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)

Free radicals play an important role in the inflammatory process of sepsis. We hypothesized that edaravone, a novel free radical scavenger, can suppress pathophysiological events and prolong survival in a neonatal sepsis cecal ligation and perforation (CLP) model. Of 32 3-day-old anesthetized and mechanically ventilated piglets, 11 received CLP only, 10 received CLP and edaravone treatment starting 30 min after CLP, and 11 constituted a sham (control) group. Mean arterial pressure (MAP), heart rate, cardiac output, arterial blood gas, serum total hydroperoxide, nitrite and nitrate, TNF-alpha, and high-mobility group box 1 (HMGB1) were measured before CLP and at 1, 3, and 6 h after CLP. Compared with the CLP group, the edaravone group showed higher MAP at 6 h, lower heart rate at 1 and 3 h, lower total hydroperoxide at 1 h, lower nitrite and nitrate at 3 and 6 h, and higher (although not significantly so) mean cardiac output at 1, 3, and 6 h. TNF-alpha elevation was delayed from 1 h in the CLP group to 3 h in the edaravone group. In the edaravone group, HMGB1 did not change significantly at any time, whereas in the CLP group, it increased at 6 h. Survival times were longer in the edaravone group than in the CLP group (15.4 +/- 1.4 vs. 10.2 +/- 1 h; P < 0.005). In addition, each of the serial dilutions of edaravone had a higher biological antioxidant potential than tempol does. In conclusion, edaravone suppressed free radicals, delayed the TNF-alpha surge, and prevented HMGB1 elevation, thereby maintaining MAP and prolonging survival time in a neonatal sepsis CLP model.
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PMID:Edaravone, a novel free radical scavenger, reduces high-mobility group box 1 and prolongs survival in a neonatal sepsis model. 1929 81

We examined our hypothesis that heme-oxygenase-1 (HO-1)-derived carbon monoxide (CO) inhibits the release of high-mobility group box 1 (HMGB1) in RAW264.7 cells activated with lipopolysaccharide (LPS) in vitro and in LPS- or cecal ligation and puncture (CLP)-induced septic mice in vivo, so that HO-1 induction or CO improves survival of sepsis in rodents. We found that pretreatment with HO-1 inducers (hemin, cobalt protoporphyrin IX) or transfection of HO-1 significantly inhibited HMGB1 release, which was blocked by HO-1 small interfering RNA, in cells activated by LPS. Carbon monoxide-releasing molecule 2 (CORM-2) but not bilirubin or deferoxamine inhibited HMGB1 release in LPS-activated macrophages. Oxyhemoglobin reversed the effect of HO-1 inducers on HMGB1 release. Translocation of HMGB1 from nucleus to cytosol was significantly inhibited by HO-1 inducers, CORM-2, or HO-1 transfection. Neutralizing antibodies to tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interferon-beta, and N(omega)-nitro-L-arginine methyl ester hydrochloride but not N-[2-(cyclohexyloxyl)-4-nitrophenyl]-methane sulfonamide (NS-398) significantly inhibited HMGB1 release in LPS-activated cells. Production of TNF-alpha, IL-1beta, and IFN-beta was significantly reduced by pretreatment of HO-1 inducers, CORM-2, or HO-1 transfection in LPS-activated cells. Plasma levels of HMGB1 in mice challenged with LPS or CLP were significantly reduced by the administration of HO-1 inducers or CORM-2, which was accompanied by either reduction (pretreatment) or no change (delayed administration) of serum TNF-alpha and IL-1beta levels. Regardless of pretreatment or delayed administration, CORM-2 and hemin rescued mice from lethal endotoxemia and sepsis induced by LPS or CLP. Taken together, we concluded that HO-1-derived CO reduces HMGB1 release in LPS-activated cells and LPS- or CLP-induced animal model of sepsis.
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PMID:Heme-oxygenase-1 induction and carbon monoxide-releasing molecule inhibit lipopolysaccharide (LPS)-induced high-mobility group box 1 release in vitro and improve survival of mice in LPS- and cecal ligation and puncture-induced sepsis model in vivo. 1936 89

Lipopolysaccharide (LPS) is an important factor in sepsis. LPS given by intraperitoneal injection induces intestinal hyperpermeability and bacterial translocation in animals and stimulates hepatic Kupffer cells to release TNF-alpha into the bile. This study aims to test the hypothesis that in response to LPS stimulation, hepatic Kupffer cells and extrahepatic macrophages release a large amount of the inflammatory cytokine high-mobility group box 1 (HMGB1) into the bile and that bile containing HMGB1 contributes to gut barrier dysfunction in experimental endotoxemia. To test this, rat common bile ducts were catheterized and bile flow rate was monitored before and during the LPS administration. Eight hours after LPS challenge, anti-HMGB1 neutralizing antibody or nonimmune (sham) IgG was injected into the duodenal lumen of endotoxemic rats; normal mice were also gavaged with normal or endotoxemic rat bile (bile collected from LPS-treated rats). We found that after LPS challenge, the bile flow rate in rats was significantly decreased at the 4- to 12-h time points, TNF-alpha concentration in the bile was markedly elevated at the 3- to 4-h time points, and bile HMGB1 levels were significantly increased at the 8- to 12-h time points. Duodenal injection with anti-HMGB1 antibody reversed LPS-induced gut barrier dysfunction in rats. In addition, feeding endotoxemic rat bile to normal mice significantly increased both mucosal permeability and bacterial translocation. The increase in permeability and bacterial translocation was reversible following removal of HMGB1 from the endotoxemic rat bile. These findings document that bile HMGB1 mediates gut barrier dysfunction in experimental endotoxemia.
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PMID:Bile high-mobility group box 1 contributes to gut barrier dysfunction in experimental endotoxemia. 1949 77

Sepsis remains a major health threat in intensive care medicine. The physiological functions of the coagulation cascade extend beyond blood coagulation and play a pivotal role in inflammation. We investigated whether the use of recombinant thrombomodulin (rTM), which has activity comparable with antithrombin, tissue factor pathway inhibitor, and activated protein C, could inhibit secretion of cytokines and high-mobility group box 1 (HMGB1) protein, thus reducing lung damage in a rat model of LPS-induced systemic inflammation. Rats treated with an intravenous injection of either rTM or saline were injected concurrently with intravenous LPS. In addition, mouse macrophage RAW264.7 cells were stimulated with LPS, with or without simultaneous rTM treatment. Histological examination revealed marked reductions of interstitial congestion, edema, inflammation, and hemorrhage in lung tissue harvested 12 h after treatment with both agents compared with LPS administration alone. LPS-induced secretion of proinflammatory cytokines and HMGB1 protein was inhibited by treatment with rTM. The presence of HMGB1 protein in the lung was examined by immunohistochemistry; the number of HMGB1-positive cells was significantly lower in LPS-treated animals that also received rTM. In the in vitro studies, rTM administration inhibited the activation of nuclear factor-kappa B by inhibiting I kappa B phosphorylation. The anticoagulant rTM blocked the LPS-induced inflammatory response and protected against acute lung injury normally associated with endotoxemia in this rat sepsis model. Given these results, rTM is a strong candidate as a therapeutic agent for various systemic inflammatory diseases.
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PMID:In vivo and in vitro effects of the anticoagulant, thrombomodulin, on the inflammatory response in rodent models. 1953 47

The cholinergic antiinflammatory pathway modulates inflammatory cytokine production through a mechanism dependent on the vagus nerve and the alpha7 subunit of the nicotinic acetylcholine receptor. GTS-21 [3-(2,4-dimethoxybenzylidene) anabaseine], a selective alpha7 agonist, inhibits inflammatory cytokine production in murine and human macrophages and in several models of inflammatory disease in vivo, but to date its antiinflammatory efficacy in human monocytes has not been characterized. We report here our findings that GTS-21 attenuates tumor necrosis factor (TNF) and interleukin 1beta levels in human whole blood activated by exposure to endotoxin. GTS-21 inhibited TNF production in endotoxin-stimulated primary human monocytes in vitro at the transcriptional level. The suppressive effect of GTS-21 was more potent than nicotine in whole blood and monocytes. Furthermore, GTS-21 attenuated TNF production in monocytes stimulated with peptidoglycan, polyinosinic-polycytidylic acid, CpG, HMGB1 (high-mobility group box 1 protein), and advanced glycation end product-modified albumin. GTS-21 decreased TNF levels in endotoxin-stimulated whole blood obtained from patients with severe sepsis. These findings establish the immunoregulatory effect of GTS-21 on human monocytes, and indicate the potential benefits of further exploration of GTS-21's therapeutic uses in human inflammatory disease.
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PMID:The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. 1959 3

The pathogenesis of sepsis is partly attributable to dysregulated inflammatory response mediated by pathogen-associated molecular patterns (PAMPs) (for example, endotoxin) and damage-associated molecular patterns (DAMPs) (for example, high-mobility group box 1 [HMGB1]). An endogenous ubiquitous polyamine, spermine, inhibits endotoxin-induced cytokine release in vitro, but its capacities to attenuate sepsis- and HMGB1-induced inflammatory responses was previously unknown. We thus tested the hypothesis that spermine protects mice against lethal sepsis by attenuating sepsis-induced local and systemic inflammatory responses. Intraperitoneal (i.p.) administration of spermine (10 mg/kg, twice daily, for 3 d) conferred a significant protection against lethal sepsis. The protective effects were associated with a significant reduction in peritoneal and serum levels of several surrogate markers of sepsis (for example, Interleukin-6 [IL-6], keratinocyte-derived chemokine [KC], monocytes chemoattractant protein-1 [MCP-1], macrophage inflammatory protein-2 [MIP-2], tissue inhibitor of metalloproteinase-1 [TIMP-1], soluble tumor necrosis factor-alpha receptor I [sTNFRI], and soluble tumor necrosis factor-alpha receptor II [sTNFRII]) during a late stage of sepsis. In vitro, spermine effectively inhibited HMGB1-induced release of the above surrogate markers in peritoneal macrophages. Thus, spermine confers protection against lethal sepsis partly by attenuating sepsis- and HMGB1-induced inflammatory responses.
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PMID:Spermine protects mice against lethal sepsis partly by attenuating surrogate inflammatory markers. 1959 12

Sepsis/multiple organ dysfunction syndrome (MODS) is a major cause of high mortality in the intensive care unit. We have recently reported that 100% oxygen treatment is beneficial to mice with zymosan-induced sterile inflammation by increasing antioxidant enzymatic activities. Yet, the use of hyperoxia is hindered by concerns that it could exacerbate organ injury by increasing free radical formation. It is believed that systemic inflammation and overproduction of reactive oxygen species (ROS) contribute to the mechanism underlying sepsis/MODS. A ROS scavenger has been proven to protect against sepsis/MODS in some animal models. Therefore, we hypothesized that ROS scavenger pretreatment might enhance the protective action of 100% oxygen treatment against zymosan-induced sterile inflammation in mice. In the present study, we showed that 100% oxygen treatment prevented the abnormal changes in serum biochemical parameters, tissue oxygenation, and organ histopathology, and improved the 14-day survival rate in zymosan-stimulated mice, indicating that 100% oxygen treatment had a protective action on sterile inflammation. We found that pretreatment with a ROS scavenger (N-acetylcysteine, vitamin C, or dimethylthiourea) abolished this protective action of 100% oxygen treatment. We also showed that 100% oxygen treatment decreased the levels of serum proinflammatory cytokines (TNF-alpha, IL-6, and high-mobility group box 1), increased the level of serum anti-inflammatory cytokine (IL-10), and upregulated the activities of serum and tissue antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in zymosan-stimulated mice, which were reversed by the pretreatment with a ROS scavenger (N-acetylcysteine, vitamin C, or dimethylthiourea). We thus conclude that ROS scavenger pretreatment partly abolishes the protective effects of 100% oxygen treatment on sterile inflammation in mice by regulating inflammatory cytokines as well as antioxidant enzymes.
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PMID:Effects of reactive oxygen species scavenger on the protective action of 100% oxygen treatment against sterile inflammation in mice. 1978 62

Hemorrhagic shock (HS) due to major trauma predisposes the host to the development of acute lung inflammation and injury. The lung vascular endothelium is an active organ that plays a central role in the development of acute lung injury through generating reactive oxygen species and synthesizing and releasing of a number of inflammatory mediators, including leukocyte adhesion molecules that regulate neutrophils emigration. Previous study from our laboratory has demonstrated that in a setting of sepsis, toll-like receptor-4 (TLR4) signaling can induce TLR2 expression in endothelial cells (ECs), thereby increasing the cells' response to TLR2 ligands. The present study tested the hypothesis that TLR4 activation by HS and the resultant increased TLR2 surface expression in ECs might contribute to the mechanism underlying HS-augmented activation of lung ECs. The results show that high-mobility group box 1 (HMGB1) through TLR4 signaling mediates HS-induced surface expression of TLR2 in the lung and mouse lung vascular endothelial cells (MLVECs). Furthermore, the results demonstrate that HMGB1 induces activation of NAD(P)H oxidase and expression of ICAM-1 in the lung, and MLVECs sequentially depend on TLR4 in the early phase and on TLR2 in the late phase following HS. Finally, the data indicate an important role of the increased TLR2 surface expression in enhancing the activation of MLVECs and augmenting pulmonary neutrophil infiltration in response to TLR2 agonist peptidoglycan. Thus, induction of TLR2 surface expression in lung ECs, induced by HS and mediated by HMGB1/TLR4 signaling, is an important mechanism responsible for endothelial cell-mediated inflammation and organ injury following trauma and hemorrhage.
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PMID:Hemorrhagic shock augments lung endothelial cell activation: role of temporal alterations of TLR4 and TLR2. 1982 41

Despite recent advances in antibiotic therapy and intensive care, sepsis is still considered to be the most common cause of death in intensive care units. Excessive production of reactive oxygen species plays an important role in the pathogenesis of sepsis. Recently, it has been suggested that molecular hydrogen (H2) exerts a therapeutic antioxidant activity by selectively reducing hydroxyl radicals (*OH, the most cytotoxic reactive oxygen species) and effectively protects against organ damage induced by I/R. Therefore, we hypothesized that H2 treatment had a beneficial effect on sepsis. In the present study, we found that H2 inhalation starting at 1 and 6 h after cecal ligation and puncture (CLP) or sham operation significantly improved the survival rate of septic mice with moderate or severe CLP in a concentration- and time-dependent manner. Furthermore, moderate or severe CLP mice showed significant multiple organ damage characterized by the increases of lung myeloperoxidase activity, wet-to-dry weight ratio, protein concentration in bronchoalveolar lavage, serum biochemical parameters, and organ histopathologic scores at 24 h after CLP operation, which was significantly attenuated by 2% H2 treatment. In addition, we found that the beneficial effects of H2 treatment on sepsis and sepsis-associated organ damage were associated with the decreased levels of oxidative product, increased activities of antioxidant enzymes, and reduced levels of high-mobility group box 1 in serum and tissue. Thus, H2 inhalation may be an effective therapeutic strategy for patients with sepsis.
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PMID:Protective effects of hydrogen gas on murine polymicrobial sepsis via reducing oxidative stress and HMGB1 release. 1999 46

In this study, we examined the effects of direct hemoperfusion through filters with immobilized polymyxin B (PMX-DHP) on leukocyte function and plasma levels of cytokines in patients with septic shock. We found that PMX-DHP caused increased expression of C-X-C chemokine receptor 1 (CXCR1) and CXCR2, along with decreased expression of CD64 and CD11b, by circulating neutrophils in patients with septic shock. Plasma levels of cytokines, including interleukin 6 (IL-6), IL-8, IL-10, and high-mobility group box 1, were elevated in patients with septic shock compared with healthy controls, but cytokine levels were not altered by PMX-DHP. These results suggest that PMX-DHP influences neutrophils via a mechanism that does not involve cytokine. Ex vivo perfusion of heparinized blood from patients with sepsis and septic shock through PMX filters in a laboratory circuit caused a significant decrease in neutrophil and monocyte counts. After 120 min of perfusion, neutrophils, monocytes, and lymphocytes were decreased by 78%, 70%, and 10%, respectively, compared with baseline values. Flow cytometric analysis indicated that activated neutrophils with high levels of CD11b/CD64 expression and low levels of CXCR1/CXCR2 expression showed preferential adhesion to PMX filters. Neutrophils isolated from the blood after ex vivo PMX perfusion caused less damage to an endothelial cell monolayer than cells from sham-treated blood, whereas neutrophil phagocytosis of opsonized Escherichia coli was unaffected. These results indicate that PMX-DHP selectively removes activated neutrophils and reduces the ability of circulating cells to cause endothelial damage. Selective removal of activated neutrophils using PMX-DHP may improve the systemic inflammatory response in patients with septic shock.
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PMID:Apheresis of activated leukocytes with an immobilized polymyxin B filter in patients with septic shock. 2038 99


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