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)

Sepsis causes brain dysfunction. Because neurotransmission requires high ascorbate and low dehydroascorbic acid (DHAA) concentrations in brain extracellular fluid, the effect of septic insult on ascorbate recycling (i.e., uptake and reduction of DHAA) and export was investigated in primary rat and mouse astrocytes. DHAA raised intracellular ascorbate to physiological levels but extracellular ascorbate only slightly. Septic insult by lipopolysaccharide and interferon-gamma increased ascorbate recycling in astrocytes permeabilized with saponin but decreased it in those with intact plasma membrane. The decrease was due to inhibition of the glucose transporter (GLUT1) that translocates DHAA because septic insult slowed uptake of the nonmetabolizable GLUT1 substrate 3-O-methylglucose. Septic insult also abolished stimulation by glutamate of ascorbate export. Specific nitric oxide synthase (NOS) inhibitors and nNOS and iNOS deficiency failed to alter the effects of septic insult. Inhibitors of NADPH oxidase generally did not protect against septic insult, because only one of those tested (diphenylene iodonium) increased GLUT1 activity and ascorbate recycling. We conclude that astrocytes take up DHAA and use it to synthesize ascorbate that is exported in response to glutamate. This mechanism may provide the antioxidant on demand to neurons under normal conditions, but it is attenuated after septic insult.
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PMID:Sepsis inhibits recycling and glutamate-stimulated export of ascorbate by astrocytes. 1619 26

Septic shock, the most severe problem of sepsis, is a lethal condition caused by the interaction of a pathogen-induced long chain of sequential intracellular events in immune cells, epithelium, endothelium, and the neuroendocrine system. The lethal effects of septic shock are associated with the production and release of numerous pro-inflammatory biochemical mediators including cytokines, nitric oxide and toxic oxygen and nitrogen radicals, together with development of massive apoptosis. As melatonin has remarkable properties as a cytokine modulator, antioxidant and anti-apoptotic agent, the present study was designed to evaluate the possible protective effect of melatonin against LPS-induced septic shock in Swiss mice. We observed that intraperitoneally (i.p.) administered-melatonin (10 mg/kg) 30 min prior, and 1 hr after i.p. LPS injection (0.75 mg/animal) markedly protected mice from the LPS lethal effects with 90% survival rates for melatonin and 20% for LPS-injected mice after 72 hr. The melatonin effect was mediated by modulating the release of pro-/anti-inflammatory cytokine levels, protection from oxidative damage and counteracting apoptotic cell death. Melatonin was able to partially counteract the increase in LPS-induced pro-inflammatory cytokine levels such as tumor necrosis factor-alpha, IL-12 and interferon-gamma at the local site of injection, while it increased the production of the anti-inflammatory cytokine IL-10 both locally and systemically. Furthermore, melatonin inhibited the LPS-induced nitrite/nitrate and lipid peroxidation levels in brain and liver and counteracted the sepsis-associated apoptotic process in spleen. In conclusion, we have demonstrated that melatonin improves the survival of mice with septic shock via its pleiotropic functions as an immunomodulator, antioxidant and anti-apoptotic mediator.
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PMID:Beneficial pleiotropic actions of melatonin in an experimental model of septic shock in mice: regulation of pro-/anti-inflammatory cytokine network, protection against oxidative damage and anti-apoptotic effects. 1620 96

Apoptosis and inflammation play an important role in the pathogenesis of direct/pulmonary acute lung injury (ALI). However, the role of the Fas receptor-driven apoptotic pathway in indirect/nonpulmonary ALI is virtually unstudied. We hypothesized that if Fas or caspase-8 plays a role in the induction of indirect ALI, their local silencing using small interfering RNA (siRNA) should be protective in hemorrhage-induced septic ALI. Initially, as a proof of principle, green fluorescent protein-siRNA was administered intratracheally into transgenic mice overexpressing green fluorescent protein. Twenty-four hours after siRNA delivery, lung sections revealed a significant decrease in green fluorescence. Intratracheally administered Cy-5-labeled Fas-siRNA localized primarily in pulmonary epithelial cells. Intratracheal instillation of siRNA did not induce lung inflammation via toll-like receptor or protein kinase PKR pathways as assessed by lung tissue interferon-alpha, tumor necrosis factor-alpha, and interleukin (IL)-6 levels. Mice subjected to hemorrhagic shock and sepsis received either Fas-, caspase-8-, or control-siRNA intratracheally 4 hours after hemorrhage. Fas- or caspase-8-siRNA significantly reduced lung tissue Fas or caspase-8 mRNA, respectively. Only Fas-siRNA markedly diminished lung tissue tumor necrosis factor-alpha, IL-6, IL-10, interferon-gamma, IL-12, and caspase-3 activity. Fas-siRNA also preserved alveolar architecture and reduced lung neutrophil infiltration and pulmonary epithelial apoptosis. These data indicate the pathophysiological significance of Fas activation in nonpulmonary/shock-induced ALI and the feasibility of intrapulmonary administration of anti-apoptotic siRNA in vivo.
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PMID:Silencing of Fas, but not caspase-8, in lung epithelial cells ameliorates pulmonary apoptosis, inflammation, and neutrophil influx after hemorrhagic shock and sepsis. 1631 69

Despite recent advances in antibiotic therapy and intensive care, sepsis remains a widespread problem in critically ill patients. The high mortality from sepsis is in part mediated by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., tumor necrosis factor, interleukin-1, and interferon-gamma) and late [e.g., high mobility group box 1 protein (HMGB1)] proinflammatory cytokines. Our discovery of HMGB1 as a late mediator of lethal systemic inflammation has initiated a new field of investigation for the development of experimental therapeutics. A popular Chinese herb, Angelica sinensis (also known as Dang Gui or Dong Quai) has been used traditionally for treating women with gynecological disorders (such as dysmenorrheal and hot flashes). Here we examined the effect of Angelica sinensis extract on endotoxin-induced HMGB1 release in vitro, and explored its therapeutic potential in animal models of lethal endotoxemia and sepsis [induced by cecal ligation and puncture (CLP)] in vivo. We demonstrated that a low-molecular-weight (<10 kDa) fraction of A. sinensis extract significantly attenuated endotoxin-induced HMGB1 release in part through interfering with its cytoplasmic translocation in macrophage cultures. Prophylactic administration of an aqueous extract of A. sinensis significantly attenuated systemic HMGB1 accumulation in vivo, and conferred a dose-dependent protection against lethal endotoxemia. Furthermore, delayed administration of A. sinensis extract beginning 24 h after CLP attenuated systemic HMGB1 accumulation, and significantly rescued mice from lethal sepsis. Taken together, these data suggest that A. sinensis contains water-soluble components that exert protective effects against lethal endotoxemia and experimental sepsis in part by attenuating systemic accumulation of a late proinflammatory cytokine, HMGB1.
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PMID:The aqueous extract of a popular herbal nutrient supplement, Angelica sinensis, protects mice against lethal endotoxemia and sepsis. 1642 12

Flagellin is the major protein component of the flagella from motile bacteria and was identified as the ligand for toll-like receptor (TLR)-5. Whereas its effects on epithelial cells have been studied in detail, activation of human peripheral blood mononuclear cells (PBMC) by flagellin is characterized only partially. By using the recombinant protein of Salmonella muenchen we confirm the proinflammatory nature of flagellin as detected by nuclear factor-kappaB activation and interleukin (IL)-8 production. Aim of the current study was to elucidate in PBMC effects of flagellin on IL-18 and Th1-like cytokine responses. We report that flagellin in pathophysiologically relevant concentrations augmented release of mature IL-18 by THP-1 monocytes, PBMC, and whole blood stimulated with nigericin or by ATP-mediated P2X7 purinergic receptor activation. Further key functions of the IL-18/IL-12/interferon-gamma (IFNgamma) pathway were upregulated by flagellin. Flagellin synergized with IL-12 for production of IFN-gamma and augmented secretion of interferon-inducible protein-10, a CXC-chemokine that is key to the generation of Th1-type responses. In contrast, neither IL-18-binding protein nor IL-4 was affected. Taken together, the present data demonstrate for the first time that flagellin at concentrations that are detectable in the blood compartment during sepsis efficiently enhances the IL-18/IL-12/IFNgamma pathway and thus Th1-like cytokine responses in PBMC.
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PMID:Interleukin-18 secretion and Th1-like cytokine responses in human peripheral blood mononuclear cells under the influence of the toll-like receptor-5 ligand flagellin. 1644 39

This study investigated the effects of arginine (Arg) on cellular adhesion molecules and intracellular Th1/Th2 cytokine expressions in mice with polymicrobial sepsis. Myeloperoxidase activity in organs was also analyzed to identify the extent of tissue injury resulting from neutrophil infiltration. Mice were randomly assigned to a normal group (NC), a control group, or an Arg group. The NC group was fed a standard chow diet. The control group was fed a common semipurified diet, and in the Arg group, part of the casein was replaced by Arg, which provided 2% of the total calories. After 3 weeks, sepsis was induced by cecal ligation and puncture (CLP) in the control and Arg groups. Mice in the experimental groups were sacrificed at 0, 6, 12, and 24 h after CLP, whereas mice in the NC group were sacrificed when the CLP was performed. Blood and organ samples were immediately collected for further analysis. Results showed that compared with the control group, plasma intracellular adhesion molecule-1 levels were significantly higher in the Arg group 12 and 24 h after CLP. Lymphocyte interferon-gamma expression in the Arg groups was significantly lower, whereas interleukin (IL)-4 expression was higher than the control group at various time points after CLP. The expression of lymphocyte CD11a/CD18 was significantly higher in the Arg group 6, 12, and 24 h after CLP than those of the corresponding control group and the NC group. PMN expressions of CD11b/CD18 in the Arg groups were higher than those in the control group at 12 and 24 h after CLP. The Arg group had higher IL-6 levels at 6 and 12 h in the kidney and intestine and 12 h in the lung after CLP. Higher myeloperoxidase activities were observed in the Arg groups at 24 h after CLP than those in the control group in various organs. These findings suggest that pretreatment with an Arg-supplemented diet enhances adhesion molecule and inflammatory cytokine expression during sepsis, which may aggravate the inflammatory reaction and increase neutrophil infiltration into tissues. In addition, Arg supplementation reduced intracellular interferon-gamma and enhanced IL-4 expression. This change may promote the Th2-type response and suppress the cellular immune response in gut-derived sepsis.
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PMID:Dietary arginine enhances adhesion molecule and T helper 2 cytokine expression in mice with gut-derived sepsis. 1652 54

Parthenolide, a sesquiterpene lactone, inhibited lipopolysaccharide (LPS) stimulated nuclear factor (NF)-kappabeta and cytokine production in vitro and in rats, and improved survival in LPS challenged Swiss albino mice. We investigated whether increased survival with parthenolide was associated directly with inhibition of NF-kappabeta and cytokines in LPS challenged C57BL/6J mice. In RAW 264.7 cells, parthenolide inhibited LPS-stimulated NF-kappabeta and cytokines (interleukin [IL]-1alpha, -1beta, -2, -4, -6, and -10, interferon-gamma, tumor necrosis factor-alpha, granulocyte macrophage-colony stimulating factor, migratory inhibitory protein-1 and -2alpha, JE, and RANTES). In mice (n = 366) receiving lethal intraperitoneal (i.p.) LPS (40 mg/kg), compared to placebo, each of 5 parthenolide doses (0.25 to 4 mg/kg i.p. following LPS) reduced survival at 168h and overall worsened the hazards ratio of survival (mean +/- S.E.M.) (1.29 +/- 0.12, p = 0.04). In other mice (241), compared to saline challenge, nonlethal LPS (2.5 mg/kg) increased NF-kappabeta in lung and kidney combined and 12 of 13 plasma cytokines early (1 and 3 h) and late (6, 9 and 12 h) (p < or = 0.002 for each). Compared to nonlethal LPS, lethal LPS increased NF-kappabeta and 12 of 13 cytokines early but not significantly and late significantly (p < or = 0.05 for each). With lethal LPS, compared to placebo, parthenolide (1 mg/kg) decreased NF-kappabeta and 10 of 13 cytokines early and increased NF-kappabeta and 11 of 13 cytokines late (p < or = 0.02 for early vs. late). Although parthenolide inhibits NF-kappabeta and cytokines in vitro, its effects on these mediators and survival in animal sepsis models vary. Theses differences must be understood before parthenolide or related agents are applied clinically for sepsis.
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PMID:Parthenolide has limited effects on nuclear factor-kappa beta increases and worsens survival in lipopolysaccharide-challenged C57BL/6J mice. 1672 96

The deregulation of inflammatory response during sepsis seems to reflect the overproduction of mediators, which suppress leukocyte functions. We investigated the intracellular mechanisms underlying the inability of neutrophils from severe septic patients to migrate toward chemoattractants. Patients with sepsis (52) and 15 volunteers were prospectively enrolled. Patients presented increased circulating levels of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-8, and IL-10. Patients showed reduced neutrophil chemotaxis to formyl-methionyl-leucyl-phenylalanine (FMLP), leukotriene B4 (LTB4) or IL-8. No difference in the transcription or expression of the IL-8 receptor, CXCR1, was detected in neutrophils from controls and patients. However, septic neutrophils failed to increase tyrosine phosphorylation and actin polymerization in response to IL-8 or LTB4. In contrast, septic neutrophils, similar to controls, showed phagocytic activity that induced actin polymerization and augmented phosphotyrosine content. Treatment of control neutrophils with cytokines and lipopolysaccharide (LPS) to mimic endogenous septic environment inhibited actin polymerization and tyrosine phosphorylation in response to IL-8 or LTB4. High expression of G protein-coupled receptor kinase 2 (GRK2) and GRK5 was detected in septic neutrophils and control cells treated with cytokines plus LPS. Data suggest that endogenous mediators produced during sepsis might continually activate circulating neutrophils, leading to GRK activation, which may induce neutrophil desensitization to chemoattractants.
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PMID:Impaired neutrophil chemotaxis in sepsis associates with GRK expression and inhibition of actin assembly and tyrosine phosphorylation. 1684 37

Hyperglycemia in critical illness is a common complication and a strong independent risk factor for morbidity and death. Intensive insulin therapy decreases this risk by up to 50%. It is unclear to what extent this benefit is due to reversal of glucotoxicity or to a direct effect of insulin, because antiinflammatory effects of insulin have already been described, but the underlying mechanisms are still poorly understood. The insulin receptor is expressed on resting neutrophils, monocytes, and B cells, but is not detectable on T cells. However, significant up-regulation of insulin receptor expression is observed on activated T cells, which suggests an important role during T cell activation. Exogenous insulin in vitro induced a shift in T cell differentiation toward a T helper type 2 (Th2)-type response, decreasing the T helper type 1 to Th2 ratio by 36%. This result correlated with a corresponding change in cytokine secretion, with the interferon-gamma to IL-4 ratio being decreased by 33%. These changes were associated with increased Th2-promoting ERK phosphorylation in the presence of insulin. Thus, we demonstrate for the first time that insulin treatment influences T cell differentiation promoting a shift toward a Th2-type response. This effect of insulin in changing T cell polarization may contribute to its antiinflammatory role not only in sepsis, but also in chronic inflammation associated with obesity and type 2 diabetes.
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PMID:Potential antiinflammatory role of insulin via the preferential polarization of effector T cells toward a T helper 2 phenotype. 1700 95

This study investigated the effects of fish oil (FO) diet on plasma intercellular adhesion molecule 1 (ICAM-1) levels and leucocyte integrin expression in polymicrobial sepsis. Mice were randomly assigned to a control group and an FO group. The control group was fed a medium-fat diet containing soyabean oil, whereas in the FO group, 70 % of the soyabean oil was replaced by FO for 3 weeks. After that, sepsis was induced by caecal ligation and puncture (CLP) in the experimental groups and mice were killed at 0, 6, 12 and 24 h, respectively, after CLP. Results showed that compared with the control group, plasma ICAM-1 levels were higher in the FO group 6 h after CLP. Intra-lymphocyte interferon-gamma expression in the FO group was lower, whereas IL-4 expression was higher than in the control group 12 and 24 h after CLP. The expression of leucocyte integrin was significantly higher in the FO group 12 and 24 h after CLP. The FO group had higher IL-6 levels at 12 h in the lungs, at 6 and 12 h in the kidneys, and at 6, 12 and 24 h in the intestines after CLP. The survival rate did not differ between the two groups after CLP. The present findings suggest that pretreatment with an FO diet enhances adhesion molecule and inflammatory cytokine expressions during sepsis, which might aggravate the inflammatory reaction and increase neutrophil infiltration into tissues. In addition, FO diet promotes the Th2-type response and suppresses cellular immune response in polymicrobial sepsis.
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PMID:Dietary fish oil enhances adhesion molecule and interleukin-6 expression in mice with polymicrobial sepsis. 1709 73


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