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)

Citrobacter rodentium causes an attaching and effacing infection of the mouse colon. Surprisingly, protective adaptive immunity against this mucosal pathogen requires a systemic T-cell-dependent antibody response. To define CD4+ T-cell effector functions promoting this systemic defense of infected epithelial surfaces, studies were undertaken in weaning-age mice lacking costimulatory molecules CD28 or CD40L or cytokines gamma interferon (IFN-gamma) or interleukin-4 (IL-4). Adoptive transfer of CD4+ T cells from wild-type, CD28(-/-), CD40L(-/-), or IFN-gamma(-/-) donors to CD4(-/-) recipients delineated functions of these CD4+ T-cell-expressed molecules on the outcome of infection. Wild-type and IL-4(-/-) mice successfully resolved infection, while 70% of IFN-gamma(-/-) mice survived. In contrast, all CD28(-/-) mice succumbed during acute infection. While fewer than half of CD40L(-/-) mice succumbed acutely, surviving mice failed to clear infection, resulting in progressive mucosal destruction, polymicrobial sepsis, and death 1 to 2 weeks later than in CD28(-/-) mice. Downstream of CD28-mediated effects, CD4+ T-cell-expressed CD40L proved essential for generating acute pathogen-specific immunoglobulin M (IgM) and early IgG, which reduced pathogen burdens. However, deficiency of CD4+ T-cell-expressed IFN-gamma did not adversely impact survival or development of protective antibody in adoptively transferred CD4(-/-) recipients, though it impacted Th1 antibody responses. These findings demonstrate that CD4+ T-cell-expressed CD40L promotes the rapid production of protective systemic antibody during acute infection, while deficiencies of IL-4 or of CD4+ T-cell-expressed IFN-gamma can be overcome. These findings have important implications for understanding the role of T-helper-cell responses during infections involving mucosal surfaces.
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PMID:CD4+-T-cell effector functions and costimulatory requirements essential for surviving mucosal infection with Citrobacter rodentium. 1636 24

We investigated the effects of a protein-bound polysaccharide, PSK, on the resistance of tumor-bearing mice against sepsis induced by cecal ligation and puncture (CLP). (a) In BALB/c mice that had received intracecal transplantation of colon 26 (C26) tumor, CLP with a 21-gauge needle significantly shortened the survival time, compared with that of non-tumor-bearing mice. Oral administration of PSK to such mice resulted in a significant prolongation of the survival time and increase of the survival rates. The effects were dependent on the timing of PSK administration and the dose. (b) CLP significantly increased the IL-10 level in serum, the IL-10 gene expression by spleen cells, the number of IL-10-producing CD4-positive T cells, and the productivity of IL-10 by spleen of tumor-bearing mice compared with that of non-tumor-bearing mice. PSK administration to such mice suppressed the increase. Further, PSK prevented the reduction of gene expression of IFN-gamma and the number of IFN-gamma-producing CD4-positive T cells and IFN-gamma productivity by spleen cells of tumor-bearing CLP-treated mice. (c) Treatment with anti-IFN-gamma monoclonal antibody before CLP significantly reduced the effects of PSK. These findings suggest that the protective effect of PSK on the CLP-induced sepsis in mice transplanted orthotopically with C26 tumor is possibly mediated by suppression of IL-10 and promotion of IFN-gamma.
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PMID:Protective effect of a protein-bound polysaccharide, PSK, on CLP-induced sepsis in mice transplanted orthotopically with colon tumor. 1636 84

Since the identification of the p38 mitogen-activated protein kinase (MAPK) as a key signal-transducing molecule in the expression of the proinflammatory cytokine tumor necrosis factor (TNF) more than 10 years ago, huge efforts have been made to develop inhibitors of p38 MAPK with the intent to modulate unwanted TNF activity in diseases such as autoimmune diseases or sepsis. However, despite some anti-inflammatory effects in animal models, no p38 MAPK inhibitor has yet demonstrated clinical efficacy in human autoimmune disorders. One possible reason for this paradox might relate to the fact that the p38 MAPK signaling cascade is involved in the functional regulation of several different cell types that all contribute to the complex pathogenesis of human autoimmune diseases. In particular, p38 MAPK has a multifaceted role in CD4 T cells that have been implicated in initiating and driving sustained inflammation in autoimmune diseases, such as rheumatoid arthritis or systemic vasculitis. Here we review recent advances in the understanding of the role of the p38 MAPK signaling cascade in CD4 T cells and the consequences that its inhibition provokes in T cell functions in vitro and in vivo. These new data suggest that p38 MAPK inhibitors may elicit several unwanted effects in human autoimmune diseases but may be useful for the treatment of allergic disorders.
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PMID:The p38 mitogen-activated protein kinase signaling cascade in CD4 T cells. 1654 79

Lipopolysaccharide (LPS) has been implicated as one of the major cause of Gram-negative bacteria-induced sepsis that are life-threatening syndromes occurring in intensive care unit patients. Many natural products derived from medicinal plants may contain therapeutic values on protecting endotoxemia-induced sepsis by virtue their ability to modulate multiple pro-inflammatory cytokines. In the present study, we show that Salvia miltiorrhiza (SM) BUNGE or Danshen, used in treatment of various systemic and surgical infections in the hospitals of China, was able to block the lethal toxicity of LPS in mice via suppression of TNF-alpha release and protection on liver injury. The ability of SM to suppress LPS-induced TNF-alpha release is further confirmed by in vitro experiments conducted on human peripheral blood leukocytes (PBL) and the RAW 264.7 macrophage cell line. Immunophenotyping by flow cytometry shows improved T-helper cell (CD4) and T-suppressor cells (CD8) ratio in SM-treated PBL and splenocytes of LPS-challenged mice. The drop in plasma glutamate-pyruvate transaminase (GPT) induced by LPS provides evidence that SM can protect hepatic damage. The present study explains some known biological activities of SM, and supports the clinical application of SM in the prevention of inflammatory diseases induced by Gram-negative bacteria.
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PMID:Protection of lethal toxicity of endotoxin by Salvia miltiorrhiza BUNGE is via reduction in tumor necrosis factor alpha release and liver injury. 1654 5

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the transmigration of polymorphonuclear neutrophils (PMN) in sepsis. Moreover, the transmigration rate of leukocytes from the blood via endothelial adhesion molecules into tissues correlates with the severity of multi organ failure. We examined the effect of the deletion of the ICAM-1 gene in polymicrobial sepsis using a cecal ligation and puncture (CLP) sepsis model in mice. Twenty male ICAM-1 knockout (KO) mice and 20 wild-type (WT) male C57BL/6 mice were studied. CLP was performed. At several time points during a 96-hour postoperative observation period, we measured mortality, body weight, and temperature. The delayed type of hypersensitivity (DTH) reaction was determined by pinna swelling after sensitization with 50 microL of dinitrofluorobenzene (DNFB) 1%. Lymphocyte subpopulations (CD4, CD8, and CD56) and cytokines [tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and interleukin-10 (IL-10)] were measured using flow cytometry and ELISA testing, respectively. Also, a histologic examination of the liver and lung was performed. CLP-induced mortality was lower in the ICAM-1 group compared to normal mice (5% vs 45.0%). So were the ratios of lymphocyte subpopulations in the KO versus the WT group [CD4: 16.4 +/- 1.6% vs 25.7 +/- 4.7%; CD8: 18.3 +/- 1.4% vs 34.9 +/- 2.9%; natural killer (NK) cells: 5.6 +/- 0.3% vs 49.5 +/- 0.7%; P < 0.01]. And also the cytokine blood levels of the KO mice were significantly lower versus the WT mice (TNF-alpha: 67.2 +/- 42.2 vs 823.9 +/- 170.5 pg/mL; IL-1beta: 5.9 +/- 0.9 vs 296.2 +/- 66.2 pg/mL; IL-6: 223.1 +/- 48.8 vs 3062.5 +/- 1222.8 pg/mL; IL-10: 34.6 +/- 5.8 vs 1565.6 +/- 448.8 pg/mL; P < 0.01). With respect to the histology, significantly less leukocyte invasion and organ damage (eg, hydropic degeneration) were present in the ICAM-1-/- group compared to controls in liver and lung tissues. The DTH reaction was significantly decreased in ICAM-1-/- mice versus WT mice (0.34 vs 0.41 mm; P < 0.05). Our results demonstrate a significant reduction of mortality after septic challenge in ICAM-1-/- mice compared to normal mice. This is associated with a decrease in lymphocyte subpopulations, cytokine levels, and DTH type 4 reaction, possibly reflecting an overall attenuation of the immune system.
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PMID:Leukocyte-endothelial interactions via ICAM-1 are detrimental in polymicrobial sepsis. 1655 57

This study reports the design of an immunofluorescent method for the co-determination of neutrophil CD64 (PMN-CD64), monocyte CD64 (MON-CD64) and monocyte HLA-DR (MON-Ia) expression with the Cell-Dyn CD4,000 haematology analyser. Normal PMN-CD64, MON-CD64 and MON-Ia expression, defined as the mean+/-2SD of 25 healthy adults after correction for isotype control staining, corresponded to 17-67, 515-1045 and 170-670 AFU respectively. Analytical reproducibility determined by duplicate analysis of 12 random samples revealed good assay consistency for all three analysed antigens, with day to day variation in normal subjects being relatively minor in significance. CD4,000 PMN-CD64 and HLA-DR values showed good inter-method correlation with flow cytometry although short term (12 h) stability studies suggested an in vitro trend for increasing PMN-CD64 and variable HLA-DR antigen expression with progressive storage. Observed ranges of PMN-CD64, MON-CD64 and MON-Ia for 109 randomly-selected clinical samples were 31-1058, 307-2843 and 10-876 AFU. Abnormal PMN-CD64 and MON-CD64 shared the same trend (upregulation) while abnormal monocyte MON-Ia was characterised by declining expression. Normal PMN-CD64 was only seen with normal (45/52) or intermediate (7/52) MON-CD64, while high PMN-CD64 was mostly associated with intermediate (18/22) or high (3/22) MON-CD64. MON-Ia expression was largely independent (p=0.04) of PMN-CD64 although marked decreases in MON-Ia were invariably associated with intermediate or high PMN-CD64. MON-Ia expression was inversely related (p<0.0001) to absolute granulocyte counts, and patients with high PMN-CD64 were more likely (8/25) to have in excess of 10% Band Cells compared to samples with normal/intermediate PMN-CD64 (0/84). When compared to C-reactive protein (CRP), high PMN-CD64 and MON-CD64 were always associated with an increased CRP concentration, but minor proportions of samples with normal PMN-CD64 (11/52) or normal MON-CD64 (11/65) could also have an increased CRP. The procedures described in this communication overcome a number of limitations associated with flow cytometry, and co-determination of CD64 and HLA-DR antigen expression may provide complimentary insights into patient heterogeneity in the assessment of suspected sepsis compared to CD64 analysis alone.
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PMID:Simultaneous determination of membrane CD64 and HLA-DR expression by blood neutrophils and monocytes using the monoclonal antibody fluorescence capability of a routine haematology analyser. 1655 67

Interactions between HIV and surgical diseases are relatively poorly described in high HIV prevalence settings. We report HIV prevalence and its associations in a prospective study of adults admitted to surgical units in Soweto, South Africa. Voluntary counselling and testing (VCT) for HIV was offered to surgical inpatients. Research nurses interviewed participants at enrolment and doctors reviewed records after discharge. In HIV-infected participants, CD4 counts and viral loads were ascertained. Of 1000 participants, 537 consented to VCT, of whom 176 (32.8%, 95% CI 28.8-36.9%) tested HIV positive. A history of tuberculosis (adjusted odds ratio (AOR) 3.0, 95% CI 1.5-6.2) or sexually transmitted infection (AOR 2.7, 95% CI 1.8-4.2) was associated with HIV infection. Diagnoses of cutaneous abscesses (OR 3.4, 95% CI 1.4-8.1) and anorectal sepsis (OR 3.1, 95% CI 1.1-9.0) were associated with HIV and indicated advanced disease. There were no differences in rates of operative procedures, wound sepsis, investigations or length of stay by HIV status. Hospital-acquired pneumonia was more common in HIV-infected participants (P=0.028). In conclusion, in this high HIV prevalence setting, resource utilisation is similar between HIV-infected and uninfected patients in surgical wards where high rates of HIV in young adults support routine HIV testing. WHO clinical staging of HIV should include anal sepsis as an indicator of advanced HIV disease.
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PMID:High rates of HIV in surgical patients in Soweto, South Africa: impact on resource utilisation and recommendations for HIV testing. 1681 22

We present the case of a 74-y-old HIV-negative female who suffered simultaneously from multiple opportunistic infections and a Klebsiella pneumoniae sepsis during high-dose steroids for giant cell arteritis. The patient was treated with a purine analog due to hairy cell leukaemia 10 y previously. Purine analog therapy can lead to long lasting defects in cell-mediated immunity. In these patients, treatment with steroids should be closely monitored with CD4 counts.
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PMID:Multiple opportunistic infections after high-dose steroid therapy for giant cell arteritis in a patient previously treated with a purine analog. 1700 40

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

Studies have indicated that there is a development of generalized immune dysfunction after septic insult. However, the mechanisms responsible for these changes remain unclear. Recently, accumulating evidence shows that several lymphocyte subpopulations such as NKT-, CD4(+)-Th2-T-, CD8(+)-T-, gammadelta-T-, and CD4+ CD25+ T regulatory cells are capable of actively contributing to the induction of septic immune suppression. Thus, our aim was to investigate the contribution of CD4+ CD25+ cells to the immune dysfunction seen in sepsis. To study this, C57BL/6J, C57BL/6-Il6(tm1Kopf) (interleukin [IL] 6 -/-), and C57BL/6-Il10(tm1Cgn) (IL-10 -/-) mice were subjected to cecal ligation and puncture (CLP) or sham operations. Twenty-four hours later, blood was collected, and splenocytes were isolated. Phenotypic expression of CD4/CD25 (by fluorescence-activated cell sorter), cell proliferation (presented as proliferation index = [with anti-CD3]/[without anti-CD3]), and immune suppressive capacity (by in vitro add-back experiments) were assessed. The results indicate a marked elevation in CD4+ CD25+ cell levels and their proliferation index after sepsis in background mice. CD4+ CD25- cells from sham and CLP mice proliferated equally. However, coculture of CD4+ CD25- with CD4+ CD25+ cells suppressed their proliferation in both sham and CLP mice. Depletion of CD25+ cells in vivo before CLP markedly restored CD4+ CD25- proliferative capacity and Th1 cytokine release while not altering plasma proinflammatory cytokine levels. Subsequently, IL-6 -/- and IL-10 -/- mice were used to elucidate the possible mediator(s) regulating the changes seen after sepsis. Although CD4+ CD25+ cells increased after septic insult in both C57BL/6J and IL-6 -/- mice, this was not observed in IL-10 -/- mice. Similarly, in vitro proliferation studies showed that proliferation index increased in CD4+ CD25+ cells from septic C57BL/6J and IL6 -/- mice, but it remained the same in IL-10 -/- mice. Surprisingly, depletion of CD25+ cells before inducing sepsis did not alter septic mortality. Together, these findings suggest that although CD4+ CD25+ T regulatory cells induced by IL-10 seem to contribute to aspects of sepsis-induced lymphoid immune suppression, the oblation of CD25+ cells does not provide a survival advantage or disadvantage.
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PMID:The contribution of CD4+ CD25+ T-regulatory-cells to immune suppression in sepsis. 1730 5


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