Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The role of A3 adenosine receptors (ARs) in sepsis and inflammation is controversial. In this study, we determined the effects of A3AR modulation on mortality and hepatic and renal dysfunction in a murine model of sepsis. To induce sepsis, congenic A3AR knockout mice (A3AR KO) and wild-type control (A3AR WT) mice were subjected to cecal ligation and double puncture (CLP). A3AR KO mice had significantly worse 7-day survival compared with A3AR WT mice. A3AR KO mice also demonstrated significantly higher elevations in plasma creatinine, alanine aminotransferase, aspartate aminotransferase, keratinocyte-derived chemokine, and TNF-alpha 24 h after induction of sepsis compared with A3AR WT mice. Renal cortices from septic A3AR KO mice exhibited increased mRNA encoding proinflammatory cytokines and enhanced nuclear translocation of NF-kB compared with samples from A3AR WT mice. A3AR WT mice treated with N6-(3-iodobenzyl)ADO-5'N-methyluronamide (IB-MECA; a selective A3AR agonist) or 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(+/-)-dihydropyridine-3,5-dicarboxylate (MRS-1191; a selective A3AR antagonist) had improved or worsened 7-day survival after induction of sepsis, respectively. Moreover, A3AR WT mice treated with IB-MECA or MRS-1191 showed acutely improved or worsened, respectively, renal and hepatic function following CLP. IB-MECA significantly reduced mortality in mice lacking the A1AR or A2aAR but not the A3AR, demonstrating specificity of IB-MECA in activating A3ARs and mediating protection against sepsis-induced mortality. We conclude that endogenous or exogenous A3AR activation confers significant protection from murine septic peritonitis primarily by attenuating the hyperacute inflammatory response in sepsis.
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PMID:A3 adenosine receptor activation decreases mortality and renal and hepatic injury in murine septic peritonitis. 1677 64

Group B streptococci (GBS) have been recognised as an ever-growing cause of serious invasive infections in non-pregnant adults, in particular in association with severe underlying diseases such as diabetes mellitus. In the present study we used mice rendered diabetic to gain further insights into host-pathogen interaction during induced GBS sepsis and septic arthritis. Type I diabetes was induced in adult CD-1 mice by low-dose streptozotocin treatment. Mice were then infected with different doses of GBS, and mortality, appearance of arthritis, growth of microorganisms in the organs and cytokine and chemokine profile were assessed in diabetic and control animals. The LD50 was significantly lower in diabetics than in controls, while both incidence and severity of arthritis were higher. A significantly higher number of microorganisms were recovered from the organs of diabetic mice than in controls. The worsening of sepsis and arthritis was associated with a significant increase in systemic and local production of IL-6, IL-1 beta, TNF-alpha, IL-10, macrophage inflammatory protein 1 alpha (MIP-1alpha), and MIP-2 and with a decrease in IFN-gamma production. Taken together, our results indicate an impaired host resistance to GBS infection in diabetics, likely due to a dysregulation of the cytokine network and prolonged local inflammatory response.
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PMID:Exacerbation of group B streptococcal sepsis and arthritis in diabetic mice. 1684 99

Sepsis results in a state of relative immunosuppression, rendering critically ill patients susceptible to secondary infections and increased mortality. Monocytes isolated from septic patients and experimental animals display a "deactivated" phenotype, characterized by impaired inflammatory and antimicrobial responses, including hyporesponsiveness to LPS. We investigated the role of the LPS/TLR4 axis and its inhibitor, IL-1 receptor-associated kinase-M (IRAK-M), in modulating the immunosuppression of sepsis using a murine model of peritonitis-induced sepsis followed by secondary challenge by intratracheal Pseudomonasaeruginosa. Septic mice demonstrated impaired alveolar macrophage function and increased mortality when challenged with intratracheal Pseudomonas as compared with nonseptic controls. TLR2 and TLR4 expression was unchanged in the lung following sepsis, whereas levels of IRAK-M were upregulated. Macrophages from IRAK-M-deficient septic mice produced higher levels of proinflammatory cytokines ex vivo and greater costimulatory molecule expression in vivo as compared with those of their WT counterparts. Following sepsis and secondary intrapulmonary bacterial challenge, IRAK-M(-/-) animals had higher survival rates and improved bacterial clearance from lung and blood compared with WT mice. In addition, increased pulmonary chemokine and inflammatory cytokine production was observed in IRAK-M(-/-) animals, leading to enhanced neutrophil recruitment to airspaces. Collectively, these findings indicate that IRAK-M mediates critical aspects of innate immunity that result in an immunocompromised state during sepsis.
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PMID:Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M. 1691 41

Immunologically active molecules such as cytokines and chemokines have been implicated in skeletal muscle weakness during sepsis as well as recovery from muscle injury. In sepsis, Toll-like receptors (TLRs) act as key sentinel molecules of the innate immune system. Here we determined skeletal muscle cell responses of two prototypical CC and CXC chemokine genes (monocyte chemoattractant protein 1 [MCP-1] and KC, respectively), to stimulation with specific TLR ligands. In addition, we examined whether NF-kappaB and calcineurin signaling are involved in these responses. Differentiated myotubes and intact whole muscles expressed TLR2, TLR4, TLR5, and TLR9. Stimulation with ligands for TLR2 (peptidoglycan) or TLR4 (LPS) elicited robust and equivalent levels of MCP-1 and KC mRNA expression, whereas stimulation of TLR5 (by flagellin) required gamma interferon priming to induce similar effects. Although both TLR2 and TLR4 ligands activated the NF-kappaB pathway, NF-kappaB reporter activity was approximately 20-fold greater after TLR4 stimulation than after TLR2 stimulation. Inhibitory effects of NF-kappaB blockade on TLR-mediated chemokine gene expression, by either pharmacological (pyrrolidine dithiocarbamate) or molecular (IKKbeta dominant-negative transfection) methods, were also more pronounced during TLR4 stimulation. In contrast, inhibitory effects on TLR-mediated chemokine expression of calcineurin blockade (by FK506) were greater for TLR2 than for TLR4 stimulation. MCP-1 and KC mRNA levels also demonstrated differential responses to NF-kappaB and calcineurin blockade during stimulation with specific TLR ligands. We conclude that skeletal muscle cells differentially utilize the NF-kappaB and calcineurin pathways in a TLR-specific manner to enable complex regulation of CC and CXC chemokine gene expression.
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PMID:Toll-like receptors differentially regulate CC and CXC chemokines in skeletal muscle via NF-kappaB and calcineurin. 1698 39

The chemokine monocyte chemoattractant protein 1/CC chemokine ligand 2 (MCP-1/CCL2) is a potent chemoattractant of mononuclear cells and a regulatory mediator involved in a variety of inflammatory diseases. In the present study, we demonstrate that mcp-1/ccl2-deficient mice are more susceptible to systemic inflammatory response syndrome induced by lipopolysaccharide and to polymicrobial sepsis induced by cecum ligation and puncture (CLP) when compared with wild-type mice. Interestingly, in the CLP model, mcp-1/ccl2-deficient mice efficiently cleared the bacteria despite an impaired recruitment of leukocytes, especially mononuclear cells. The increased lethality rate in these models correlates with an impaired production of interleukin (IL) 10 in vivo. Furthermore, macrophages from mcp-1/ccl2-deficient mice activated with lipopolysaccharide also produced lower amounts of IL-10 and similar tumor necrosis factor compared with wild-type mice. We observed a drastic increase in the amounts of macrophage migration inhibitory factor at 6 and 24 h after CLP in mcp-1/ccl2-deficient mice. These results indicate that endogenous MCP-1/CCL2 positively regulates IL-10 but negatively controls macrophage migration inhibitory factor during peritoneal sepsis, thus suggesting an important immunomodulatory role for MCP-1/CCL2 in controlling the balance between proinflammatory and anti-inflammatory factors in sepsis.
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PMID:Increased susceptibility to septic and endotoxic shock in monocyte chemoattractant protein 1/cc chemokine ligand 2-deficient mice correlates with reduced interleukin 10 and enhanced macrophage migration inhibitory factor production. 1704 15

The role of neutrophils in the immune response has long been regarded as mainly phagocytic, but recent publications have indicated the production of several cytokines by polymorphonuclear leucocytes (PMN). The results of the individual reports, however, vary considerably. In this study, we established a cytokine profile of pure human neutrophils and demonstrated that minor contamination of peripheral blood mononuclear cells (PBMCs) in PMN preparations can lead to false-positive results. In our hands, peripheral blood PMN fail to produce the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha). Instead, they secrete large amounts of the chemokine IL-8 and the anti-inflammatory IL-1 receptor antagonist (IL-1ra). Additionally, PMN preparations of a high purity show production of the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and growth-related oncogene-alpha (GRO-alpha), as well as macrophage colony-stimulating factor (M-CSF). The neutrophil therefore represents a novelty by producing the antagonist of IL-1beta (i.e. IL-1ra) in the absence of IL-1beta itself. To support our results, we differentiated stem cells from human cord blood into PMN and monocytes, respectively. These in vitro-differentiated PMN showed the same cytokine profile as peripheral blood PMN lacking IL-1beta, while differentiated monocytes produced the expected IL-1beta in addition to IL-1ra. The clear anti-inflammatory nature of their cytokine profile enables PMN to antagonize pro-inflammatory signals in experimental conditions. It is therefore possible that PMN play a key role in immune regulation by counteracting a dysregulation of the inflammatory process. Clinical studies, in which administration of recombinant G-CSF had a favourable effect on the outcome of severe infections and even sepsis without worsening inflammation, could thus be explained by our results.
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PMID:Polymorphonuclear leucocytes selectively produce anti-inflammatory interleukin-1 receptor antagonist and chemokines, but fail to produce pro-inflammatory mediators. 1706 11

Severe injury deranges immune function and increases the risk of sepsis and multiple organ failure. Kupffer cells play a major role in mediating posttraumatic immune responses, in part via different Toll-like receptors (TLR). Although mitogen-activated protein kinases (MAPK) are key elements in the TLR signaling pathway, it remains unclear whether the activation of different MAPK are TLR specific. Male C3H/HeN mice underwent midline laparotomy (i.e., soft tissue injury), hemorrhagic shock (MAP approximately 35 mm Hg for 90 min), and resuscitation. Kupffer cells were isolated 2 h thereafter, lysed and immunoblotted with antibodies to p38, ERK1/2, or JNK proteins. In addition, cells were preincubated with specific inhibitors of p38, ERK1/2, or JNK MAPK followed by stimulation with the TLR2 agonist, zymosan; the TLR4 agonist, LPS; or the TLR9 agonist, CpG DNA. Cytokine (TNF-alpha, interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and KC) production was determined by cytometric bead array after 24 h in culture. MAPK activity as well as TNF-alpha, MCP-1, and KC production by Kupffer cells were significantly increased following trauma-hemorrhage. TLR4 activation by LPS stimulation increased the levels of all measured cytokines. CpG-stimulated TLR9 signaling increased TNF-alpha and IL-6 levels; however, it had no effect on chemokine production. Selective MAPK inhibition demonstrated that chemokine production was mediated via p38 and JNK MAPK activation in TLR2, -4, and -9 signaling. In contrast, TNF-alpha and IL-6 production was differentially regulated by MAPK depending on the TLR pathway stimulated. Thus, Kupffer cell TLR signaling employs different MAPK pathways in eliciting cytokine and chemokine responses following trauma-hemorrhage.
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PMID:The role of MAPK in Kupffer cell toll-like receptor (TLR) 2-, TLR4-, and TLR9-mediated signaling following trauma-hemorrhage. 1711 77

Very low birth weight (VLBW) infants with suspected late-onset infection requiring sepsis screening were enrolled in a prospective study to evaluate the diagnostic utilities of a comprehensive panel of key chemokines and cytokines, both individually and in combination, to identify diagnostic markers for early recognition of bacterial sepsis and necrotizing enterocolitis (NEC). Plasma chemokines interleukin (IL)-8, interferon-gamma-inducible protein 10 (IP-10), monokine induced by interferon-gamma (MIG), monocyte chemoattractant protein 1 (MCP-1), growth-related oncogene-alpha (GRO-alpha), and regulated upon activation of normal T cell expressed and secreted (RANTES) and cytokines IL-1beta, IL-6, IL-10, IL-12p70, and tumor necrosis factor alpha (TNF-alpha) were measured at the onset of sepsis (0 h) and 24 h later. Of 155 suspected infection episodes, 44 were classified as infected. Concentrations of all studied inflammatory mediators (except IL-1beta and RANTES) were significantly higher in the infected than in the noninfected group at 0 h, but the levels decreased precipitously by 24 h. IP-10 with a plasma cutoff concentration > or = 1250 pg/mL could identify all septicemic and NEC cases and had the highest overall sensitivity (93%) and specificity (89%) at 0 h. We conclude that preterm infants have the ability to induce a robust chemokine and cytokine response during sepsis, and IP-10 is a sensitive early marker of infection.
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PMID:IP-10 is an early diagnostic marker for identification of late-onset bacterial infection in preterm infants. 1721 Nov 48

Protein C (PC) plays an important role in vascular function, and acquired deficiency during sepsis is associated with increased mortality in both animal models and in clinical studies. This study explored the consequences of PC suppression on the kidney in a cecal ligation and puncture model of polymicrobial sepsis. This study shows that a rapid drop in PC after sepsis is strongly associated with an increase in blood urea nitrogen, renal pathology, and expression of known markers of renal injury, including neutrophil gelatinase-associated lipocalin, CXCL1, and CXCL2. The endothelial PC receptor, which is required for the anti-inflammatory and antiapoptotic activity of activated PC (APC), was significantly increased after cecal ligation and puncture as well as in the microvasculature of human kidneys after injury. Treatment of septic animals with APC reduced blood urea nitrogen, renal pathology, and chemokine expression and dramatically reduced the induction of inducible nitric oxide synthase and caspase-3 activation in the kidney. The data demonstrate a clear link between acquired PC deficiency and renal dysfunction in sepsis and suggest a compensatory upregulation of the signaling receptor. Moreover, these data suggest that APC treatment may be effective in reducing inflammatory and apoptotic insult during sepsis-induced acute renal failure.
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PMID:Role of protein C in renal dysfunction after polymicrobial sepsis. 1730 Nov 89

Antibody-based approaches to pneumococcal disease may hold promise for immunocompromised patients in whom vaccines are less immunogenic and/or in the context of antimicrobial resistance. Antibody-mediated protection against experimental pneumococcal pneumonia has been shown to depend on immunoregulation, but the relationship between antibody and protection against pneumococcal sepsis and immunoregulation has not been examined. Similarly, the requirement for B and T cells for antibody efficacy is not known. In this study, we determined the efficacy of the human pneumococcal capsular polysaccharide serotype 3-specific antibody, A7 (immunoglobulin M [IgM]), in secretory IgM (sIgM)(-/-), CD4(-/-), CD8(-/-), muMT(-/-), and SCID mice and investigated its effect on cytokine and chemokine expression in sera and spleens from mice with intact cellular immunity. A7 is known to be protective against systemic infection with serotype 3 and to require complement for efficacy. Compared to that of an isotype control antibody, A7 administration prolonged the survival of mice of each immunodeficient strain and was associated with a significant reduction in CFU in blood, lung, and spleen samples and a significantly reduced level of keratinocyte-derived chemokine (KC), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2) expression in normal and sIgM(-/-) mice. Studies with mice treated with penicillin revealed similar reductions in CFU and similar levels of IL-6, KC, or MIP-2 expression in A7- and penicillin-treated mice. These findings demonstrate that natural IgM and B and T cells are dispensable for A7-mediated protection against experimental pneumococcal sepsis and suggest that the efficacy of antibody-mediated protection depends on immunomodulation. Taken together, our data extend the association between antibody-mediated protection and immunomodulation to protection against systemic pneumococcal infection and to a clinically important serotype often responsible for pneumococcal sepsis.
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PMID:A human monoclonal immunoglobulin M reduces bacteremia and inflammation in a mouse model of systemic pneumococcal infection. 1730 Dec 14


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