UMLS:C0036690 - FACTA Search

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

Lipid bodies are rapidly inducible, specialized cytoplasmic domains for eicosanoid-forming enzyme localization, which we hypothesize to have specific roles in enhanced inflammatory mediator production during pathological conditions, including sepsis. However, little is known about the origins, composition, or functions of lipid bodies in vivo. We show that lipid body numbers were increased in leukocytes from septic patients in comparison with healthy subjects. Analogously, the intrathoracic administration of LPS into mice induced a dose- and time-dependent increase in lipid body numbers. Pretreatment with anti-CD14 or anti-CD11b/CD18 mAb drastically inhibited LPS-induced lipid body formation. Moreover, LPS failed to form lipid bodies in C3H/HeJ (TLR4 mutated) mice, demonstrating a requisite role for LPS receptors in lipid body formation. LPS-induced lipid body formation was also inhibited by the platelet-activating factor-receptor antagonists, suggesting a role for endogenous platelet-activating factor. The eicosanoid-forming enzymes, 5-lipoxygenase and cyclooxygenase-2, were immunolocalized within experimentally induced (LPS in mice) or naturally occurring (septic patients) lipid bodies. The proinflammatory cytokine involved in the pathogenesis of sepsis, TNF-alpha, was also shown to colocalize within lipid bodies. Prior stimulation of leukocytes to form lipid bodies enhanced the capacity of leukocytes to produce leukotriene B(4) and PGE(2). In conclusion, our studies indicate that lipid bodies formed after LPS stimulation and sepsis are sites for eicosanoid-forming enzymes and cytokine localization and may develop and function as structurally distinct, intracellular sites for paracrine eicosanoid synthesis during inflammatory conditions.
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PMID:Lipopolysaccharide-induced leukocyte lipid body formation in vivo: innate immunity elicited intracellular Loci involved in eicosanoid metabolism. 1244 60

Cordyceps pruinosa has been used in traditional folk medicine to treat numerous diseases. The molecular mechanism of C. pruinosa pharmacological and biochemical actions of macrophages in inflammation has not been clearly elucidated. We examined how the methanol extract of C. pruinosa regulates production of IL-1beta, TNF-alpha, nitric oxide (NO), and prostaglandin E(2) (PGE(2)) in vitro and in vivo. The extract inhibits these inflammatory mediators in LPS-stimulated murine macrophage cell line RAW264.7 and primary macrophages, by suppressing gene expression of IL-1beta, TNF-alpha, inducible nitric oxide synthase, and cyclooxygenase-2. Moreover, the extract suppresses the nuclear transcription factor NF-kappaB activation in LPS-stimulated RAW264.7 cells. Administration of the extract significantly decreases the plasma levels of these inflammatory mediators in LPS-injected mice. These results suggest that the C. pruinosa methanol extract suppresses inflammation through suppression of NF-kappaB-dependent inflammatory gene expression, suggesting that the C. pruinosa extract may be beneficial for treatment of endotoxin shock or sepsis.
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PMID:Methanol extract of Cordyceps pruinosa inhibits in vitro and in vivo inflammatory mediators by suppressing NF-kappaB activation. 1283 77

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

Silymarin is known to have hepatoprotective and anticarcinogenic effects. Recently, anti-inflammatory effect of silymarin is attracting an increasing attention, but the mechanism of this effect is not fully understood. Here, we report that silymarin protected mice against lipopolysaccharide (LPS)-induced sepsis. In this model of sepsis, silymarin improved the rate of survival of LPS-treated mice from 6 to 38%. To further investigate the mechanism responsible for anti-septic effect of silymarin, we examined the inhibitory effect of silymarin on interleukin-1beta (IL-1beta) and prostaglandin E2 (PGE2) production in macrophages. Silymarin dose-dependently suppressed the LPS-induced production of IL-1beta and PGE2 in isolated mouse peritoneal macrophages and RAW 264.7 cells. Consistent with these results, the mRNA expression of IL-1beta and cyclooxygenase-2 was also completely blocked by silymarin in LPS-stimulated RAW 264.7 cells. Moreover, the LPS-induced DNA binding activity of nuclear factor-kappaB/Rel was also inhibited by silymarin in RAW 264.7 cells. Taken together, these results demonstrate that silymarin has a protective effect against endotoxin-induced sepsis, and suggest that this is mediated, at least in part, by the inhibitory effect of silymarin on the production of IL-1beta and PGE2.
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PMID:Protection against lipopolysaccharide-induced sepsis and inhibition of interleukin-1beta and prostaglandin E2 synthesis by silymarin. 1466 40

Macrophages are an abundant source of cyclooxygenase-2 (COX-2) enzymatic products, but a specific mechanism for macrophage COX-2 gene expression has not been described. We examined whether PU.1, a myeloid-specific Ets family transcription factor, is involved. Sequence analysis revealed two potential c-Ets binding sites in the COX-2 promoter (COX-2p) which bind to immunoreactive PU.1. Chromatin immunoprecipitation analysis shows inducible PU.1 binding to these sites in response to lipopolysaccharide, and COX-2 protein production is augmented by ectopic expression of PU.1 but not by PU.1S148A, indicating that PU.1 phosphorylation is likely involved. Interestingly, expression of PU.1 results in acetylation of CCAAT/enhancer-binding protein-beta (C/EBP-beta) and increased production of COX-2 protein. Coimmunoprecipitation experiments suggest a role for p300 in C/EBP-beta acetylation and COX-2 expression. In contrast, E1A inhibits acetylation of C/EBP-beta and is correlated with decreased COX-2 expression. Together, these data suggest that PU.1 is activated by phosphorylation of Ser148 in response to lipopolysaccharide treatment and subsequently binds to sequences in the endogenous COX-2p in a time-dependent manner. Concomitantly, C/EBP-beta becomes acetylated, and expression of the COX-2 gene increases. We speculate that a combinatorial role of PU.1 and C/EBP-beta mediates the robust production of COX-2 products by macrophages which occurs in Gram-negative bacterial sepsis.
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PMID:Transcriptional regulation of the cyclooxygenase-2 gene in macrophages by PU.1. 1496 10

The aim of this study was to investigate the effects of ascorbic acid on hepatic vasoregulatory gene expression during polymicrobial sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Rats received either vehicle (n = 10) or ascorbic acid (AA, 100 mg/kg, n = 10) intravenously immediately after the CLP procedure. Serum aminotransferase levels and hepatic lipid peroxides markedly increased 24 h after CLP and this increase was attenuated by AA treatment. The hepatic concentrations of reduced glutathione decreased in CLP animals. This decrease was inhibited by AA. CLP significantly increased the mRNA level of ET-1 (p < 0.01) and ETB receptor (p < 0.01) in livers; an increase that was prevented by AA treatment. There were no significant changes in ETA mRNA expression among any of the experimental groups. There were significant increases in the mRNA expression of nitric oxide synthases (p < 0.01) and heme oxygenase-1 (p < 0.01) in livers from CLP animals. This increase was prevented by AA treatment. The expression of tumor necrosis factor-alpha and cyclooxygenase-2 mRNAs significantly increased 4.9-fold (p < 0.01) and 4.4-fold (p < 0.01) in livers from CLP animals, respectively. This increase was attenuated by AA treatment. Our data suggest that AA reduces oxidative stress and lipid peroxidation, regulates the hepatic vasoregulatory gene expression in polymicrobial sepsis and thus it could reduce hepatic microvascular dysfunction during sepsis.
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PMID:Effect of ascorbic acid on hepatic vasoregulatory gene expression during polymicrobial sepsis. 1530 68

Cyclooxygenase-2 (COX-2) is induced in response to lipopolysaccharide (LPS). However, the signaling mechanisms of LPS-induced COX-2 expression in cardiomyocytes are not well understood. The aim of this study was to investigate the role of gp91(phox)-containing NADH oxidase signaling pathway in LPS-induced COX-2 expression in cardiomyocytes. Cultured neonatal mouse cardiomyocytes showed basal COX-2 expression and PGE2 production. In response to LPS, COX-2 expression and PGE2 production increased by two- to four-fold, which were completely blocked by a selective COX-2 inhibitor NS398. LPS also increased NADH oxidase (gp91(phox) and p47(phox) subunits) expression and superoxide generation. Deficiency of gp91(phox) or suppression of p22(phox) expression decreased NADH oxidase activity and down-regulated COX-2 expression and PGE2 production stimulated by LPS. Pharmacological inhibitors of NADH oxidase prevented LPS-induced COX-2 expression and PGE2 production. The effect of NADH oxidase was mediated through MAPK activation, since inhibition of NADH-oxidase activity prevented phosphorylation of ERK1/2, p38, and JNK1/2, as well as selective inhibition of each subfamily of MAPK by siRNAs and a dominant negative mutant of JNK1 decreased COX-2 expression and completely abrogated PGE2 production in response to LPS. Furthermore, LPS-induced NF-kappaB activation was decreased by inhibition of NADH oxidase, ERK1/2 or JNK1/2 activation, suggesting that LPS increases NF-kappaB activity and COX-2 expression via NADH oxidase-dependent activation of ERK1/2 and JNK1/2. In conclusion, NADH oxidase signaling represents a novel pathway leading to COX-2 expression via MAPK/NF-kappaB-dependent mechanisms in cardiomyocytes during LPS stimulation. Our study suggests that gp91(phox)-containing NADH oxidase is a potential therapeutic target of sepsis.
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PMID:NADH oxidase signaling induces cyclooxygenase-2 expression during lipopolysaccharide stimulation in cardiomyocytes. 1554 60

The transcription factor nuclear factor-kappaB (NF-kappaB) plays a key role in expression of many inflammatory genes responsible for the pathophysiology of sepsis-induced acute lung injury. We investigated whether the introduction of synthetic double-stranded oligodeoxynucleotides (ODNs) with consensus NF-kappaB sequence as transcription factor decoy can prevent acute lung injury with suppression of pulmonary expression of multiple genes involved in its pathological process in a cecal ligation and puncture septic mouse model. NF-kappaB decoy ODNs were introduced with the aid of the hemagglutinating virus of Japan-envelope vector method. Northern blot analysis indicated that transfection of NF-kappaB decoy ODN, but not of its scrambled form, resulted in a significant inhibition of sepsis-induced gene overexpression of inducible nitric-oxide synthase (iNOS), cyclooxygenase-2, histamine H(1)-receptor, platelet-activating factor receptor, and bradykinin B(1) and B(2) receptors in lung Histological damage in lungs tissues. (wall thickening, inflammatory infiltrate, and hemorrhage), increased pulmonary vascular permeability, and blood gas exchange impairment were clearly documented in mice after cecal ligation and puncture. These changes were strongly eliminated by the introduction of NF-kappaB decoy but not of scrambled ODN. The effects of the iNOS inhibitor FR260330 on these histological and functional derangements compared unfavorably with those of NF-kappaB decoy ODN transfection. Our results suggest that ODN decoy, acting as in vivo competitor for the transcription factor's ability to bind to cognate recognition sequence, may represent an effective strategy in the treatment of septic acute lung injury.
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PMID:Nuclear factor-kappaB decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis. 1557 32

San-Huang-Xie-Xin-Tang (SHXT) is a traditional Chinese medicinal formula containing Coptidis rhizoma, Scutellariae radix and Rhei rhizoma. The present study aimed to determine the preventive effects of standardized SHXT on lipopolysaccharides (LPS)-induced arterial hypotension, protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), cytokines formation and prostaglandin E2 (PGE2) production. LPS-induced activation of iNOS has been recognized to increase cytokines and nitric oxide, some of them play predominant roles in sepsis. Intravenous injection of LPS (10 mg/kg) caused a marked decrease of the mean arterial pressure in normotensive rats. However, the LPS-induced arterial hypotension was inhibited by SHXT (0.01 and 0.03 g/kg), when it was given 30 min before LPS. Moreover, plasma level of cytokines and PGE2 were lowered by SHXT. In RAW 264.7 cells, SHXT (20-200 microg/ml) dose-dependently inhibited LPS (1 microg/ml)-induced iNOS and COX-2 expression, and it also significantly decreased LPS-induced cytokines in a dose-dependent manner. In conclusion, our data suggest that SHXT prevented LPS-induced arterial hypotension, which might be mediated through its inhibition activities on the expression of iNOS and COX-2, cytokines formation and PGE2 production. Therefore, its protection activity against LPS-induced arterial hypotension and inflammatory mediators release might be beneficial in the treatment of endotoxin shock and/or associated inflammation.
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PMID:San-Huang-Xie-Xin-Tang reduces lipopolysaccharides-induced hypotension and inflammatory mediators. 1558 56

Macrophage prostaglandin E2 (PGE2) production is important in cellular immune suppression and in affecting the potential development of sepsis after trauma. We hypothesized that macrophage PGE2 production after trauma is regulated by mitogen-activated protein kinase (MAPK) and nuclear factor kappa B (NF-kappaB). Mice were subjected to trauma and splenic macrophages isolated 7 days later. Macrophages from traumatized mice showed increased cyclooxygenase-2 (COX-2) mRNA, protein expression, and PGE2 production compared with controls. Increased phosphorylation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), and p38 kinase was observed in macrophages from traumatized mice. Pharmacologic inhibition of MAPK blocked trauma-induced COX-2 expression, and PGE2 production. Trauma macrophages showed increased IkappaBalpha phosphorylation and NF-kappaB binding to DNA. Inhibiting IkappaBalpha blocked trauma-induced NF-kappaB activity, COX-2 expression and PGE2 production. This suggests that trauma-induced PGE2 production is mediated through MAPK and NF-kappaB activation and offers potential for modifying the macrophages' responses following injury.
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PMID:Enhanced expression of cyclooxygenase-2 and prostaglandin E2 in response to endotoxin after trauma is dependent on MAPK and NF-kappaB mechanisms. 1589 Mar 24

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