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:C0036690 (sepsis)
59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant human interleukin (IL)-11 is a multifunctional cytokine with hematopoietic, immunomodulatory, and epithelial cell protective activities. IL-11alpha receptors are expressed on the luminal surface of intestinal epithelial cells. It was hypothesized that orally administered IL-11 would prevent mucosal damage and protect against microbial invasion in a neutropenic rat model of gram-negative sepsis. IL-11 was administered daily by enteric, coated multiparticle pellets over the course of chemotherapy-induced neutropenia. Compared with the placebo group, IL-11-treated rats retained mucosal mass and had prolonged survival time, reduced pathologic changes, and reduced systemic levels of bacterial endotoxin and concentrations of Pseudomonas aeruginosa in target tissues. Enterocyte messenger RNA levels for tumor necrosis factor-alpha and interferon-gamma revealed that oral IL-11 reduced but did not prevent increased expression of these cytokine genes. These results indicate that orally administered IL-11 may preserve epithelial cell integrity in the presence of cytoreductive chemotherapy. This may represent a new treatment strategy for the prevention of infection in neutropenic hosts.
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PMID:Orally administered recombinant human interleukin-11 is protective in experimental neutropenic sepsis. 1250 48

Natural killer (NK) cells have a well-established role in host defense against viral infections and malignancies. However, their function in bacterial infection and sepsis is poorly defined. We hypothesized that NK cells, as a major producer of interferon-gamma during sepsis, would be important in host defense against bacterial infections. Cecal ligation and puncture (CLP) was performed on Swiss Webster mice depleted of NK cells by pretreatment with anti-asialo GM1 and control mice given immunoglobulin G (IgG) antibody. NK cell-depleted mice had significantly higher anaerobic bacterial counts in the liver and peritoneal lavage fluid, as well as higher aerobic counts in the liver and blood 4 h after CLP. Macrophage phagocytosis, nitric oxide production, and interleukin (IL)-6 levels at 4 h were also decreased in mice depleted of NK cells compared with controls. Greater neutrophil influx into the peritoneum, indicated by higher myeloperoxidase levels, was also seen in NK cell-depleted mice. At 8 and 18 h after CLP, bacterial counts were similar between groups, and overall survival rates were not significantly different. Peritoneal IL-12 levels significantly increased by 18 h in normal mice, but not in NK cell-depleted animals. Our data suggest that NK cells participate in the early local and systemic eradication of bacteria and regulation of IL-12 during polymicrobial sepsis. These effects are likely due to their interactions with macrophages.
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PMID:Natural killer cells participate in bacterial clearance during septic peritonitis through interactions with macrophages. 1257 23

Inducible nitric oxide synthase (iNOS) expression in blood vessels contributes to the vascular hyporeactivity characteristic of sepsis. Our previous work demonstrated in vitro that ascorbate inhibits iNOS expression in lipopolysaccharide- and interferon-gamma-stimulated skeletal muscle endothelial cells (ECs) through an antioxidant mechanism. The present study evaluated in vivo the hypothesis that administration of ascorbate decreases oxidative stress, prevents endothelial iNOS expression, and improves vascular reactivity in septic skeletal muscle. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). Plasma nitrite and nitrate (NOx) levels were elevated by 6 h after CLP. Prior ascorbate bolus injection (200 mg/kg body wt iv) blocked the elevation of plasma NOx and abolished the expression of iNOS protein and activity in the septic skeletal muscle. We also demonstrated that iNOS mRNA determined by RT-PCR was induced in the microvascular ECs of the muscle at 3 h after CLP. This induction was attenuated by prior ascorbate administration. Ascorbate inhibition of iNOS expression was associated with decreased oxidant levels in the septic muscle. Moreover, ascorbate administration restored partially the baseline arterial pressure and preserved completely the microvascular constriction and arterial pressure responses to norepinephrine in CLP mice. These results suggest that early administration of ascorbate may be a valuable adjunct treatment of sepsis.
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PMID:Ascorbate inhibits iNOS expression and preserves vasoconstrictor responsiveness in skeletal muscle of septic mice. 1263 47

We developed a model of sequential influenza A virus (IAV)-Neisseria meningitidis serogroup C (Nm) infection in BALB/c mice. Mice infected intranasally with a sublethal IAV dose (260 pfu) were superinfected intranasally with Nm. Fatal meningococcal pneumonia and bacteremia were observed in IAV-infected mice superinfected with Nm on day 7, but not in those superinfected on day 10. The susceptibility of mice to Nm superinfection was correlated with the peak interferon-gamma production in the lungs and decrease in IAV load. After Nm challenge, both IAV-infected and uninfected control mice produced the inflammatory cytokines interleukin (IL)-1 and IL-6. However, IL-10 was detected in susceptible mice superinfected on day 7 after IAV infection, but not in resistant mice. This model of dual IAV-Nm infection was also used to evaluate the role of bacterial virulence factors in the synthesis of the capsule. A capsule-defective mutant was cleared from the lungs, whereas a mutant inactivated for the crgA gene, negatively regulating expression of the pili and capsule, upon contact with host cells, retained invasiveness. Therefore, this model of meningococcal disease in adult mice reproduces the pathogenesis of human meningococcemia with fatal sepsis, and is useful for analyzing known or new genes identified in genomic studies.
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PMID:A model of meningococcal bacteremia after respiratory superinfection in influenza A virus-infected mice. 1275 52

Streptococcus pneumoniae is a major public health problem and new strategies for the development of cost-effective alternative vaccines are important. The use of protein antigens such as PspA (pneumococcal surface protein A) is a promising approach to increase coverage at reduced costs. We have previously described the induction of a strong antibody response by a DNA vaccine expressing a C-terminal fragment of PspA. Fusion of this fragment with the cytoplasmic variant of SV40 large T-antigen (CT-Ag) caused reduction in specific interferon-gamma produced by stimulated spleen cells. In this work we show that the DNA vaccine expressing the C-terminal region of PspA elicits significant protection in mice against intraperitoneal challenge with a virulent strain of S. pneumoniae. Furthermore, fusion with CT-Ag completely abrogated the protection elicited by DNA immunization with this fragment. In this case, protection did not correlate with total anti-PspA antibody production nor with total IgG2a levels. The anti-PspA sera obtained from both constructs showed equivalent opsonic activity of pneumococci, indicating that the antibodies produced were functional. We could, though, observe a correlation between a lower IgG1:IgG2a ratio, which is indicative of a stronger bias towards Th1 responses, and protection. We also show that a vector expressing the most variable N-terminal alpha-helical region induces higher antibody formation, with increased protection of mice against intraperitoneal challenge with a more virulent strain of S. pneumoniae. As a whole, these results indicate that antibodies elicited against PspA would not be solely responsible for the protection induced by DNA vaccination and that cell-mediated immune responses could also be involved in protection against pneumococcal sepsis.
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PMID:Protective efficacy of PspA (pneumococcal surface protein A)-based DNA vaccines: contribution of both humoral and cellular immune responses. 1277 Jul 60

Staphylococcal enterotoxin B (SEB) is an important member of the superantigen family, which exerts a number of pathological effects in the human, as well as susceptible animals. The present study was conducted to observe the time course and tissue distribution of SEB in postburn Staphylococcus aureus infection; meanwhile, the relationship between SEB and multiple organ dysfunction was also studied. Eighty-six male Wistar rats were randomly divided into four groups as follows: normal control group (n = 10); scald control group (n = 10); postburn sepsis group (n = 50) in which rats inflicted with 20% total body surface area (TBSA) III degrees scald followed by SEB-producing S. aureus challenge were further divided into 0.5-, 2-, 6-, 12-, and 24-h subgroups, with 10 rats in each subgroup; and SEB monoclonal antibody (MAb) treatment group (n = 16) in which a dose of 4 mg/kg SEB MAb was given intravenously just before S. aureus challenge, and the rats were further divided into 2- and 6-h subgroups. It was found that after thermal injury combined with S. aureus infection, SEB was widely distributed to the liver, kidneys, lungs, and heart, exacerbating the pathophysiology of multiple organ dysfunction induced by postburn sepsis. At the same time, the gene and protein expressions of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were also markedly upregulated in various tissues. Early treatment with SEB-specific MAb-MAb2D(1)-could markedly decrease SEB levels in plasma as well as in various tissues, and could significantly reduce the 6-h mortality rate (17.64% [3/17] vs. 55.6% [20/36], P = 0.02). These data suggested that neutralization of SEB is effective in ameliorating S. aureus sepsis and subsequent multiple organ damage, which might be attributed to its inhibitory effect on inflammatory mediator formation.
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PMID:The potential role of Staphylococcal enterotoxin B in rats with postburn Staphylococcus aureus sepsis. 1292 98

Circulating levels of calcitonin precursors (CTpr), including procalcitonin (ProCT), increase up to several thousand-fold in human sepsis, and immunoneutralization improves survival in two animal models of this disease. Herein, we analyzed inflammation-mediated calcitonin I gene (CALC I) expression in human adipocyte primary cultures and in adipose tissue samples from infected and noninfected patients with different levels of serum ProCT. In ex vivo differentiated adipocytes, the expression of CT mRNA increased 24-fold (P < 0.05) after the administration of Escherichia coli endotoxin (lipopolysaccharide) and 37-fold (P < 0.05) after IL-1beta administration by 6 h. ProCT protein secretion into culture supernatant increased 13.5-fold (P < 0.01) with lipopolysaccharide treatment and 15.2-fold (P < 0.01) with IL-1beta after 48 h. In coculture experiments, adipocyte CT mRNA expression was evoked by E. coli-activated macrophages in which CT mRNA was undetectable. The marked IL-1beta-mediated ProCT release was inhibited by 89% during coadministration with interferon-gamma (IFNgamma). In patients with infection and markedly increased serum ProCT, CT mRNA was detected in adipose tissue biopsies. Hence, we demonstrate that ProCT, which is suspected to mediate deleterious effects in sepsis and inflammation, is a novel product of adipose tissue secretion. The inhibiting effect of IFNgamma on IL-1beta-induced CT mRNA expression and on ProCT secretion might explain previous observations that serum ProCT concentrations increase less in systemic viral compared with bacterial infections.
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PMID:In vitro and in vivo calcitonin I gene expression in parenchymal cells: a novel product of human adipose tissue. 1296 10

Neutrophil-specific granule deficiency (SGD) is a rare, congenital disease characterized by atypical neutrophil structure and function, resulting in recurrent bacterial infections from early infancy. Homozygous recessive mutations in the CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) gene were described in two of five SGD patients, indicating loss of C/EBPepsilon function as the primary genetic defect in this disease. C/EBPepsilon is expressed in murine and human macrophages. Macrophages from the C/EBPepsilon-deficient mice show impaired differentiation, phagocytic activity, and transcription of macrophage-specific genes. To determine if monocyte/macrophage cells are impacted in SGD, we analyzed phenotypic features of peripheral blood (PB) monocytes in a SGD individual lacking functional C/EBPepsilon. Flow cytometric analysis of PB leukocytes revealed aberrant expression of CD45, CD11b, CD14, CD15, and CD16 on cells from the SGD individual. Also, the PB CD14(+) cells from this individual, weakly stained for the monocyte-specific enzyme, nonspecific esterase, and electron microscopic examination, indicated morphologic differences between the SGD cells and those from normal controls. Serum interleukin (IL)-6 levels in the SGD individual during a severe bacterial infection were lower compared with levels in other non-SGD individuals with sepsis. In contrast, serum IL-8 levels were markedly elevated in the SGD individual compared with those of non-SGD individuals in sepsis. PB CD14(+) cells from the SGD individual expressed higher IL-8 mRNA levels compared with normal controls in response to lipopolysaccharide and interferon-gamma. These phenotypic and functional alterations of PB monocytes in the SGD individual suggest that C/EBPepsilon plays a critical role in monocyte/macrophage development of humans and is consistent with observations in the murine system. This study implicates abnormalities in monocytes/macrophages and neutrophils in the onset and development of SGD.
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PMID:Phenotypic and functional alterations of peripheral blood monocytes in neutrophil-specific granule deficiency. 1457 62

Septic shock is the most common cause of death in intensive care units, and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived proinflammatory cytokines, in which activation of nuclear factor-kappaB (NF-kappaB) plays an important role. PC-SPES is an eight-herb mixture active against a variety of malignancies, including prostate cancer and leukemia. In this study, we demonstrated that PC-SPES inhibited the LPS-induced NF-kappaB reporter activity in RAW264.7 macrophages. Electrophoretic mobility shift assay showed that PC-SPES inhibited the binding of NF-kappaB to specific DNA sequences; however, it did not affect either degradation of inhibitory kappaBalpha or nuclear translocation of NF-kappaB. Also, we explored the effect of PCSPES on LPS-induced mitogen-activated protein (MAP) kinase signaling; PC-SPES did not affect LPS-induced phosphorylation of MAP kinases, including c-Jun NH2-terminal kinase, p38, and extracellular signal-regulated kinase 1/2. Moreover, PC-SPES decreased the production of proinflammatory cytokines and inducible enzymes, such as tumor necrosis factor (TNF) alpha, interleukin (IL)-1beta, IL-6, cyclooxygenase-2, as well as inducible nitric-oxide synthase in RAW264.7 macrophages and peritoneal macrophages from C57BL/6 mice after the cells were stimulated by either LPS or LPS and interferon-gamma. Furthermore, PC-SPES rescued C57BL/6 mice from death caused by LPS-induced septic shock in conjunction with decreased serum levels of TNFalpha and IL-1beta. Together, PC-SPES is a potent inhibitor of NF-kappaB and might be useful for the treatment of sepsis and inflammatory diseases.
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PMID:PC-SPES: a potent inhibitor of nuclear factor-kappa B rescues mice from lipopolysaccharide-induced septic shock. 1464 83

Gammadelta T cells link innate and adaptive immune systems and may regulate host defence. Their role in systemic inflammation induced by trauma or infection (sepsis) is still obscured. The present study was aimed to investigate functions of lung gammadelta T cells and their response to experimental sepsis. Mice were subjected to caecal ligation and puncture (CLP) to induce sepsis and acute lung injury (ALI), or to the sham operation. Animals were killed 1, 4, and 7 days postoperatively; lungs were examined by histology, and isolated cells were studied by flow cytometry. Absolute number of gammadelta T cells progressively increased in lungs during sepsis, and reached a seven-fold increase at day 7 after CLP (3.84 +/- 0.41 x 10(5)/lung; P = 0.0002 versus sham). A cellular dysfunction was revealed one day after CLP, as manifested by low cytolytic activity (22.3 +/- 7.1%; P < 0.05 versus sham), low interferon-gamma (IFN-gamma; 8.5 +/- 2.5%; P < 0.05 versus control) and interleukin-10 (IL-10) expression, and high tumour necrosis factor-alpha expression (19.5 +/- 1.7%; P < 0.05 versus control). The restoration of cytotoxicity, and increase in IFN-gamma and IL-10 expression was observed at day 7 of CLP-induced sepsis. In summary, our results demonstrate significant progressive accumulation of gammadelta T cells in lungs during CLP-induced ALI. The temporary functional suppression of lung gammadelta T cells found early after CLP may influence the outcome of sepsis, possibly being associated with uncontrolled inflammatory lung damage.
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PMID:Response of lung gammadelta T cells to experimental sepsis in mice. 1509 94


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