects of hrG-CSF and pentoxifylline interact with each other in neutrophils. To this end, we studied the effects of pentoxifylline on TNF- and G-CSF-induced modulation of neutrophil chemotaxis and O2 release. TNF and G-CSF decreased directed migration of neutrophils to FMLP or IL-8. High-dose pentoxifylline (1 mM) was able to counteract the effect of TNF but not that of G-CSF on neutrophil migration. In the presence of pentoxifylline, TNF and G-CSF were unable to stimulate respiratory burst. In contrast, pre-exposure of cells to pentoxifylline followed by washing increased the priming effect of TNF or hrG-CSF on neutrophil respiratory burst activity. The methylxanthine derivative by itself showed no effect on spontaneous and fMLP-stimulated O2 release by neutrophils. Stimulation of neutrophil respiratory burst by pentoxifylline may not be detectable in the presence of pentoxifylline due to its known oxygen-radical scavenging function. Results suggest that by blocking the inflammatory action of TNF on neutrophils, pentoxifylline may diminish endothelial cell damage caused by inhibited neutrophil chemotaxis. On the other hand, since transiently present pentoxifylline may enhance the respiratory burst activity of TNF- or hrG-CSF-primed neutrophils, concomitant administration of pentoxifylline and hrG-CSF to patients with SIRS/sepsis might diminish beneficial effects of the latter and additional deleterious effects might occur.
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PMID:Pentoxifylline differentially regulates migration and respiratory burst activity of the neutrophil. 970 61

Neutrophils (polymorphonuclear neutrophils; PMN) and a redundant system of chemotactic cytokines (chemokines) have been implicated in the pathogenesis of the acute respiratory distress syndrome in patients with sepsis. PMN express two cell surface receptors for the CXC chemokines, CXCR1 and CXCR2. We investigated the expression and function of these receptors in patients with severe sepsis. Compared with normal donors, CXCR2 surface expression was down-regulated by 50% on PMN from septic patients (p < 0.005), while CXCR1 expression persisted. In vitro migratory responses to the CXCR1 ligand, IL-8, were similar in PMN from septic patients and normal donors. By contrast, the migratory response to the CXCR2 ligands, epithelial cell-derived neutrophil activator (ENA-78) and the growth-related oncogene proteins, was markedly suppressed in PMN from septic patients (p < 0.05). Ab specific for CXCR1 blocked in vitro migration of PMN from septic patients to IL-8 (p < 0.05), but not to FMLP. Thus, functionally significant down-regulation of CXCR2 occurs on PMN in septic patients. We conclude that in a complex milieu of multiple CXC chemokines, CXCR1 functions as the single dominant CXC chemokine receptor in patients with sepsis. These observations offer a potential strategy for attenuating adverse inflammation in sepsis while preserving host defenses mediated by bacteria-derived peptides such as FMLP.
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PMID:Expression and function of the chemokine receptors CXCR1 and CXCR2 in sepsis. 997 13

Polymorphonuclear neutrophil (PMNL) activation enhances microbial clearance but also contributes to the vascular damage and multiorgan failure associated with severe meningococcal sepsis. By use of a whole blood model of meningococcal bacteremia, loss of PMNL L-selectin and up-regulation of CD11b was observed in response to Neisseria meningitidis serogroups B and C, which is followed by opsonophagocytosis. PMNL priming with either Escherichia coli lipopolysaccharide (LPS) or FMLP prior to meningococcal challenge resulted in enhancement of both PMNL L-selectin shedding (1.5- to 4-fold) and phagocytosis (2- to 3-fold). Blockade of meningococcal LPS lipid A with recombinant bactericidal/permeability-increasing protein (rBPI21) resulted in partial inhibition of the PMNL activation and phagocytosis response to N. meningitidis. The effect of rBPI21 was reversed by excess E. coli LPS or FMLP. It is proposed that PMNL priming by N. meningitidis results in an exaggerated activation and phagocytosis response to the organism.
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PMID:Neutrophil response to Neisseria meningitidis: inhibition of adhesion molecule expression and phagocytosis by recombinant bactericidal/permeability-increasing protein (rBPI21). 1019 Dec 39

Infectious complications are still a major cause of morbidity and mortality after organ transplantation, and early therapy would certainly reduce the risk associated with severe infections. We therefore investigated the significance of polymorphonuclear leukocyte (PMN) functional tests as predictive markers for infection in transplant patients under immunosuppressive therapy in a longitudinal study. In 41 patients, blood PMN migration and reactive oxygen species release, the blood levels of PMN elastase, malondialdehyde, neopterin, sICAM-1 and sVCAM-1, and urine neopterine were measured in 3- and 4-day intervals after liver-, kidney-, kidney-pancreas-, and heart and lung transplantation. PMN migration was determined in whole blood and estimated by the amount of PMNs to penetrate into a membrane filter upon FMLP stimulation. Three groups of patients were formed according to their postoperative course. Group I patients (n = 23) had no or only minor local infection, group II patients (n = 11) had infections with distinct systemic involvement, and group III patients (n = 7) developed sepsis. A first elastase-level of over 100 mg/L after surgery, followed by a drop in the amount of blood PMNs ready to migrate, on FMLP stimulation, to below 12 %, turned out to be a marker for impending infection, whereas all other parameters tested were not predictive. In six of seven group III patients, this marker became positive (sensitivity 85.7 %) up to 15 days before clinical manifestation of sepsis. In group I (largely uneventful recovery) only one of 23 patients was positive (specificity 95.6 % ), whereas group II patients were in between (4 of 11 positive). By this method it seems possible to diagnose severe infections in the pre-clinical phase, which may help prevent them if treatment is begun promptly.
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PMID:Polymorphonuclear leukocyte functions as predictive markers for infections after organ transplantation. 1083 47

Early postoperative infections and septic complications are predominant causes of morbidity and mortality in patients following orthotopic liver transplantation (OLTx). Prophylactic granulocyte colony-stimulating factor (G-CSF) administration after OLTx was found to decrease the number of sepsis episodes and sepsis-related mortality. Since polymorphonuclear neutrophils (PMNs) are one of the major determinants of antimicrobial defense, alteration of their functions may influence the development of sepsis in these patients. Therefore, we investigated in vitro whether or not priming with G-CSF affects the neutrophils' respiratory burst (RB) in immunosuppressed liver-transplanted patients. Venous blood was drawn from liver allograft recipients (n=12) between the 5th and 15th day postoperatively. Patients without clinical signs of infection or rejection were included in this study. Leukocytes were obtained as supernatant following sedimentation and incubated with 1000 IE ml-1 G-CSF. The RB was measured by the intracellular oxidation of non-fluorescent dihydrorhodamine to the fluorescent rhodamine by flow cytometry. The results were expressed as a percentage of increasing stimulation compared to the control responses, which are made up of the percentage of cells with RB reaction after stimulation with phorbol ester (PMA), bacteria (E. coli), or the combination of a cytokine (TNF-alpha) and a bacterial peptide (FMLP) in the absence of G-CSF. In vitro priming with G-CSF resulted in significantly increased activity of the RB after PMA (from 71.7% to 85.6%) and TNF-alpha/FMLP (from 58.4% to 72.7%) stimulation. These data demonstrate that G-CSF in vitro augments the RB of PMNs, thereby suggesting a possible therapeutic role for G-CSF as immunomodulating agent during bacterial and fungal infections following OLTx.
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PMID:Neutrophil respiratory burst following liver transplantation: in vitro effects of granulocyte colony-stimulating factor. 1142 85

Upon activation, polymorphonuclear leucocytes (PMN) release bactericidal/permeability-increasing protein, (BPI) from their azurophil granules. BPI selectively binds to the lipopolysaccharide (LPS) on gram-negative bacteria and induces their death. This study examined plasma BPI concentration levels in healthy newborns and in newborns with clinical sepsis, and the ability of PMN from preterm and term infants to release BPI. We also studied the release of myeloperoxidase (MPO), and the surface expression of adhesion molecule CD11b on PMN. In infants with clinical sepsis, plasma BPI concentration was higher, 27.8 microg/L [8.6-883; median (range)] (n = 11), than in healthy term infants 8.9 microg/L (3.9-179) (n = 17), and in adults 7.3 microg/L (0.7 -18.4) (n = 15); p = 0.014, Kruskal-Wallis. In preterm infants (n = 8), the ability of PMN to release BPI in vitro after stimulation with PMA was 8.8, in term infants it was 15.9 (n = 29; p > 0.05 vs. preterm infants) and in adults 23.4 ng/10(6) PMN (n = 15; p = 0.024 and p > 0.05 vs. preterm and term infants, respectively). The corresponding values of MPO were 20.0 ng/10(6) (11.3-46.7) in preterms, 19.0 ng/10(6) (2.2-223.7) in terms, and 27.8 ng/10(6) (9.1-80.7) in adults; p = 0.67 between groups. In infants with clinical sepsis, CD11b level was higher, 292 RFU (234-403) than the basal CD11b expression levels in healthy newborn infants, 116 RFU (76-145); P = 0.0001. FMLP-stimulated PMN CD11b expressions in preterm cord blood, 1071 RFU (552-1286) and in term cord blood, 918 (567-1472) were on the same level, but lower than that in adult blood, 1592 (973-1946); p < 0.001, ANOVA. Our findings suggest that in preterm infants the ability to release BPI is lower than in adults and term infants. These findings suggest that premature neonates have an impaired ability to mobilize BPI, possibly contributing to their marked susceptibility to infections with Gram-negative bacteria.
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PMID:Extracellular release of bactericidal/permeability-increasing protein in newborn infants. 1203 58

Early studies have demonstrated that the unique phenomenon ATP aerobic synthesis on neutrophilic plasma membranes is observed when neutrophils are activated with the chemoattractive peptide FMLP. This paper presents the results of the study of a possible association of ATP plasma membranous synthesis with priming, with the occurrence of respiratory explosion and apoptosis of the neutrophils isolated from the blood of donors and patients with surgical infection of different severity. The interaction of neutrophilic plasma membranes with FMLP and with hTNF (was attended by ATP synthesis. Examining the level of FMLP-stimulated production of superoxide in patients with surgical infection revealed that the amount of the superoxide produced by neutrophils noticeably decreased and droppped by more than 5 times in sepsis. The FMLP-stimulated plasma membranous synthesis of ATP was determined in the same patients. A decrease in the production of superoxide was simultaneously accompanied by a reduction in the plasma membranous synthesis of ATP. Both the plasma membranous synthesis of ATP and the production of superoxide declined in sepsis at the most. The neutrophils isolated from peripheral blood of the same patients showed DNA damage whose degree was directly related to the condition of a patient. The maximum DNA damages were observed in sepsis. The findings suggest that apoptosis is induced in surgical infection in the peripheral neutrophils. The DNA damage and the FMLP-stimulated plasma membranous synthesis of ATP was estimated in the neutrophils isolated from the inflammation focus. It turned out that in local surgical infection, there were the maximum DNA damages and the FMLP-stimulated plasma membranous synthesis of ATP was lower than that in the peripheral neutrophils. It can be suggested that the FMLP-stimulated plasma membranous synthesis of ATP may be a regulators of neutrophilic functional states in surgical infection and sepsis.
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PMID:[Neutrophilic respiratory response in surgical infection and an association with plasma membranous synthesis of ATP]. 1221 72

We evaluated neutrophil activation by measuring its phagocytic ability and oxidative burst activity in 16 patients with sepsis and 16 healthy volunteers. We also focused on neutrophil apoptosis as a regulatory mechanism of the inflammatory response. Neutrophil phagocytosis was evaluated by the detection of propidium iodide (PI)-labeled Staphylococcus aureus added to whole blood. Reactive oxygen species (ROS) formation was quantified by measuring the oxidation of 2',7' dichlorofluorescein diacetate (DCFH-DA) at baseline and after cell stimulation with phorbol myristate acetate (PMA), and bacterial cells (killed S. aureus) or products (lipopolysaccharide [LPS] and N-formyl-methionyl-leucyl-phenylalanine [FMLP]). Apoptosis was assessed in neutrophils stained with annexin V and PI. Neutrophil phagocytic ability was increased in patients with sepsis compared with healthy controls (median geometric mean fluorescence intensity [GMFI] was 101.9 and 54.7, respectively; P = 0.05). ROS formation was enhanced in patients with sepsis compared with healthy volunteers at baseline (median GMFI 275.6 and 52.1, respectively; P < 0.001), and after stimulation with S. aureus (median GMFI 2395.8 and 454.9, respectively; P < 0.001), PMA (median GMFI 1120.6 and 307.5, respectively; P = 0.003), FMLP (median GMFI 792.4 and 123.2, respectively; P < 0.001), and LPS (median GMFI 624.8 and 144.8, respectively; P < 0.001). Early neutrophil apoptosis was increased in patients with sepsis compared with healthy volunteers (median 11.3% and 9.1%, respectively; P = 0.03). These data demonstrate that neutrophil function is enhanced in patients with sepsis. Additionally, circulating neutrophils from patients with sepsis presented with increased early apoptosis, which may be consequence of a regulatory mechanism of the inflammatory response.
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PMID:Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. 1292 90

Sepsis-induced acute lung injury is characterized by activation and injury of pulmonary microvascular endothelial cells (PMVEC), increased neutrophil-PMVEC adhesion and migration, and trans-PMVEC high-protein edema. Inducible NO synthase (iNOS) inhibits septic murine neutrophil migration in vivo and in vitro. The effects of NO in human neutrophil-PMVEC interactions are not known. We isolated human PMVEC using magnetic bead-bound anti-PECAM antibody. Confluent PMVEC at passage 3-4 were co-cultured with human neutrophils for assessment of neutrophil-PMVEC adhesion, and trans-PMVEC neutrophil migration and Evans-Blue dye-labeled albumin leak. Two NO donors (spermine-NONOate, S-nitroso-N-acetylpenicillamine) attenuated both cytomix-enhanced neutrophil-PMVEC adhesion by 64+/-14% (p<0.01) and 32+/-3% (p<0.05), respectively, and cytomix-induced trans-PMVEC neutrophil migration by 85+/-16% (p<0.01) and 43+/-5% (p<0.01), respectively. Correspondingly, iNOS inhibition with 1400W enhanced cytomix-stimulated neutrophil migration by 52+/-3% (p<0.01), but had no effect on neutrophil-PMVEC adhesion. Conversely, a peroxynitrite donor (SIN-1) increased both neutrophil-PMVEC adhesion (38+/-2% vs. 14+/-1% control, p<0.01) and trans-PMVEC neutrophil migration; with both effects were completely inhibited by scavenging of NO, superoxide, or peroxynitrite (p<0.05 for each). Scavenging of peroxynitrite also eliminated cytomix-induced neutrophil adhesion and migration. Blocking CD18-dependent neutrophil adhesion prevented cytomix-stimulated trans-PMVEC EB-albumin leak (p<0.05), while inhibiting neutrophil migration paradoxically enhanced cytomix-stimulated EB-albumin leak (11+/-1% vs. 7+/-0.5%, p<0.01). FMLP-induced neutrophil migration had no effect on trans-PMVEC EB-albumin leak. In summary, we report differential effects, including the inhibitory action of NO and stimulatory effect of ONOO(-) on human neutrophil-PMVEC adhesion and trans-PMVEC migration under cytomix stimulation. Moreover, neutrophil-PMVEC adhesion, but not trans-PMVEC migration, contributes to human PMVEC barrier dysfunction.
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PMID:Human neutrophil-pulmonary microvascular endothelial cell interactions in vitro: differential effects of nitric oxide vs. peroxynitrite. 1861 52


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