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)

LPS has been implicated in the pathogenesis of endothelial cell death associated with Gram-negative bacterial sepsis. The binding of LPS to the TLR-4 on the surface of endothelial cells initiates the formation of a death-inducing signaling complex at the cell surface. The subsequent signaling pathways that result in apoptotic cell death remain unclear and may differ among endothelial cells in different organs. We sought to determine whether LPS and cycloheximide-induced cell death in human lung microvascular endothelial cells (HmVECs) was dependent upon activation of the intrinsic apoptotic pathway and the generation of reactive oxygen species. We found that cells overexpressing the anti-apoptotic protein Bcl-X(L) were resistant to LPS and cycloheximide-induced death and that the proapoptotic Bcl-2 protein Bid was cleaved following treatment with LPS. The importance of Bid was confirmed by protection of Bid-deficient (bid(-/-)) mice from LPS-induced lung injury. Neither HmVECs treated with the combined superoxide dismutase/catalase mimetic EUK-134 nor HmVECs depleted of mitochondrial DNA (rho(0) cells) were protected against LPS and cycloheximide-induced death. We conclude that LPS and cycloheximide-induced death in HmVECs requires the intrinsic cell death pathway, but not the generation of reactive oxygen species.
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PMID:The intrinsic apoptotic pathway is required for lipopolysaccharide-induced lung endothelial cell death. 1764 Oct 50

In septic shock, systemic vasodilation and myocardial depression contribute to the systemic hypotension observed. Both components can be attributed to the effects of mediators that are released as part of the inflammatory response. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression that develops in a canine model of septic shock. Lzm-S binds to the endocardial endothelium, resulting in the production of nitric oxide (NO), which, in turn, activates the myocardial soluble guanylate cyclase (sGC) pathway. In the present study, we determined whether Lzm-S might also play a role in the systemic vasodilation that occurs in septic shock. In a phenylephrine-contracted canine carotid artery ring preparation, we found that both canine and human Lzm-S, at concentrations similar to those found in sepsis, produced vasorelaxation. This decrease in force could not be prevented by inhibitors of NO synthase, prostaglandin synthesis, or potassium channel inhibitors and was not dependent on the presence of the vascular endothelium. However, inhibitors of the sGC pathway prevented the vasodilatory activity of Lzm-S. In addition, Aspergillus niger catalase, which breaks down H(2)O(2), as well as hydroxyl radical scavengers, which included hydroquinone and mannitol, prevented the effect of Lzm-S. Electrochemical sensors corroborated that Lzm-S caused H(2)O(2) release from the carotid artery preparation. In conclusion, these results support the notion that when Lzm-S interacts with the arterial vasculature, this interaction results in the formation of H(2)O(2), which, in turn, activates the sGC pathway to cause relaxation. Lzm-S may contribute to the vasodilation that occurs in septic shock.
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PMID:Lysozyme, a mediator of sepsis that produces vasodilation by hydrogen peroxide signaling in an arterial preparation. 1826 14

Oxygen free radicals may cause tissue injury in perinatal asphyxia. We measured plasma and cerebrospinal fluid levels of malondialdehyde and plasma levels of glutathione peroxidase, catalase, and superoxide dismutase in 50 term newborns with perinatal asphyxia and eight newborns without asphyxia. Neonates with sepsis, major congenital malformations, and hemolytic disease were excluded. The levels of plasma and cerebrospinal fluid malondialdehyde, as well as of plasma glutathione peroxidase, catalase, and superoxide dismutase, were significantly higher in newborns with perinatal asphyxia, and demonstrated a progressive increase with greater severity of hypoxic ischemic encephalopathy. Higher levels of plasma and cerebrospinal fluid malondialdehyde and plasma catalase were documented in newborns who died from hypoxic ischemic encephalopathy, compared with those who survived, but no such difference was found in plasma levels of glutathione peroxidase and superoxide dismutase. The data of the present study suggest that, despite the increased activities of antioxidant enzymes in perinatal asphyxia, these neonates experience higher degrees of oxidative stress, as evidenced by increased levels of plasma and cerebrospinal fluid malondialdehyde. Hence, oxygen free radicals can be considered to play a significant role in the pathophysiology of perinatal asphyxia.
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PMID:Oxidative stress in perinatal asphyxia. 1827 52

Besides excess cytokine and NO production, enhanced oxygen radical formation was referred to contribute to the impaired hepatic gluconeogenesis during sepsis or endotoxemia. Therefore, we tested the hypothesis that genetic overexpression of the Cu/Zn-superoxide dismutase (SOD-1) may restore the sepsis-related lack of the norepinephrine-induced increase in hepatic gluconeogenesis and whole-body glucose oxidation. Anesthetized, ventilated, and instrumented wild-type control, and heterozygous and homozygous SOD-1-overexpressing mice received hydroxyethyl starch and norepinephrine to maintain normotensive hemodynamics measured at 18, 21, and 24 h after cecal ligation and puncture (CLP) or sham operation. Hepatic gluconeogenesis and whole-body glucose oxidation were calculated from liver tissue isotope and expiratory 13CO2 enrichments during continuous i.v. 1,2,3,4,5,6-13C6-glucose. Superior mesenteric artery and portal vein flows (ultrasound flow probes) and hepatic microcirculatory perfusion (Laser Doppler flowmetry) and O2 saturation (remission spectrophotometry) were comparable in the CLP and sham-operated animals, without any difference related to the mouse strain. Despite continuous i.v. norepinephrine necessary in the CLP mice, both glycemia and hepatic gluconeogenesis were similar, irrespective of the presence of sepsis and the genetic strain. Glucose oxidation rate progressively increased in the CLP groups, again without difference between the genetic strains. The surgery- and CLP-induced increase in liver cell oxidative DNA damage (tail moment in the comet assay) was less pronounced in the homozygous mice. Heterozygous nor homozygous SOD-1 overexpression did not improve the sepsis-related impairment of carbohydrate metabolism, possibly because of the lacking increase of the tissue catalase and the mitochondrial SOD activity, and the ongoing i.v. norepinephrine.
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PMID:The effect of superoxide dismutase overexpression on hepatic gluconeogenesis and whole-body glucose oxidation during resuscitated normotensive murine septic shock. 1831 3

The organ that is affected first and most severely in intraabdominal sepsis is the lung. Oxygen radicals and active neutrophils in the lung are important sources for severe pulmonary inflammation leading to acute lung injury (ALI)/acute respiratory distress syndrome. The aim of this study was to investigate the effects of leflunomide, an immunomodulatory agent, on oxidant/antioxidant status with nitric oxide (NO) level and myeloperoxidase (MPO) activity in rats with sepsis-induced ALI. Fifty male Wistar albino rats were divided into five groups: control, sham, sepsis, leflunomide (10 mg/kg, intragastrically for two doses with an 8 h interval prior to the experiment) and sepsis + leflunomide. After the animals were anesthetized with ketamine and xylazine, the abdominal cavity was opened and ligated just below the ileocaecal valve with 3-0 silk. The antimesentric surface of the cecum was perforated and the cecum was gently compressed until fecal matter was extruded to induce sepsis. None of the rats received antibiotics during the experimental procedures. The experiment was ended 24 h after cecal ligation puncture (CLP) with the cervical dislocation under anesthesia. The lung tissues were removed for analysis of biochemical parameters and light microscopic investigation. The lung superoxide dismutase (SOD), catalase and glutathione peroxidase activities were decreased in the sepsis group as compared to the group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and SOD activity were significantly higher in group sepsis + leflunomide than sham, control, leflunomide and sepsis group (P < 0.05). The lung MPO, malondialdehyde (MDA), protein carbonyl and NO levels were higher in the sepsis group when compared to group control, sham, leflunomide and sepsis + leflunomide (P < 0.05), and MPO, MDA and NO levels were higher in the sepsis + leflunomide group than in the sham, control and leflunomide group (P < 0.05). The light microscopic evaluation showed that pulmonary architecture was preserved, and infiltration of neutrophil and edema decreased in sepsis + leflunomide group. The grade of alveolar damage was significantly decreased in sepsis + leflunomide group in comparison with sepsis group (P < 0.05). Our findings suggested that leflunomide attenuated the lung injury after CLP-induced sepsis by inhibition of neutrophils accumulation and increasing endogenous antioxidant capacity.
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PMID:Does leflunomide attenuate the sepsis-induced acute lung injury? 1851 12

Septic shock was formerly recognized as a consequence of Gram-negative bacteraemia, but at present the incidence of Gram-positive sepsis seems to be more relevant, contributing for more than 50% of cases. Staphylococcal aureus can induce toxic shock in humans through the production of potent toxins termed Staphylococcal enterotoxins, from which Staphylococcal enterotoxin type B (SEB) is one of most studied. Platelets are reported to participate in pathogenesis of severe sepsis, but the exact role of platelets in this event is poorly investigated, particularly that caused by Gram-positive bacteria. Therefore, we have used the model of platelet adhesion to fibrinogen-coated plates to investigate the actions of SEB on human platelets. Ninety-six-well microtiter plates were coated with human fibrinogen (50 microg/mL), and human washed platelet suspension (6 x 10(6) platelets) was added to each well. Adherent platelets were quantified through measurement of acid phosphatase activity. Staphylococcal enterotoxin B (0.0001-30 microg/mL, incubated for 5 to 60 min) time- and dose-dependently inhibited platelet adhesion. This response was modified neither by the protein synthesis inhibitor puromycin (0.01 and 0.1 mM) nor by the superoxide scavengers superoxide dismutase (SOD, 100 units/mL) and polyethylene glycol-SOD (30 U/mL). The peroxide hydrogen (H(2)O(2)) scavenger catalase polyethylene glycol (1000 U/mL) significantly attenuated the platelet adhesion inhibition by SEB. The cAMP and cGMP levels were not changed by SEB (0.0001-30 microg/mL, 60 min). Our findings suggest that H(2)O(2) at least partly contributes to the inhibitory responses of human platelet adhesion by SEB.
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PMID:Inhibitory effects of staphylococcal enterotoxin type B on human platelet adhesion in vitro. 1892 11

This study was designed to compare the effect of pretreatment with N-acetylcysteine (NAC) and beta -glucan (beta GLU) on inflammatory response in a rat model of sepsis. The study was performed in the animal laboratory of the Kahramanmaras Sutcu Imam University, School of Medicine. Forty rats were randomized into four groups (control, sham, NAC, and beta GLU). Control and Sham groups received saline or NAC (200 mg/kg, po) in the NAC group and beta GLU (50 mg/kg, po) in the betaGLU group via intragastric gavage once a day for 10 days and 30 min prior to surgery. Sepsis was induced by cecal ligation and puncture (CLP) in rats. In the NAC, beta GLU, and control groups, a laparotomy was performed with the CLP procedure. In the sham group, laparotomy was performed and cecum was manipulated but not ligated or perforated. TNF-alpha and IL-6 levels were significantly elevated in the control group and decreased in the NAC and beta GLU groups. IL-10 levels were significantly increased in the beta GLU group (p < .05). Superoxide dismutase and catalase levels in the liver tissue were significantly increased in the NAC and beta GLU groups, whereas superoxide dismutase levels were higher in the beta GLU pretreatment group than the NAC pretreatment group (p < 0.05). Malondialdehyde levels in the liver tissue were significantly elevated in the control group and decreased in the NAC and beta GLU groups (p < .05). Prophylactic administration of NAC or beta GLU similarly ameliorated sepsis syndrome by reduction of the proinflammatory cytokines and increase of the anti-inflammatory cytokine levels and accession of cellular antioxidants, which protect cells from oxidative stress, thereby recruiting inflammatory cells into tissue.
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PMID:Protective effects of N-acetylcysteine and beta-glucan pretreatment on oxidative stress in cecal ligation and puncture model of sepsis. 1916 Jan 31

Enterococci are Gram-positive, catalase-negative, non-spore-forming, facultative anaerobic bacteria, which usually inhabit the alimentary tract of humans in addition to being isolated from environmental and animal sources. They are able to survive a range of stresses and hostile environments, including those of extreme temperature (5-65 degrees C), pH (4.5-10.0) and high NaCl concentration, enabling them to colonize a wide range of niches. Virulence factors of enterococci include the extracellular protein Esp and aggregation substances (Agg), both of which aid in colonization of the host. The nosocomial pathogenicity of enterococci has emerged in recent years, as well as increasing resistance to glycopeptide antibiotics. Understanding the ecology, epidemiology and virulence of Enterococcus species is important for limiting urinary tract infections, hepatobiliary sepsis, endocarditis, surgical wound infection, bacteraemia and neonatal sepsis, and also stemming the further development of antibiotic resistance.
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PMID:The ecology, epidemiology and virulence of Enterococcus. 1938 84

In septic shock, cardiovascular collapse is caused by the release of inflammatory mediators. We previously found that lysozyme (Lzm-S), released from leukocytes, contributed to the myocardial depression and arterial vasodilation that develop in canine models of septic shock. To cause vasodilation, Lzm-S generates hydrogen peroxide (H(2)O(2)) that activates the smooth muscle soluble guanylate cyclase (sGC) pathway, although the mechanism of H(2)O(2) generation is not known. To cause myocardial depression, Lzm-S binds to the endocardial endothelium, resulting in the formation of nitric oxide (NO) and subsequent activation of myocardial sGC, although the initial signaling event is not clear. In this study, we examined whether the myocardial depression produced by Lzm-S was also caused by the generation of H(2)O(2) and whether Lzm-S could intrinsically generate H(2)O(2) as has been described for other protein types. In a canine ventricular trabecular preparation, we found that the peroxidizing agent Aspergillus niger catalase, that would breakdown H(2)O(2), prevented Lzm-S- induced decrease in contraction. We also found that compound I, a species of catalase formed during H(2)O(2) metabolism, could contribute to the NO generation caused by Lzm-S. In tissue-free experiments, we used a fluorometric assay (Ultra Amplex red H(2)O(2) assay) and electrochemical sensor techniques, respectively, to measure H(2)O(2) generation. We found that Lzm-S could generate H(2)O(2) and, furthermore, that this generation could be attenuated by the singlet oxygen quencher sodium azide. This study shows that Lzm-S, a mediator of sepsis, is able to intrinsically generate H(2)O(2). Moreover, this generation may activate H(2)O(2)-dependent pathways leading to cardiovascular collapse in septic shock.
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PMID:Lysozyme, a mediator of sepsis that intrinsically generates hydrogen peroxide to cause cardiovascular dysfunction. 1954 85

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


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