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)

Systemic kinetics of three inflammatory mediators (bactericidal/permeability-increasing protein [BPI], soluble intercellular adhesion molecule [sICAM], and soluble E-selectin [sE-selectin]) were studied during the development of ventilator-associated pneumonia (VAP) (n = 42), diagnosed on quantitative cultures of bronchoscopic samples. From a pool of collected samples, nested samples were used to measure mediators on Days -4, -2, 0, and +2, relative to diagnosis. Correlations between systemic levels of mediators and clinical severity of infection (VAP with or without severe sepsis or septic shock) and patient outcome (mortality at Day 10 after diagnosis) were studied. Predictive values of inflammatory mediators were compared with daily Simplified Acute Physiology Score II (SAPS II) values and the logarithmic number of bacteria in bronchoscopic samples. During the development of VAP, increasing SAPS II scores and rising systemic mediator levels were only found in patients in whom VAP was accompanied with severe sepsis or septic shock. Values of SAPS II and plasma levels of BPI and sE-selectin, but not sICAM, increased from the day of diagnosis on in patients who died within 10 d of diagnosis. Systemic levels of inflammatory mediators did not better predict clinical severity or patient outcome than daily SAPS II scores. The logarithmic number of bacteria in bronchoscopic samples poorly correlated with circulating levels of inflammatory mediators, severity of infection, and patient outcome. Our findings show that a clinical scoring system (SAPS II score) is at least as good as a predictor for the clinical severity of infection and patient outcome, and provide new information on the kinetics of inflammatory mediators during the development of VAP.
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PMID:Prediction of clinical severity and outcome of ventilator-associated pneumonia. Comparison of simplified acute physiology score with systemic inflammatory mediators. 976 55

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

The activation of phagocytes by lipopolysaccharide (LPS) has been implicated in the pathogenesis of Gram-negative sepsis. Although the interaction between CD14 and LPS is a key event in the signaling cascade, the molecular mechanism by which cellular activation occurs remains obscure. We hypothesized that the main function of CD14 was to bind LPS and transfer it to a second receptor, which then initiates the subsequent signal for cellular activation. Thus, surface binding of LPS to the cell membrane would be the critical step that CD14 carries out. To test this hypothesis, we examined the activity of two other proteins known to bind LPS, lipopolysaccharide-binding protein and bactericidal/permeability-increasing protein. We found that when these normally soluble proteins were expressed in Chinese hamster ovary-K1 fibroblasts as glycosylphosphatidylinositol-anchored proteins, both could substitute for CD14 in initiating LPS signaling. Pharmacological studies with synthetic lipid A analogues demonstrated that these surface expressed LPS-binding proteins had characteristics that were qualitatively identical to membrane CD14. These data support the hypothesis that a receptor distinct from CD14 functions as the actual signal transducer and suggest that surface binding of LPS to the cell membrane is the crucial first step for initiating downstream signaling events.
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PMID:Membrane expression of soluble endotoxin-binding proteins permits lipopolysaccharide signaling in Chinese hamster ovary fibroblasts independently of CD14. 1031 11

Lipopolysaccharide (LPS) is the major mediator of gram-negative septic shock. Molecules that bind LPS and neutralize its toxic effects could have important clinical applications. We showed that serum amyloid P component (SAP) neutralizes LPS. A SAP-derived peptide, consisting of amino acids 27 to 39, inhibited LPS-mediated effects in the presence of human blood. In this study, we used a pepscan of overlapping 15-mer peptides and distinguished two additional LPS-binding regions within the SAP molecule, identified in the regions spanning amino acids 61 to 75 and 186 to 200. The corresponding SAP-derived peptides, pep61-75 and pep186-200, inhibited the binding of fluorescein isothiocyanate-labeled LPS to monocytes as efficiently as a bactericidal/permeability-increasing protein (BPI)-derived 15-mer peptide comprising amino acids 85 to 99. The same SAP-derived peptides very potently inhibited LPS-induced priming of phagocytes in human blood. Also, SAP-derived pep186-200 caused a prolonged survival of actinomycin D-sensitized mice treated with LPS to induce septic shock, indicating a potential use of this peptide in the defense against serious gram-negative sepsis in humans.
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PMID:Lipopolysaccharide (LPS)-binding synthetic peptides derived from serum amyloid P component neutralize LPS. 1033 82

Lower limb ischemia-reperfusion injury (IRI) is associated with increased gut permeability to endotoxin, which not only directly damages enterocytes but also stimulates a systemic inflammatory response syndrome (SIRS), compounding gut injury. Recombinant bactericidal/permeability-increasing protein (rBPI21) is a novel anti-endotoxin therapy with proven benefit in sepsis. Its potential role in modulating remote gut injury in hind limb IRI was studied. Male Wistar rats were chosen for a prospective randomized control trial (n = 10 per group). The control group and two groups undergoing 3 hr bilateral hind limb ischemia with 2 hr reperfusion (I/R) were randomized to receive intravenously either control protein thaumatin at 2 mg/kg or rBPI21 at 2 mg/kg, respectively. Quantitative morphometric assessment of the small bowel was used as a measure of gut injury and, using an ex vivo everted gut sac model, translocation of 14C-labeled polyethylene glycol (PEG) was used as a measure of gut permeability. Our results indicate that hind limb IRI is associated with remote gut mucosal injury and increased permeability to macromolecules. rBPI21 anti-endotoxin therapy modulates remote gut injury associated with lower limb IRI in this model.
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PMID:Gut mucosal injury is attenuated by recombinant bactericidal/permeability-increasing protein in hind limb ischemia-reperfusion injury. 1141 83

OBJECTIVE: To investigate the effect and mechanism of bactericidal/permeability-increasing protein (BPI) on sepsis induced by intra-abdominal infection in rats. METHODS: Cecal ligation and puncture (CLP) was made on 20 rats with sepsis induced by intra-abdominal infection. BPI or equal volume of physiological saline (PS) was intra-abdominally given immediately and 12 h after CLP, respectively (2.5 mg/kg of BPI each time). Plasma endotoxin levels were determined with limulus amebocyte chromogenic assay. RESULTS: (1) The survival time in BPI group was significantly higher than that in PS group. (2) The values of the mean arterial pressure (MAP), the left ventricular systolic pressure (LVSP), the isovolumic ventricular pressure (IP), and the maximal change of left intraventricular pressure (+/-dp/dtmax) in BPI group, although decreasing, were markedly higher than those in PS group. (3) Plasma glutamic-pyruvic transaminase (GPT) and urea nitrogen levels in BPI group, though increasing, were obviously lower than those in PS group. (4) There was no significant change of plasma endotoxin levels in BPI group, while plasma endotoxin levels markedly increased in PS group. CONCLUSIONS: BPI has obvious protective effect on sepsis induced by intra-abdominal infection, which might be related to its neutralization of endotoxin.
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PMID:Effect of bactericidal/permeability-increasing protein on sepsis induced by intra-abdominal infection in rats. 1190 Jun 62

OBJECTIVE: To investigate the effect of bactericidal/permeability-increasing protein(BPI) on the outcome of sepsis in mice and its possible mechanism. METHODS: Sepsis was induced by injection of 2x10(6) colony-formed unit E. coli J5 via the tail vein. BPI of 5 mg/kg or equal volume of normal saline(NS) were injected intravenously at the same time. Endotoxin and TNFalpha levels in serum were assayed using a chromogenic limulus amebocyte lysate test and ELISA respectively. RESULTS: Seventy-two hour survival rate of septic mice was significantly higher in the BPI group (15/18) than in the NS group(8/18, P<0.01). Serum endotoxin levels in the BPI group (1.3+/-0.3 and 0.7+/-0.4 &mgr;g/L) were significantly lower than those in the NS group (3.9+/-0.8 and 2.5+/-0.9 &mgr; g/L, P<0.01) 0.5 and 1 hour following injection of bacteria respectively. The peak levels of serum tumor necrosis factor-alpha(TNFalpha)in the BPI group (1.9+/-0.6 &mgr;g/L) were also markedly lower than those in the NS group (3.8+/-0.8 &mgr;g/L, P<0.01) 1.5 hours following bacterial injection. But there was no significant difference in blood bacterial count between the BPI and NS groups 0.5, 1.5 and 3.0 hours after injection of bacteria. CONCLUSIONS: BPI has a marked protective effect on E. coli sepsis, which might be related to its action against bacterial endotoxin and its inhibition of TNFalpha production in sepsis.
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PMID:Protective effect of bactericidal/permeability-increasing protein in mice with E. coli sepsis. 1190 55

Sepsis is an important cause of pediatric morbidity and mortality. Improving the outcome of pediatric sepsis requires diverse efforts, including prevention, early recognition, improvements in early management and transport, and physiology-directed care. Awareness that septic shock represents a pathophysiologic host response to infection has prompted investigation of immune mediators and coagulation factors as potential targets for anti-sepsis therapies. Advancements thus far include: the potential prevention of neonatal sepsis with granulocyte colony-stimulating factor; recognition of clindamycin as a potential inhibitor of endotoxin release; improved outcome from meningococcal disease in children treated with bactericidal/permeability-increasing protein (rBPI21); and improved outcome from sepsis in premature infants treated with pentoxifylline. Further randomized controlled studies of immunomodulatory agents are indicated and a few are in progress. Current studies on genetic propensities in cytokine and coagulation protein expression may explain variability in patient outcomes and eventually lead to genomics-based therapeutics.
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PMID:Improving the outcome of septic shock in children. 1196 95

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

Both large burns and severe gram-negative sepsis are associated with acute myocardial contractile dysfunction. Because others have reported that burn injury may be followed by transient endotoxemia, we hypothesized that bacterial endotoxin induces contractile impairment after burn trauma. We tested this hypothesis in two rodent models. In each model, postburn myocardial contractility was assessed using Langendorff preparations of excised hearts. In the first model, mice expressing either a mutant form of or no Toll-like receptor 4 (TLR4), a critical element of the mammalian endotoxin receptor, were resistant to postburn myocardial contractile dysfunction. In the second model, starting 30 min or 4 h after burn injury, rats were infused with recombinant bactericidal/permeability-increasing protein (rBPI(21)), a protein that binds and neutralizes endotoxin. Hearts from rBPI(21)-treated animals were completely protected from postburn contractile impairment. Because burn-induced contractile dysfunction can be prevented either by blocking signaling through the endotoxin receptor or by neutralizing circulating LPS, bacterial endotoxin may contribute to impaired myocardial contractility after burn injury.
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PMID:TLR4 inactivation and rBPI(21) block burn-induced myocardial contractile dysfunction. 1223 19


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