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)

Dendritic cells (DCs) are professional antigen-presenting cells and members of the adoptive immunity. In addition, they play an important role in innate immunity within the systemic inflammatory response to trauma and sepsis. In this study, gene expression patterns of DC in patients with multiple trauma were studied. Total RNA was isolated from highly purified DCs (purity>95%) that were enriched from peripheral blood mononuclear cells and whole blood, respectively. Samples were obtained from 10 multiple trauma patients (injury severity score, 35.4+/-10.6 on day of admission) and 5 healthy volunteers (control). Aliquots of target cDNAs and reference samples (cDNA derived from the monocytic cell line SIGM5) were cohybridized on a thematic medium-density microarray assessing 780 inflammation-related transcripts. Twenty transcripts were up-regulated in DCs of multiple trauma patients compared with healthy volunteers, whereas these differences were missed when RNA from whole blood was subjected to transcriptomic profiling. This cluster included central effector molecules of DC such as transcripts encoding for 5-lipoxygenase and the corresponding leukotriene 4 receptor, which regulate DC migration, adoptive immune responses, and airway inflammation, as well as CD74, CXCL4, or platelet factor 4, a chemokine not implicated as a product of DCs to date. In addition, genes involved in antiapoptosis (BCL2), intracellular signal transduction (mitogen-activated protein kinase), and secretion of mediators (VAMP2) were found to be up-regulated. The up-regulated transcripts suggest that life span and signaling function of DCs are altered by trauma. Furthermore, these data confirm and expand the central role of chemokines and lipid mediators as effector molecules of DC-mediated immune responses in systemic inflammation associated with severe trauma.
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PMID:Altered gene expression patterns in dendritic cells after severe trauma: implications for systemic inflammation and organ injury. 1832 45

Postoperative or posttraumatic sepsis remains one of the leading causes of morbidity and mortality in hospital populations, especially in populations in intensive care units (ICUs). Central to the successful control of sepsis-associated infections is the ability to rapidly diagnose and treat disease. The ability to identify sepsis patients before they show any symptoms would have major benefits for the health care of ICU patients. For this study, 92 ICU patients who had undergone procedures that increased the risk of developing sepsis were recruited upon admission. Blood samples were taken daily until either a clinical diagnosis of sepsis was made or until the patient was discharged from the ICU. In addition to standard clinical and laboratory parameter testing, the levels of expression of interleukin-1beta (IL-1beta), IL-6, IL-8, and IL-10, tumor necrosis factor-alpha, FasL, and CCL2 mRNA were also measured by real-time reverse transcriptase PCR. The results of the analysis of the data using a nonlinear technique (neural network analysis) demonstrated discernible differences prior to the onset of overt sepsis. Neural networks using cytokine and chemokine data were able to correctly predict patient outcomes in an average of 83.09% of patient cases between 4 and 1 days before clinical diagnosis with high sensitivity and selectivity (91.43% and 80.20%, respectively). The neural network also had a predictive accuracy of 94.55% when data from 22 healthy volunteers was analyzed in conjunction with the ICU patient data. Our observations from this pilot study indicate that it may be possible to predict the onset of sepsis in a mixed patient population by using a panel of just seven biomarkers.
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PMID:Presymptomatic prediction of sepsis in intensive care unit patients. 1848 Feb 35

Fractalkine (FTK) is a unique member of the CX3C chemokine family by acting through the CX3CR1 receptor. Membrane-bound FTK acts like an adhesion molecule, whereas soluble FTK (sFTK) acts as a classic chemokine ligand. Whether this chemokine plays a role in sepsis is still not clear. Using a mouse model of cecal ligation and puncture (CLP)-induced sepsis, we found that FTK levels were elevated in plasma 24 h after CLP. Reverse transcription-polymerase chain reaction results showed that FTK messenger RNA levels were upregulated, whereas CX3CR1 messenger RNA levels were downregulated in lungs after CLP procedure. To study the role of FTK in lung injury during sepsis, we injected exogenous sFTK into the mice before the CLP procedure. We found that plasma FTK levels were further elevated by sFTK. Mice that were injected with FTK had a lower myeloperoxidase activity in lungs compared with the CLP group. Furthermore, macrophage inflammatory protein 2, IL-1beta, and IL-6 levels in lungs were reduced after the injection of FTK. Treatment with sFTK also attenuated lung morphological changes in histological sections. To find out whether sFTK had an effect on leukocyte rolling and adherence, intravital microscope was used. Results showed that sFTK significantly attenuated leukocyte adhesion but had little effect on leukocyte rolling in mesenteric microcirculation. Taken together, our findings suggest that FTK may be a novel chemokine that modulates neutrophil infiltration and chemokine and cytokine production during sepsis.
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PMID:Administration of exogenous fractalkine, a CX3C chemokine, is capable of modulating inflammatory response in cecal ligation and puncture-induced sepsis. 1849 8

Fatal cases of acute shock complicating Clostridium sordellii endometritis following medical abortion with mifepristone (also known as RU-486) used with misoprostol were reported. The pathogenesis of this unexpected complication remains enigmatic. Misoprostol is a pharmacomimetic of PGE(2), an endogenous suppressor of innate immunity. Clinical C. sordellii infections were associated with intravaginal misoprostol administration, suggesting that high misoprostol concentrations within the uterus impair immune responses against C. sordellii. We modeled C. sordellii endometritis in rats to test this hypothesis. The intrauterine but not the intragastric delivery of misoprostol significantly worsened mortality from C. sordellii uterine infection, and impaired bacterial clearance in vivo. Misoprostol also reduced TNF-alpha production within the uterus during infection. The intrauterine injection of misoprostol did not enhance mortality from infection by the vaginal commensal bacterium Lactobacillus crispatus. In vitro, misoprostol suppressed macrophage TNF-alpha and chemokine generation following C. sordellii or peptidoglycan challenge, impaired leukocyte phagocytosis of C. sordellii, and inhibited uterine epithelial cell human beta-defensin expression. These immunosuppressive effects of misoprostol, which were not shared by mifepristone, correlated with the activation of the G(s) protein-coupled E prostanoid (EP) receptors EP2 and EP4 (macrophages) or EP4 alone (uterine epithelial cells). Our data provide a novel explanation for postabortion sepsis leading to death and also suggest that PGE(2), in which production is exaggerated within the reproductive tract during pregnancy, might be an important causal determinant in the pathogenesis of more common infections of the gravid uterus.
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PMID:Misoprostol impairs female reproductive tract innate immunity against Clostridium sordellii. 1868 13

The ScpC protease of Streptococcus pyogenes degrades interleukin-8 (IL-8), a chemokine that mediates neutrophil transmigration and activation. The ability to degrade IL-8 differs dramatically among clinical isolates of S. pyogenes. Bacteria expressing ScpC overcome immune clearance by preventing the recruitment of neutrophils in soft tissue infection of mice. To study the role of ScpC in streptococcal sepsis, we generated an ScpC mutant that did not degrade IL-8 and thus failed to prevent the recruitment of immune cells as well as to cause disease after soft tissue infection. In a murine model of sepsis, challenge with the ScpC mutant resulted in more severe systemic disease with higher bacteremia levels and mortality than did challenge with the wild-type strain. As expected, the blood level of KC, the murine IL-8 homologue, increased in mice infected with the ScpC mutant. However, the elevated KC levels did not influence neutrophil numbers in blood, as it did in soft tissue, indicating that additional factors contributed to neutrophil transmigration in blood. In addition, the absence of ScpC increased tumor necrosis factor, IL-6, and C5a levels in blood, which contributed to disease severity. Thus, the ScpC mutant triggers high neutrophil infiltration but not lethal outcome after soft tissue infection, whereas intravenous infection leads to highly aggressive systemic disease.
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PMID:The ScpC protease of Streptococcus pyogenes affects the outcome of sepsis in a murine model. 1857

Chemokines play pivotal roles in regulating a wide variety of biological processes by modulating cell migration and recruitment. Deregulation of chemokine signaling can alter cell recruitment, contributing to the pathogenic states associated with autoimmune disease, inflammatory disorders, and sepsis. During chemotaxis, lipid rafts and their resident signaling molecules have been demonstrated to partition to different parts of the cell. Herein, we investigated the role of lipid raft resident Src-family kinases (SFK) in stromal cell-derived factor 1/CXCL12-mediated chemotaxis. We have shown that Lck-deficient J.CaM 1.6 cells are defective in CXCL12-mediated chemotaxis in contrast to their parental counterpart, Jurkat cells. Ectopic expression of the SFK hematopoietic cell kinase (Hck) in J.CaM 1.6 cells reconstituted CXCL12 responsiveness. The requirement of lipid raft association of SFK was assessed using both isoforms of Hck: the dually acylated p59(Hck) isoform that is targeted to lipid rafts and the monoacylated p61(Hck) isoform that is nonraft-associated. We have shown using several gain and loss of acylation alleles that dual acylation of Hck was required for CXCL12-mediated chemotaxis in J.CaM 1.6 cells. These results highlight the importance of the unique microenvironment provided by lipid rafts and their specific contribution in providing specificity to CXCL12 signaling.
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PMID:Dual acylation and lipid raft association of Src-family protein tyrosine kinases are required for SDF-1/CXCL12-mediated chemotaxis in the Jurkat human T cell lymphoma cell line. 1863 89

Chronic inflammation and acute exacerbations are pathophysiological features of chronic obstructive pulmonary disease (COPD). An impaired immune response to bacterial pathogens can contribute to both of them. Nucleotide oligomerization domain 2 (NOD2) is an intracellular receptor of innate immunity for muramyldipeptide (MDP). Mutations of the NOD2 gene followed by decreased recognition of MDP are associated with chronic intestinal inflammation and pulmonary complications of patients with allogenic stem cell transplant and sepsis. Our study provides evidence that NOD2, toll-like receptor 4 (TLR4) and the adapter protein receptor-interacting protein 2 (RIP2) are induced by tumor-necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) in the bronchial epithelial cell line BEAS-2B. We also demonstrate that lipopolysaccharide (LPS) can further increase NOD2 transcription in a TNF-alpha and IFN-gamma-induced activation state. In addition, we show that, while MDP fails to enhance CXCL-8 release from otherwise unstimulated BEAS-2B cells, a 12 h prestimulation period with TNF-alpha and IFN-gamma primes the cells for an additional increase of CXCL-8 secretion via induction of NOD2 and RIP2. LPS itself significantly augments CXCL-8 production and co-administration of MDP further increases cytokine secretion. Finally, overexpression of an SNP13 mutant decreased MDP-induced chemokine production in BEAS-2B cells compared with NOD2 wild type overexpression. Taken together, our work indicates that MDP and NOD2 play an important role for CXCL-8 release of BEAS-2B cells following LPS-challenge via synergistic interactions between MDP and LPS.
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PMID:Muramyldipeptide modulates CXCL-8 release of BEAS-2B cells via NOD2. 1864 46

Sex is increasingly recognized as a major factor in the outcome of patients who have trauma and sepsis. Moreover, sex steroids influence chemokine/adhesion molecule expression and neutrophil accumulation. Heat shock proteins, heat shock factor 1, and peroxisome proliferator-activated receptor [gamma] coactivator 1 are regulated by the estrogen receptors and consequently contribute to organ protection after trauma-hemorrhage. Additionally, sex steroids regulate inflammatory cytokines, leading to increased morbidity and mortality. This article deals with trauma-hemorrhage and examines the following: 1) the evidence for sex differences; 2) the mechanisms by which sex hormones affect organ protection; 3) the tissue-specific effect of sex hormone receptors; and 4) the effect of genomic and nongenomic (i.e. membrane-initiated steroid signaling) pathways of sex hormones after trauma. The available information indicates that sex steroids modulate cardiovascular responses after trauma. Thus, alteration or modulation of the prevailing hormone milieu at the time of injury seems to be a novel therapeutic option for improving outcome after injury
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PMID:The role of estrogen and receptor agonists in maintaining organ function after trauma-hemorrhage. 1866 49

Ligands from dying cells are a source of Toll-like receptor (TLR) activating agents. Although TLR3 is known to respond to RNA from necrotic cells, the relative importance of this response in vivo during acute inflammatory processes has not been fully explored. We observed the involvement of TLR3 activation during experimental polymicrobial septic peritonitis and ischemic gut injury in the absence of an exogenous viral stimulus. In TLR3-deficient mice, increased chemokine/cytokine levels and neutrophil recruitment characterized the initial inflammatory responses in both injury models. However, the levels of inflammatory chemokines and tumor necrosis factor alpha quickly returned to baseline in tlr3(-/-) mice, and these mice were protected from the lethal effects of sustained inflammation. Macrophages from tlr3(-/-) mice responded normally to other TLR ligands but did not respond to RNA from necrotic neutrophils. Importantly, an immunoneutralizing antibody directed against TLR3 attenuated the generation of inflammatory chemokines evoked by byproducts from necrotic neutrophils cultured with wild-type macrophages. In vivo, anti-TLR3 antibody attenuated the tissue injury associated with gut ischemia and significantly decreased sepsis-induced mortality. Collectively, these data show that TLR3 is a regulator of the amplification of immune response and serves an endogenous sensor of necrosis, independent of viral activation.
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PMID:TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. 1883 47

Mincle (also called as Clec4e and Clecsf9) is a C-type lectin receptor expressed in activated phagocytes. Recently, we have demonstrated that Mincle is an FcRgamma-associated activating receptor that senses damaged cells. To search an exogenous ligand(s), we screened pathogenic fungi using cell line expressing Mincle, FcRgamma, and NFAT-GFP reporter. We found that Mincle specifically recognizes the Malassezia species among 50 different fungal species tested. Malassezia is a pathogenic fungus that causes skin diseases, such as tinea versicolor and atopic dermatitis, and fatal sepsis. However, the specific receptor on host cells has not been identified. Mutation of the putative mannose-binding motif within C-type lectin domain of Mincle abrogated Malassezia recognition. Analyses of glycoconjugate microarray revealed that Mincle selectively binds to alpha-mannose but not mannan. Thus, Mincle may recognize specific geometry of alpha-mannosyl residues on Malassezia species and use this to distinguish them from other fungi. Malassezia activated macrophages to produce inflammatory cytokines/chemokines. To elucidate the physiological function of Mincle, Mincle-deficient mice were established. Malassezia-induced cytokine/chemokine production by macrophages from Mincle(-/-) mice was significantly impaired. In vivo inflammatory responses against Malassezia was also impaired in Mincle(-/-) mice. These results indicate that Mincle is the first specific receptor for Malassezia species to be reported and plays a crucial role in immune responses to this fungus.
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PMID:C-type lectin Mincle is an activating receptor for pathogenic fungus, Malassezia. 1917 87


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