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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Group B streptococcus (GBS) imposes a major health threat to newborn infants. Little is known about the molecular basis of GBS-induced sepsis. Both heat-inactivated whole GBS bacteria and a heat-labile soluble factor released by GBS during growth (GBS-F) induce nuclear translocation of NF-kappaB, the secretion of TNF-alpha, and the formation of NO in mouse macrophages. Macrophages from mice with a targeted disruption of MyD88 failed to secrete TNF-alpha in response to both heat-inactivated whole bacteria and GBS-F, suggesting that Toll-like receptors (TLRs) are involved in different aspects of GBS recognition. Immune cell activation by whole bacteria differed profoundly from that by secreted GBS-F. Whole GBS activated macrophages independently of TLR2 and TLR6, whereas a response to the secreted GBS-F was not observed in macrophages from TLR2-deficient animals. In addition to TLR2, TLR6 and CD14 expression were essential for GBS-F responses, whereas TLR1 and TLR4 or MD-2 did not appear to be involved. Heat lability distinguished GBS-F from peptidoglycan and lipoproteins. GBS mutants deficient in capsular polysaccharide or beta-hemolysin had GBS-F activity comparable to that of wild-type streptococci. We suggest that CD14 and TLR2 and TLR6 function as coreceptors for secreted microbial products derived from GBS and that cell wall components of GBS are recognized by TLRs distinct from TLR1, 2, 4, or 6.
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PMID:Novel engagement of CD14 and multiple toll-like receptors by group B streptococci. 1173 28

Much research has focused on the responses to microbial products of immune cells such as monocytes, macrophages, and neutrophils. Although the liver is a primary response organ in various infections, relatively little is known about the antimicrobial responses of its major cell type, the hepatocyte. It is now known that the recognition of bacteria occurs via cell-surface proteins that are members of the Toll-like receptor (TLR) family. In addition, lipopolysaccharide (LPS) is bound by circulating LPS-binding protein (LBP) and presented to cell-surface CD14, which in turn interacts with TLR and transduces an intracellular signal. We investigated the CD14 and TLR2 responses of whole liver and isolated hepatocytes, and demonstrated that these cells can be induced to express the molecules necessary for responses to both Gram-positive and Gram-negative bacteria. Our findings may have clinical implications for pathological states such as sepsis.
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PMID:The hepatocyte as a microbial product-responsive cell. 1175 5

Neonatal bacterial sepsis is often characterized by a fulminant clinical course and highly elevated plasma levels of proinflammatory cytokines. To evaluate in vitro activation of the neonatal immune system by specific infectious stimuli, cord blood cells from healthy neonates were examined for expression of tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, and IL-8 in response to Streptococcus agalactiae (GBS), lipopolysaccharide (LPS), and lipoteichoic acid (LTA). Cytokine-expression was compared in mononuclear cells from cord and adult peripheral blood. TNF-alpha and IL-6 levels in the supernatant of cord blood cell cultures were significantly higher after stimulation with heat-killed GBS (10(7)/mL) than with LPS (2 microg/mL) or LTA (2 microg/mL) (TNF-alpha: 2215 versus 267.5 versus 40 pg/mL, p = 0.001; IL-6: 9667 versus 4909 versus 919 pg/mL, p = 0.006). mRNA expression of TNF-alpha, IL-1beta, IL-6, and IL-8 was equally pronounced after stimulation with either GBS, LPS, or LTA in cord or adult blood cells at various times. A MAb directed against the monocyte receptor molecule CD14 did not inhibit the release of cytokines in cord blood mononuclear cells after stimulation with GBS. In summary, activation of cord blood cells by infectious stimuli is comparable to the adult immune response in terms of expression of proinflammatory cytokines. GBS in particular proves to be a potent activator of the neonatal immune system when compared with LPS and LTA. CD14 seems not to be a crucial molecule for activation of cord blood cells by GBS.
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PMID:Cytokine expression of cord and adult blood mononuclear cells in response to Streptococcus agalactiae. 1186 34

No data on lipopolysaccharide-binding protein (LBP) in newborns with sepsis have been available up to now. We therefore determined levels of LBP and soluble CD14 (sCD14) in plasma of healthy and septic neonates in order to evaluate their potential diagnostic role. The study included prospectively collected patient samples of two recently published studies on cytokine expression in neonatal sepsis. Twenty-nine septic patients were enrolled in the present analysis. Samples--either cord blood or peripheral blood--from patients admitted within the first 24 h of life for suspicion of sepsis and cord blood samples of a control group of 40 healthy mature infants delivered spontaneously were analyzed. For seven patients of the septic group, a second sample collected between 24 and 48 h of life was available. Levels of sCD14 and LBP in plasma were determined by an enzyme immunoassay using recombinant CD14 and LBP as standards. LBP and sCD14 were correlated to cytokine plasma levels. In septic neonates, LBP (median, 36.6 versus 7.8 microg/ml; P < 0.001) and sCD14 (median, 0.42 versus 0.28 microg/ml; P < 0.001) levels were highly elevated when compared to those of healthy neonates and strongly correlated to granulocyte colony-stimulating factor (G-CSF), interleukin-1beta (IL-1beta), IL-6, and IL-8 levels. LBP levels in septic neonates analyzed between 24 and 48 h of life even increased when compared to samples obtained at or shortly after delivery (median, 36.6 versus 60 microg/ml; P = 0.038). In summary, levels of LBP in plasma of neonates with early-onset sepsis are significantly elevated; the elevated plasma levels seem to persist for more than 24 h, which could provide the clinician with a prolonged time period to identify the newborn with bacterial sepsis.
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PMID:Elevated levels of lipopolysaccharide-binding protein and soluble CD14 in plasma in neonatal early-onset sepsis. 1187 91

Streptococcus suis capsular type 2 is an important aetiologic agent of swine meningitis, and it has been highlighted as a cause of occupational disease leading to meningitis and fulminant sepsis in humans. The objective of the present work was to study the ability of S. suis type 2 to induce the release of tumour necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, IL-8 and monocyte chemotactic protein one (MCP-1) by human monocytic THP-1 cells. The induction of these five cytokines was dose- and incubation time-dependent, and it was significantly enhanced by pre-treatment of cells with interferon gamma. IL-8 levels were markedly higher compared with those obtained with the other cytokines. However, elevated levels of MCP-1 and IL-6 were also observed. Levels of cytokine induced by heat-killed or live bacteria were similar. Pre-treatment of cells with anti-CD14 monoclonal antibodies suggested that this important host receptor is partially implicated in TNF, IL-1, IL-6 and MCP-1 production, while CD14-independent pathways seem to be responsible for IL-8 production after S. suis stimulation. In addition, blocking studies with anti-TNF and anti-IL-1 antibodies revealed that these cytokines are involved in amplification of the S. suis-induced cytokine cascade. When several different S. suis strains of human or porcine origin were compared, a very heterogeneous pattern of cytokine production was observed. Human strains did not exhibit a clear tendency to induce higher cytokine release by human THP-1 monocytes. The synergistic effect of the up-regulation of cytokines during S. suis meningitis may mediate many of the inflammatory reactions, including the sequestration of leucocytes at the site of infection.
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PMID:CD14-dependent and -independent cytokine and chemokine production by human THP-1 monocytes stimulated by Streptococcus suis capsular type 2. 1187 46

In the present study, we investigated the effect of RWJ-67657, a p38 MAP kinase inhibitor, upon in vivo LPS-induced monocyte cytokine production and upon monocyte LPS-hyporesponsiveness. Thirty minutes before a single injection of LPS (4 ng/kg BW), healthy male volunteers received a single oral dose of RWJ-67657 at increasing dosages (0-1400 mg). Blood samples (pre-medication, 3, 6 and 24 h after LPS) were immediately incubated with LPS (reflecting LPS-hyporesponsiveness) or without LPS (reflecting in vivo monocyte stimulation) for 4 h at 37 degrees C. Following red blood cells lysis and white blood cell permeabilization, cells were labelled with alpha-CD14-FITC and alpha-IL-1beta, alpha-IL-12 or alpha-TNFalpha (PE-labelled), fixed, and analysed using flow cytometry. In vivo LPS injection resulted in an increased percentage of circulating monocytes producing IL-1beta, TNFalpha and IL-12 only at 3 h after the LPS injection. This was dose-dependently inhibited by RWJ-67657 treatment. LPS-hyporesponsiveness to in vitro LPS treatment was most prominent at 3 and 6 h after the in vivo LPS injection; compared with pre-medication monocytes, at these intervals a reduced percentage of monocytes produced IL-1beta, TNFalpha or IL-12 after the in vitro LPS stimulus. At t = 6 h, this LPS-hyporesponsiveness could dose-dependently be inhibited by RWJ-67657 treatment of the volunteers. We therefore conclude that p38 MAP kinase inhibition with RWJ-67657 inhibited monocyte production of cytokines following in vivo LPS injection. Treatment with RWJ-67657 also reversed the LPS-hyporesponsiveness. Whether this result can be extended to the clinical situation remains to be elucidated. Patients with sepsis or an otherwise high risk for multi-organ failure are potential study groups.
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PMID:Monocyte intracellular cytokine production during human endotoxaemia with or without a second in vitro LPS challenge: effect of RWJ-67657, a p38 MAP-kinase inhibitor, on LPS-hyporesponsiveness. 1187 59

Sepsis is a common cause of morbidity and mortality, particularly in immunocompromised and critically ill patients. Recently, a new designation, systemic inflammatory response syndrome(SIRS), has been studied. When an abnormal generalized inflammatory reaction is due to an infection, the terms sepsis and SIRS are synonymous. The systemic response to infection is mediated via the macrophage-derived cytokines that target end organ receptors in response to injury or infection. One strategy used to perturb the septic cascade is to block a particular inflammatory molecule. Results have been published on clinical trials in sepsis patients treated with several monoclonal antibodies, such as antiendotoxin antibodies, anti-tumor necrosis factor antibodies, and anti CD14 antibodies. In this chapter, the results of clinical trials in patients and in vivo data from animal models of sepsis are summarized.
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PMID:[Monoclonal antibodies against inflammatory mediators for the treatment of patients with sepsis]. 1190 76

The innate immune system is in the vanguard of host defenses against infection. Recognition of invasive microbial pathogens is mediated by pattern recognition receptors on the surface of immune cells that recognize pathogen-associated molecular motifs. Considerable progress has been made in recent years in understanding how bacterial products initiate sepsis. In gram-negative sepsis, the LPS-binding protein (LBP), CD14 and the recently identified Toll-like receptor 4 (TLR4) are key molecules for the recognition of endotoxin (lipopolysaccharide, LPS) by cells of the myelomonocytic lineage. In gram-positive sepsis, components of the bacterial cell wall (peptidoglycan, PGN; lipoteichoic acids, LTA) have been shown to activate myeloid cells through an interaction with a receptor complex composed of CD14, TLR2 and perhaps also TLR6 (PGN) or CD14 and TLR4 (LTA). By contrast, gram-positive exotoxins act as superantigens and directly stimulate T lymphocytes by cross-linking the MHC class II of antigen presenting cells to specific chains of the T cell receptor. Immune cells activated by microbial pathogens release numerous effector molecules, which orchestrate the innate and adaptive host defenses. Furthermore, bacteria and microbial toxins directly activate the complement and coagulation systems, which play an important part in the host defensive response. Severe sepsis and septic shock can be viewed as clinical manifestations of a failing innate immune response that ultimately results in an overstimulation of the physiological host response. The pathogenesis of sepsis is far more complex that was initially anticipated. However, combined research efforts of basic scientists and clinical investigators continue to provide critical information for the identification of novel therapeutic targets. The exciting results obtained recently with treatment strategies designed to correct coagulation abnormalities occurring during sepsis are an example of how research may ultimately translate into improved patient care.
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PMID:Pathogenesis of septic shock: implications for prevention and treatment. 1193 63

Staphylococcus aureus is one of the most significant pathogens in human sepsis and endocarditis. S. aureus can initiate blood coagulation, leading to the formation of microthrombi and multiorgan dysfunction in sepsis, whereas in endocarditis the bacterium induces fibrin clots on the inner surface of the heart, so-called endocardial vegetations. In the present study, we show that live and heat-killed S. aureus bacteria are potent inducers of procoagulant activity in human peripheral blood mononuclear cells. Furthermore, purified peptidoglycan, the main cell wall component of S. aureus, induced procoagulant activity in mononuclear cells in a concentration-dependent fashion. The procoagulant activity in these cells was dependent on expression of tissue factor, since antibodies to tissue factor inhibited the effect of peptidoglycan. In mononuclear cells stimulated with peptidoglycan, reverse transcription-PCR showed tissue factor gene expression, and the gene product was detected by enzyme-linked immunosorbent assay. Finally, flow cytometry identified tissue factor at the surface of CD14-positive monocytes. Peptidoglycan is known to induce proinflammatory cytokine production in monocytes. The present investigation shows that peptidoglycan also activates the extrinsic pathway of coagulation by inducing the expression of tissue factor in these cells. This mechanism helps to explain the procoagulant activity, which plays such an important role in the pathogenicity of severe S. aureus infections.
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PMID:Peptidoglycan from Staphylococcus aureus induces tissue factor expression and procoagulant activity in human monocytes. 1201 Sep 95

Recognition of bacterial lipopolysaccharide (LPS) by the innate immune system elicits strong pro-inflammatory responses that can eventually cause a fatal sepsis syndrome in humans. LPS-mediated activation of mammalian cells is believed to involve the interaction of LPS with lipopolysaccharide-binding protein (LBP) in the serum and, subsequently with CD14. Although there is no doubt that CD14 binds LPS, CD14 is not capable of initiating a transmembrane activation signal because it is a glycosylphosphatidylinositol (GPI)-anchored protein. Accumulating evidence has suggested that LPS must interact with a transmembrane receptor(s) that is responsible for signal transduction. Integrins CD11c and/or CD18, Toll-like receptors (TLRs), as well as CD55, have been suggested to serve this function. Recently, we have revealed that a signalling complex of receptors is formed following LPS stimulation, which comprises heat-shock proteins (Hsps) 70 and 90, chemokine receptor 4 (CXCR4) and growth differentiation factor 5 (GDF5). Taking into account the discovery of the TLRs and the LPS-activation cluster, we propose a new model of LPS recognition.
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PMID:Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. 1207 69


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