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)

Neisseria meningitidis is a major cause of sepsis and/or meningitis. These bacteria normally cause disease only in humans, however, mice expressing human CD46 are susceptible to meningococcal disease. To explain the sensitivity of CD46 transgenic mice to meningococci, we evaluated early immune responses. Stimulation of TNF, IL-6, and IL-10 was stronger in CD46 transgenic mice compared with nontransgenic mice, and resembled human responses. In CD46 transgenic mice, bacterial clearance in blood started at later time points, and neutrophil numbers in blood were lower compared with nontransgenic mice. Further, elevated levels of activated microglia cells and cyclooxygenase-2 were observed in brain of infected CD46 transgenic mice. Intraperitoneal administration of meningococci lead to increased levels of macrophages only in the i.p. cavity of CD46 transgenic mice. Most of the responses were impaired or absent using LPS-deficient meningococci, showing the importance of LPS in the early immune response to meningococcal infection. Taken together, these data demonstrate that responses in mice expressing human CD46 mimic human meningococcal disease in many aspects, and demonstrate novel important links between CD46 and the innate immune system.
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PMID:Human-like immune responses in CD46 transgenic mice. 1597 77

Sepsis is the leading cause of death in critically ill surgical patients. Septic hepatic dysfunction, an important determinant of outcome, although poorly understood, includes inappropriate expression of vasoregulatory genes. In this study the effect of alpha-tocopherol was determined on the expression of hepatic vascular stress genes in response to sepsis. Rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). Rats received either vehicle or alpha-tocopherol (AT, 15 mg/kg), intraperitoneally injected for 3 d prior to CLP procedure. Serum aminotransferase activities and hepatic lipid peroxides levels markedly increased 24 h after CLP, and this rise was attenuated by AT treatment. The hepatic concentrations of reduced glutathione decreased in CLP animals, which was inhibited by AT. CLP significantly increased mRNA levels of endothelin (ET)-1 and ET(B) receptor in livers, which was not prevented by AT treatment. There were no significant changes in ET(A) mRNA expression among any of the experimental groups. There were significant increases in the mRNA expression of inducible nitric oxide synthase and heme oxygenase-1 in livers of CLP animals, and this was prevented by AT treatment. The expression of tumor necrosis factor-alpha and cyclooxygenase-2 mRNA increased 4.9-fold and 4.4-fold, respectively, in livers of CLP animals. This increase was attenuated by AT treatment. Our data suggest that sepsis induces an imbalance in hepatic vasoregulatory gene expression and that AT ameliorates altered expression of vasodilators through its free radical scavenging activity.
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PMID:Effect of alpha-tocopherol on the expression of hepatic vascular stress genes in response to sepsis. 1632 23

Highly inducible heme oxygenase (HO)-1 is protective against acute and chronic inflammation. HO-1 generates carbon monoxide (CO), ferrous iron, and biliverdin. The aim of this study was to investigate the protective effects of biliverdin against sepsis-induced inflammation and intestinal dysmotility. Cecal ligation and puncture (CLP) was performed on Sprague-Dawley rats under isoflurane anesthesia with and without intraperitoneal biliverdin injections, which were done before, at the time of CLP, and after CLP. In vivo gastrointestinal transit was carried out with fluorescein-labeled dextran. Jejunal circular muscle contractility was quantified in vitro using organ bath-generated bethanechol dose-response curves. Neutrophilic infiltration into the muscularis externa was quantified. The jejunal muscularis was studied for cytokine mRNA expressions [interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, inducible nitric oxide synthase, cyclooxygenase-2, biliverdin, IL-10, and HO-1] using real-time RT-PCR. Biliverdin treatment prevented the sepsis-induced suppression of gastrointestinal muscle contractility in vivo and in vitro and significantly decreased neutrophilic infiltration into the jejunal muscularis. Inflammatory mRNA expressions for small bowel IL-6 and MCP-1 were significantly reduced after biliverdin treatment in CLP-induced septic animals compared with untreated septic animals. The anti-inflammatory mediator expression of small bowel IL-10 was significantly augmented after CLP at 3 h compared with untreated septic animals. These findings demonstrate that biliverdin attenuates sepsis-induced morbidity to the intestine by selectively modulating the inflammatory cascade and its subsequent sequelae on intestinal muscularis function.
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PMID:Biliverdin protects against polymicrobial sepsis by modulating inflammatory mediators. 1653 73

The cyclooxygenase-2 (Cox-2) gene plays a role in a variety of normal and pathophysiological conditions. Expression of the Cox-2 gene is induced in a broad range of cells, in response to many distinct stimuli. The ability to monitor and quantify Cox-2 expression noninvasively in vivo may facilitate a better understanding of the role of Cox-2, both in normal physiology and in different diseases. We generated a "knock-in" mouse in which the firefly luciferase reporter enzyme is expressed at the start site of translation of the endogenous Cox-2 gene. Correlation of luciferase and Cox-2 expression was confirmed in heterozygous Cox-2luc/+ mouse embryonic fibroblasts isolated from the knock-in mouse. In an acute sepsis model, following injection of interferon gamma and endotoxin, ex vivo imaging and Western blotting demonstrated coordinate Cox-2 and luciferase induction in multiple organs. Using both paw and air pouch inflammation models, we can monitor repeatedly localized luciferase expression in the same living mouse. Cox-2luc/+ knock-in mice should provide a valuable tool to analyze Cox-2 expression in many disease models.
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PMID:Imaging cyclooxygenase-2 (Cox-2) gene expression in living animals with a luciferase knock-in reporter gene. 1655 23

Artemisia vestita Wall., a traditional Tibetan medicine, has wide clinical application for inflammatory diseases. However, its molecular mechanism of anti-inflammatory effect is poorly understood. In the present study, we investigated the anti-inflammatory activity and underlying mechanism of the ethanol extract from Artemisia vestita (AV-ext) on lipopolysaccharide (LPS)-induced sepsis. Pretreatment with AV-ext significantly decreased the levels of tumor necrosis factor-alpha (TNF-alpha) in serum and liver and lung tissues, and improved the survival of mice with experimental sepsis. AV-ext also remarkably reduced the expression levels of TNF-alpha, interleukin-1beta and cyclooxygenase-2 in LPS-stimulated RAW 264.7 macrophages and dose dependently suppressed the activation of mitogen-activated protein kinases (MAPKs), such as p38, extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK). Furthermore, pretreatment with AV-ext dose dependently inhibited the activation of nuclear factor-kappaB (NF-kappaB), as well as the degradation and phosphorylation of inhibitory kappaB (IkappaB) in LPS-activated RAW 264.7 macrophages. These results collectively reveal that AV-ext inhibits TNF-alpha release from macrophages by suppressing MAPK and NF-kappaB signaling pathways and suggest that AV-ext may be beneficial for the treatment of endotoxin shock or sepsis.
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PMID:Ethanol extract from Artemisia vestita, a traditional Tibetan medicine, exerts anti-sepsis action through down-regulating the MAPK and NF-kappaB pathways. 1659 87

Sepsis induced by exposure to lipopolysaccharide (LPS) can be life-threatening and lead to multiple-organ dysfunction. Sepsis-associated cardiac dysfunction is a primary cause of mortality. The response of isolated cardiac myocytes to LPS exposure is poorly understood. Cultured neonatal rat ventricular cardiomyocytes were used to evaluate the response to LPS exposure. Other authors have reported that LPS exposure at doses sufficient to induce tumor necrosis factor alpha (TNF-alpha) production and apoptosis in adult cardiomyocytes do not induce apoptosis in neonatal cardiomyocytes. We therefore hypothesized that neonatal cardiomyocytes have innate protective mechanisms that protect from septic damage. Cultured neonatal rat ventricular cardiomyocytes were stimulated by exposure to LPS for varying lengths of time. NFkappaB signaling pathways, TNF-alpha production, and Akt activation were monitored. We also assessed the induction of apoptosis in these cells by monitoring caspase-3 activity. LPS rapidly stimulates nuclear translocation of NFkappaB and Akt activation. TNF-alpha production is also stimulated. However, high doses of LPS are unable to induce apoptosis in these cells, and protection is not a function of Akt activation. LPS treatment also stimulated the levels of cyclooxygenase-2 and the production of downstream metabolites, specifically PGE2 and 15deoxyDelta12-14PGJ2 (15dPGJ2). Specific inhibition of cyclooxygenase-2 activity induced apoptosis in the presence of LPS, whereas direct exposure to 15dPGJ2 at pharmacological levels induced apoptosis. Neonatal rat ventricular cardiomyocytes have innate protective mechanisms that prevent apoptotic cell death after LPS exposure. Metabolic products of arachidonic acid metabolized by the cyclooxygenase pathway can be potentially apoptotic or antiapoptotic. The balance of these products within these cells may define the cellular response to LPS exposure.
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PMID:The response of neonatal rat ventricular myocytes to lipopolysaccharide-induced stress. 1668 21

Abnormal production of inflammatory cytokines and chemokines is a key feature of bacterial endotoxin, lipopolysaccharide (LPS)-induced inflammation, and cytotoxicity; however, the mechanisms regulating production of inflammatory markers remain unclear. Herein, we show that inhibition of the aldehyde-metabolizing enzyme aldose reductase (AR; AKR1B3) modulates NF-kappaB-dependent activation of inflammatory cytokines and chemokines in mouse serum, liver, heart, and spleen. Pharmacological inhibition or small interfering RNA ablation of AR prevented the biosynthesis of tumor necrosis factor-alpha, interleukin 1beta, interleukin-6, macrophage-chemoattractant protein-1, and cyclooxygenase-2 and prostaglandin E(2) in LPS-activated RAW264.7 murine macrophages. The AR inhibition or ablation significantly attenuated LPS-induced activation of protein kinase C (PKC) and phospholipase C (PLC), nuclear translocation of NF-kappaB, and phosphorylation and proteolytic degradation of IkappaBalpha in macrophages. Furthermore, treatment of macrophages with 4-hydroxy-trans-2-nonenal (HNE), and cell-permeable esters of glutathionyl-4-hydroxynonanal (GS-HNE) and glutathionyl-1,4-dihydroxynonane (GS-DHN) activated NF-kappaB and PLC/PKC. Pharmacological inhibition or antisense ablation of AR that catalyzes the reduction of GS-HNE to GS-DHN prevented PLC, PKC, IKKalpha/beta, and NF-kappaB activation caused by HNE and GS-HNE, but not by GS-DHN, suggesting that reduced GS-lipid aldehydes catalyzed by AR propagate LPS-induced production of inflammatory markers. Collectively, these data provide evidence that inhibition of AR may be a significant therapeutic approach in preventing bacterial endotoxin-induced sepsis and tissue damage.
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PMID:Aldose reductase mediates the lipopolysaccharide-induced release of inflammatory mediators in RAW264.7 murine macrophages. 3071 8

The systemic inflammatory response syndrome (SIRS) is a life-threatening medical condition characterized by a severe and generalized inflammatory state that can lead to multiple organ failure and shock. The CNS regulates many features of SIRS such as fever, cardiovascular, and neuroendocrine responses. Central and systemic manifestations of SIRS can be induced by LPS or IL-1beta administration. The crucial role of IL-1beta in inflammation has been further highlighted by studies of mice lacking caspase 1 (casp1, also known as IL-1beta convertase), a protease that cleaves pro-IL-1beta into mature IL-1beta. Indeed, casp1 knockout (casp1(-/-)) mice survive lethal doses of LPS. The key role of IL-1beta in sickness behavior and its de novo expression in the CNS during inflammation led us to test the hypothesis that IL-1beta plays a major role modulating the brain transcriptome during SIRS. We show a gene-environment effect caused by LPS administration in casp1(-/-) mice. During SIRS, the expression of several genes, such as chemokines, GTPases, the metalloprotease ADAMTS1, IL-1RA, the inducible nitric oxide synthase, and cyclooxygenase-2, was differentially increased in casp1(-/-) mice. Our findings may contribute to the understanding of the molecular changes that take place within the CNS during sepsis and SIRS and the development of new therapies for these serious conditions. Our results indicate that those genes may also play a role in several neuropsychiatric conditions in which inflammation has been implicated and indicate that casp1 might be a potential therapeutic target for such disorders.
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PMID:Caspase 1 deficiency reduces inflammation-induced brain transcription. 1748 63

Necrotizing enterocolitis (NEC) is the most common surgical emergency in premature infants. The underlying etiology of NEC remains unknown, although bacterial colonization of the gut, formula feeding, and perinatal stress have been implicated as putative risk factors. The disease is characterized by exuberant gut inflammation leading to ischemia and coagulation necrosis of the intestinal epithelium. The molecular and cellular mechanisms responsible for these pathologic changes are poorly understood. It has been shown that various exogenous and endogenous mediators such as lipopolysaccharide, inflammatory cytokines, platelet activating factor, and nitric oxide may play a role in the pathogenesis of NEC. Recent studies in our laboratory and others have established a link between NEC and activation of cyclooxygenase-2, the enzyme that catalyzes the rate-limiting step in the biosynthesis of prostanoids. The challenge is in defining the molecular signaling pathways leading to accumulation of these mediators early in the disease progression, before the onset of tissue necrosis and systemic sepsis. Identification and characterization of these pathways could lead to the development of novel treatment strategies to alleviate the morbidity and mortality associated with NEC.
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PMID:Molecular signaling in necrotizing enterocolitis: regulation of intestinal COX-2 expression. 1761 75

Cyclooxygenase-2 (Cox-2) is an inducible enzyme responsible for the formation of inflammatory prostanoids such as prostaglandins and thromboxane. Its role in the pathophysiology of inflammatory states like sepsis is increasingly recognized. Recently, we demonstrated that sepsis upregulates the endotoxin receptor Toll-like receptor 4 (TLR4) in rat kidney. Because Cox-2 is one of the downstream products of TLR4 activation, we hypothesized that sepsis-induced changes in renal Cox-2 expression are TLR4 dependent. Indeed, we show that in Sprague-Dawley rats, cecal ligation and puncture (a sepsis model) increases Cox-2 expression in cortical and medullary thick ascending loops (cTAL and mTAL, respectively) as well as inner medullary collecting ducts. These are all sites of increased TLR4 expression during sepsis. To determine the actual dependence on TLR4, we measured Cox-2 expression in wild-type and mutant mice which harbor a TLR4 gene deletion (TLR4-/-). In wild-type mice, sepsis increased Cox-2 expression in proximal tubules, cTAL, and mTAL. In contrast, septic TLR4-/- mice showed no significant increase in cTAL or mTAL Cox-2 expression. Furthermore, renin was absent from juxtaglomerular cells of TLR4-/- mice. We conclude that the dependence of sepsis-induced renal Cox-2 expression on TLR4 is tubule specific. The TLR4-dependent Cox-2 expression is mostly restricted to cortical and medullary thick ascending loops of Henle that characteristically express and secrete Tamm-Horsfall protein.
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PMID:Sepsis induces an increase in thick ascending limb Cox-2 that is TLR4 dependent. 1763 95


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