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)

We studied the effect of deferoxamine (DFX), an iron chelator, which can also act as a free radical scavenger, in an experimental murine model of sepsis. In vivo studies demonstrated that pretreatment of mice with DFX reduces tumor necrosis factor alpha (TNF-alpha) serum levels and increases the rate of survival of mice inoculated with lethal doses of lipopolysaccharide (LPS) or Escherichia coli O111:B4. By using the iron chelated form of DFX (ferrioxamine) the same results were obtained, suggesting that in this model, DFX could act as a free radical scavenger. On the other hand, DFX prevents mortality induced either by LPS or murine recombinant TNF-alpha in D(+)-galactosamine (GalN)-sensitized mice. These protective actions of DFX correlate with an attenuated tissue damage observed in lungs, livers and kidneys of LPS-treated animals and GalN-sensitized mice inoculated with TNF-alpha.
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PMID:Deferoxamine reduces tissue injury and lethality in LPS-treated mice. 1098 58

CD14 is a pattern recognition receptor on myeloid cells and plays a pivotal role in an innate immune system that is responsible for Gram-negative and Gram-positive bacteria infection. Lipopolysaccharide (LPS), a cell wall component of Gram-negative bacteria, can induce production of a large quantity of proinflammatory cytokines into the circulation mediated by CD14-mediated macrophages and monocytes. These cytokines eventually cause septic shock. Several in vitro and in vivo studies have shown that suppression of a CD14 function by a CD14 antibody led to an inhibition of the production of proinflammatory cytokines such as TNF-alpha, IL-1 beta, and IL-8. In the present study, we found that CD14 antisense oligonucleotide (ODN) can prevent lethal LPS shock in D-galactosamine-sensitized mice. This ODN inhibited CD14 expression in a mouse macrophage cell line, RAW264.7, and suppressed production of TNF-alpha in LPS-stimulated RAW264.7 cells. Furthermore, we designed a consensus antisense ODN that could hybridize human and mouse CD14 RNA, and we evaluated its efficacy. The consensus antisense ODN rescued mice primed with Mycobacterium bovis bacillus Calmette-Guerin (BCG) from the LPS-induced lethal shock. In this model, the CD14 antisense ODN down-regulated LPS-elicited CD14 expression in the liver, resulting in a decrease in LPS-induced TNF-alpha production. These findings suggest that the CD14 antisense ODN is distributed in the liver and efficiently suppresses LPS-induced TNF-alpha production by reducing CD14 expression on Kupffer cells. This CD14 antisense ODN may be useful for the development of a therapeutic agent against sepsis and septic shock.
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PMID:Protection of mice from LPS-induced shock by CD14 antisense oligonucleotide. 1133 97

A delayed or deficient immunological protection as well as an overstimulation of the mucosal immune system may act as possible additional promoters of sepsis-induced lung injury in patients suffering from a severe septic condition. Lectin-binding patterns in pulmonary tissue samples obtained at autopsy from septic patients and control individuals were studied using 11 carbohydrate-specific lectins (Con A, UEA, GSA I, GSA II, MPA, PNA, Jac, WGA, MAA, LPA, and SNA). There were no differences in the secretory product of serous parts of bronchial glands detectable in the two study groups, whereas lectin binding patterns of alveolar epithelium and mucous parts of subepithelial seromucous glands were different in sepsis cases when compared to controls. Apart from differences in binding sites for alpha-mannose, N-acetyl-neuraminic acid and alpha-(2-6)-galactose (as detected by different expression for Con A, MAA and SNA) in the two study groups, the main finding was that no binding sites for alpha-N-acetyl-galactosamine (as investigated by MPA immunoreactivity) could be detected on alveolar epithelial cells and mucous parts of subepithelial seromucous glands in sepsis cases in contrast to the presence of such binding sites in the control cases. We hypothesize that the finding of an altered secretory product of alveolar epithelial cells and bronchial glands in sepsis may be a result of specific carbohydrate deprivation or consumption, respectively, possibly due to direct bacterial effects or pathogenetic events in response to bacterial toxins during the complex cascade of the host's systemic inflammatory response in sepsis. The altered type of mucus glycoprotein physiologically secreted by alveolar epithelium and mucous parts of subepithelial seromucous glands of the bronchi with subsequent loss of a considerable proportion of protection of the mucosal barrier in sepsis may play an important additional role in the development of sepsis-induced lung injury.
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PMID:Lectin binding patterns of alveolar epithelium and subepithelial seromucous glands of the bronchi in sepsis and controls--an approach to characterize the non-specific immunological response of the human lung to sepsis. 1196 49

Bacterial toxins, including endotoxin/LPS as well as superantigens, are major causative agents of multi-organ failure associated with sepsis and liver disease. However, the precise mechanisms initiating cell activation by the toxins have not been clarified. We compared lethal shock and cytokine production in response to LPS with responses to the superantigen staphylococcal enterotoxin B (SEB) in both LPS-responsive C3H/HeN mice and LPS-hyporesponsive C3H/HeJ mice treated with D-galactosamine (GalN). LPS was not lethal and did not induce production of TNF-alpha in C3H/HeJ mice. In contrast, SEB produced lethal shock associated with liver failure and induced cytokines such as TNF-alpha, IFN-gamma, and IL-2 in both C3H/HeN and C3H/HeJ mice. Peritoneal macrophages from C3H/HeJ mice did not produce TNF-alpha in vitro in response to SEB or LPS. However, no significant difference was observed in production of TNF-alpha in response to stimulation in vitro by SEB between C3H/HeN and C3H/HeJ splenic lymphocytes. We have demonstrated that SEB causes lethal toxicity associated with liver injury in LPS-hyporesponsive C3H/HeJ mice and that as the underlying mechanism, the normal T-cell function in these mice still maintained the sensitivity to SEB since the genetic defect of C3H/HeJ mice unresponsive to LPS and SEB is restricted in macrophages/monocytes and does not extend to T cells.
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PMID:Staphylococcal enterotoxin B induces hepatic injury and lethal shock in endotoxin-resistant C3H/HeJ mice despite a deficient macrophage response. 1223 Sep 15

This review addresses our present-day knowledge on the role of different cellular adhesion molecules, cytokines and glycoproteins for the detection of sepsis-induced injury in the microvasculature of the human lung using immunohistochemistry. Through the induction and modulation of endothelial cell adhesion molecules, such as E-selectin (CD 62E), the vascular endothelium controls leukocyte extravasation into tissue. E-Selectin, not expressed by unstimulated endothelium, is activated by cytokines and initiates neutrophil recruitment in sepsis-induced lung injury. Since E-selectin is strongly expressed in the pulmonary microvasculature in sepsis-associated fatalities, the immunohistochemical detection of an intense expression of E-selectin in lung tissue is a valuable diagnostic tool in the forensic postmortem elucidation of death due to sepsis. VLA-4 (CD49d/CD29) is strongly expressed on intravascular, interstitial and intra-alveolar leukocytes in sepsis-associated fatalities, whereas in non-septic fatalities an irregular weak immunoreactivity can be observed on interstitial leukocytes and no positive immunohistochemical expression can be observed on intravascular or intra-alveolar leukocytes. ICAM-1 (CD54) is strongly expressed on endothelial cells of the pulmonary microvasculature and on pulmonary macrophages and lymphocytes in sepsis-associated fatalities. In contrast, an infrequent weak immunohistochemical reaction for ICAM-1 is found on pulmonary endothelium and on perivascular leukocytes in non-septic fatalities. The up-regulation of both cellular adhesion molecules can be considered as an useful immunohistochemical postmortem marker of sepsis. Lactoferrin (LF) is an iron-binding glycoprotein located in specific (secondary) granules of leukocytes and plays a central role in the host response to infectious stimuli in providing both bacteriostatic and bactericidal protection. There is a statistically significant association between an enhanced expression of LF on pulmonary leukocytes in sepsis-related fatalities in contrast to non-septic controls. The immunohistochemical detection of an enhanced expression of LF can contribute to the postmortem discrimination between sepsis and non-septic fatalities. Application of carbohydrate-specific lectins (ConA, UEA, GSA I, GSA II, MPA, PNA, Jac, WGA, MAA, LPA, SNA) on deparaffinated lung tissue sections from sepsis-associated fatalities and control cases results to some extent in different staining patterns of alveolar epithelial cells and subepithelial seromucous glands of the bronchi. Apart from differences in binding sites for alpha-mannose, N-acetyl-neuraminic acid and alpha-(2-6)-galactose (as detected by different expression for ConA, MAA and SNA), the main finding is that no binding sites for alpha-N-acetyl-galactosamine (as investigated by MPA immunoreactivity) can be detected on alveolar epithelial cells and mucous parts of subepithelial seromucous glands in sepsis cases in contrast to the presence of such binding sites in controls. Since most intracellular pathogens persist in macrophages and epithelial cells during infection, it is likely that these pathogens contribute to a continual deprivation or consumption, respectively, of glycoproteins physiologically secreted by alveolar epithelial and glandular cells at different time points and stages of infection and may, among other mechanisms, by reducing pathogen clearance amplify the inflammatory response. Vascular endothelial growth factor (VEGF), an angiogenic and chemotactic peptide, is abundantly expressed in normal lung tissue, especially in alveolar and bronchial epithelium, glandular cells of the bronchi, and activated alveolar macrophages. Pulmonary VEGF immunostaining differs in sepsis when compared to healthy individuals. In the latter a preponderant strong VEGF immunoreaction can be found on alveolar epithelium (predominately type II pneumocytes), bronchial epithelium and glandular cells of the bronchi and bronchioli, and activated alveolar macrophages. In contrast, in sepsis no VEGF immunopositivity can beivity can be observed on bronchial epithelium or glandular cells of the bronchi and bronchioli, and no or relatively sparse VEGF immunoreactivity is found on alveolar epithelial cells. The precise mechanisms of the decreased pulmonary VEGF expression in septic patients under conditions of intensive care medicine are not clear at present. During the complex cascade of excessive pro-inflammatory and anti-inflammatory mediator release involved in the host's systemic inflammatory response in the development of sepsis-induced lung injury, VEGF expression may be suppressed in sepsis by a hitherto not identified agent or the interaction of different mediators of cellular inflammation. For the detection of sepsis-induced lung injury the aforementioned markers can be used sufficiently, e.g. to give immunohistochemical evidence of a previously undiagnosed sepsis and to confirm or rule out a presumed diagnosis of a sepsis-associated fatality. The employment of the presented immunohistochemical methods will be particularly helpful when macroscopical and routine histological autopsy findings in cases of suspected fatal sepsis are unspecific or unconvincing, respectively, and clinical data on the patient's previous history are not available. Referring to the forensic argumentation regarding causality on the subject of possibly fatal septic complications, e.g. in the sequel of diagnostic or therapeutic iatrogenic injection procedures or being relevant to pressure sore-associated fatalities, aetiopathogenetic conclusions can be optimized on the basis of the described micromorphological investigations.
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PMID:Immunohistochemical detection of sepsis-induced lung injury in human autopsy material. 1293 35

Sepsis represents a growing concern in high-risk patients and there has been a lack of effective preventives and therapies. Bacterial/permeability increasing protein (BPI) is a human neutrophil granule-associated defense molecule specific for Gram-negative bacteria and their products. To develop a BPI-transgene-based prophylactic or therapeutic modality, we have developed a recombinant, replication-deficient adenoviral vector expressing full-length human BPI protein (AdhBPI). The expression of BPI is under control of a murine cytomegalovirus (CMV) promoter. Using in vitro and in vivo systems, AdhBPI-mediated gene transfer led to extracellular secretion of BPI protein, which effectively neutralized endotoxin (lipopolysaccharide [LPS]) and markedly reduced the production of proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and macrophage inflammatory protein 2 (MIP-2) by freshly isolated murine alveolar macrophages. By using a mouse model of nonlethal sepsis elicited with LPS, we demonstrated that in vivo gene transfer of BPI was able to markedly inhibit the effect of a large dose of LPS on cytokine responses when injected intraperitoneally. Furthermore, such in vivo BPI gene transfer also improved the survival of mice suffering from lethal septic shock elicited by intraperitoneal injection of d-galactosamine and LPS. Thus, our results suggest that human BPI gene transfer vector has the potential to be used as a therapeutic agent for septic conditions.
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PMID:Protection from endotoxemia by adenoviral-mediated gene transfer of human bactericidal/permeability-increasing protein. 1450 3

1. Sepsis is associated with leukocyte activation and recruitment in the liver. We investigated the role of lymphocyte function antigen-1 (LFA-1) in endotoxin-induced leukocyte-endothelium interactions, microvascular perfusion failure, hepatocellular injury and apoptosis in the liver by use of gene-targeted mice, blocking antibodies and a synthetic inhibitor of LFA-1 (LFA703). For this purpose, mice were challenged with lipopolysaccharide (LPS)+D-galactosamine (Gal), and intravital microscopy of the liver microcirculation was conducted 6 h later. 2. The number of firmly adherent leukocytes in response to LPS/Gal was reduced by 48% in LFA-1-deficient mice. Moreover, endotoxin-induced increases of apoptosis and enzyme markers of hepatocellular injury were decreased by 64 and 69-90%, respectively, in LFA-1-deficient mice. Furthermore, sinusoidal perfusion was improved in endotoxemic mice lacking LFA-1. 3. A similar protective pattern was observed in endotoxemic mice pretreated with an antibody against LFA-1. Thus, immunoneutralization of LFA-1 reduced endotoxin-induced leukocyte adhesion by 55%, liver enzymes by 64-66% and apoptosis by 42%, in addition to the preservation of microvascular perfusion. 4. Administration of a novel statin-derived inhibitor of LFA-1, LFA703, significantly decreased leukocyte adhesion (more than 56%) and the subsequent liver injury in endotoxemic mice. 5. Thus, this study demonstrates a pivotal role of LFA-1 in supporting leukocyte adhesion in the liver. Moreover, interference with LFA-1-mediated leukocyte adhesion protects against endotoxemic liver damage, and may constitute a potential therapeutic strategy in sepsis.
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PMID:Lymphocyte function antigen-1 mediates leukocyte adhesion and subsequent liver damage in endotoxemic mice. 1474 17

Despite the remarkable progress in intensive care medicine, sepsis and shock continue to be major clinical problems in intensive care units. Septic shock may be associated with a toxic state initiated by the stimulation of monocytes by bacterial toxins such as endotoxin, which is released into the bloodstream. This study describes the role of oxidative stress in endotoxin-induced metabolic disorders. We demonstrate that endotoxin injection results in lipid peroxide formation and membrane injury in experimental animals, causing decreased levels of free radical scavengers or quenchers. Interestingly, it was also suggested that tumor necrosis factor (TNF)-induced oxidative stress occurs as a result of bacterial or endotoxin translocation under conditions of reduced reticuloendothelial system function in various disease states. In addition, we suggest that intracellular Ca2+, Zn2+, or selenium levels may participate, at least in part, in the oxidative stress during endotoxemia. On the other hand, it is also suggested that the extent of endotoxin-induced nitric oxide (NO) formation may be due, at least in part, to a change in heme metabolic regulation during endotoxemia. However, in our experimental model, NO is not crucial for lipid peroxide formation during endotoxemia. Sho-saiko-to is one of the most frequently prescribed Kampo medicines and has primarily been used to treat chronic hepatitis. We report that Sho-saiko-to decreases the rh TNF-induced lethality in galactosamine-hypersensitized mice and protects mice against oxygen toxicity and Ca2+ overload in the cytoplasm or mitochondria during endotoxemia. We further suggest that Sho-saiko-to shows a suppressive effect on NO generation in macrophages stimulated with endotoxin and that it may be useful in improving endotoxin shock symptoms.
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PMID:[Metabolic aspects of endotoxin as a model of septic shock--approached from oxidative stress]. 1497 49

The methanol extract of Anacardium occidentale stem bark was evaluated for activities against the lipopolysaccharide (LPS)-induced septic shock, as well as LPS-induced microvascular permeability in mice. Pre-treatment with Anacardium occidentale extract (25-200 mg/kg) caused a dose-dependent and significant (p < 0.05) reduction in the elevated levels of alanine and aspartate aminotransferases in the sera of D-galactosamine-primed mice injected with LPS. The highest dose of the extract studied (200 mg/kg) produced a 100% protection against death from sepsis. Pentoxifylline (100 mg/kg) and L-NAME (5 mg/kg) offered 100% protection against LPS-induced septic shock, and produced marked reduction in elevated levels of transferases. A dose-related inhibition of LPS-induced microvascular permability in mice was also produced by pentoxifylline, L-NAME and the extract.
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PMID:Effects of Anacardium occidentale stem bark extract on in vivo inflammatory models. 1550 26

Antioxidants have been shown to be effective in murine models of sepsis. Protocatechuic acid has antioxidant activity. In the present study, the protective effects of protocatechuic acid and its derivatives were investigated in a mouse model of septic shock induced by lipopolysaccharide (LPS)/D-galactosamine (GalN). Pretreatment of animals with protocatechuic acid effectively suppressed LPS/GalN-induced lethality; protocatechuic acid isopropyl ester was the most effective among the various derivatives of protocatechuic acid. Protocatechuic acid isopropyl ester was also effective in protection against the high-dose LPS-induced shock. Pretreatment with protocatechuic acid isopropyl ester effectively suppressed the LPS/GalN-induced increase in plasma tumor necrosis factor (TNF)-alpha alanine aminotransferase (ALT), nitrite/nitrate levels, and hepatic malondialdehyde levels. In contrast, it markedly enhanced the LPS/GalN-induced increase in plasma interleukin (IL)-10 levels, without any changes in IL-6 plasma levels. These results suggest that protocatechuic acid isopropyl ester could be useful for the prevention of sepsis.
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PMID:Protective effect of protocatechuic acid isopropyl ester against murine models of sepsis: inhibition of TNF-alpha and nitric oxide production and augmentation of IL-10. 1557 25


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