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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Morbidity and mortality rates are very high in obstructive jaundice when it is associated with sepsis and multiple organ failure. Nitric oxide (NO) formation and increased expression of inducible nitric oxide synthase (iNOS) also take place in obstructive jaundice (OJ). N-Acetylcysteine (NAC) has a beneficial effect by demonstrating anti-inflammatory activity such as inhibits cytokine expression/release, inhibiting the adhesion molecule expression and inhibiting nuclear factor kappa B (NFkappaB). The aim of this study was to investigate the effects of NAC on liver and renal tissue iNOS, and liver tissue lipid peroxidation in lipopolysaccharide (LPS) induced obstructive jaundice. We randomized 48 rats into six groups. Group A: Sham group; group B: OJ group; group C: OJ+NAC; group D: OJ+LPS (Escherichia coli LPS serotype L-2630, 100mg, Sigma) group E: OJ+NAC+LPS; group F: OJ+LPS+NAC. NAC was started subcutaneously 100mg/kg. LPS was injected intraperitoneally and then at the tenth day we sacrificed the rats. Liver malondialdehyde (MDA) increased and liver ATPase decreased in groups B-D when compared to group A. After the administration of NAC (groups C-E), liver MDA levels decreased, tissue ATPase levels increased as compared to other groups. The liver and renal tissue iNOS expression was increased in groups B, D, and F. After the administration of NAC (groups C-E) the liver and renal tissue iNOS expression were decreased. Our results indicated that NAC prevented the deleterious effects of LPS in OJ by reducing iNOS expression via lipid peroxidation in liver and renal tissue; if it was administrated before LPS. But NAC failed to prevent the iNOS expression and lipid peroxidation if there was established endotoxemia in OJ.
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PMID:The effect of N-acetylcysteine (NAC) on liver and renal tissue inducible nitric oxide synthase (iNOS) and tissue lipid peroxidation in obstructive jaundice stimulated by lipopolysaccharide (LPS). 1472 17

Inflammatory response leading to organ dysfunction and failure continues to be the major problem after injury in many clinical conditions such as sepsis, severe burns, acute pancreatitis, haemorrhagic shock, and trauma. In general terms, systemic inflammatory response syndrome (SIRS) is an entirely normal response to injury. Systemic leukocyte activation, however, is a direct consequence of a SIRS and if excessive, can lead to distant organ damage and multiple organ dysfunction syndrome (MODS). When SIRS leads to MODS and organ failure, the mortality becomes high and can be more than 50%. Acute lung injury that clinically manifests as acute respiratory distress syndrome (ARDS) is a major component of MODS of various aetiologies. Inflammatory mediators play a key role in the pathogenesis of ARDS, which is the primary cause of death in these conditions. This review summarizes recent studies that demonstrate the critical role played by inflammatory mediators such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, platelet activating factor (PAF), IL-10, granulocyte macrophage-colony stimulating factor (GM-CSF), C5a, intercellular adhesion molecule (ICAM)-1, substance P, chemokines, VEGF, IGF-I, KGF, reactive oxygen species (ROS), and reactive nitrogen species (RNS) in the pathogenesis of ARDS. It is reasonable to speculate that elucidation of the key mediators in ARDS coupled with the discovery of specific inhibitors would make it possible to develop clinically effective anti-inflammatory therapy.
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PMID:Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. 1474 96

Cecal ligation and puncture (CLP)-induced sepsis in mice was associated with perturbations in vascular adhesion molecules. In CLP mice, lung vascular binding of (125)I-monoclonal antibodies to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 revealed sharp increases in binding of anti-ICAM-1 and significantly reduced binding of anti-VCAM-1. In whole lung homogenates, intense ICAM-1 up-regulation was found (both in mRNA and in protein levels) during sepsis, whereas very little increase in VCAM-1 could be measured although some increased mRNA was found. During CLP soluble VCAM-1 (sVCAM-1) and soluble ICAM-1 (sICAM-1) appeared in the serum. When mouse dermal microvascular endothelial cells (MDMECs) were incubated with serum from CLP mice, constitutive endothelial VCAM-1 fell in association with the appearance of sVCAM-1 in the supernatant fluids. Under the same conditions, ICAM-1 cell content increased in MDMECs. When MDMECs were evaluated for leukocyte adhesion, exposure to CLP serum caused increased adhesion of neutrophils and decreased adhesion of macrophages and T cells. The progressive build-up in lung myeloperoxidase after CLP was ICAM-1-dependent and independent of VLA-4 and VCAM-1. These data suggest that sepsis disturbs endothelial homeostasis, greatly favoring neutrophil adhesion in the lung microvasculature, thereby putting the lung at increased risk of injury.
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PMID:Disturbed homeostasis of lung intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 during sepsis. 1503 31

The relative contribution of the pro-inflammatory cytokines tumour necrosis factor (TNF)-alpha and interleukin (IL)-1 beta and the lipopolysaccharide (LPS)-induced pathways that result in endothelial activation during sepsis are not fully understood. We have examined the effects of plasma obtained from LPS-treated human whole blood on the expression of E-selectin and intercellular adhesion molecule-1 (ICAM-1) on human endothelial cells. Stimulation of blood with 10 pg/ml of LPS is sufficient to produce plasma that induces E-selectin and ICAM-1 expression, while direct induction by LPS alone requires a 100-fold higher concentration. Characteristics for the plasma-induced adhesion molecule expression were similar to the LPS-induced production of TNF-alpha and IL-1 beta in blood. A complete inhibition of E-selectin and ICAM-1 expression was observed when antibodies against TNF-alpha and IL-1 beta were added to plasma prior to the incubation to endothelial cultures. Significant inhibition was even observed if antibodies were added to the cultures up until 3 h after LPS-conditioned plasma. The plasma-induced adhesion molecule response could also be prevented with inhibitors of nuclear factor (NF)-kappaB, such as pyrollidine dithiocarbamate. These findings emphasize the central role of TNF-alpha and IL-1 beta in LPS-induced endothelial activation and suggest that simultaneous neutralization of these cytokines or their common pathways may, even after the initial stimulus, prevent endothelial response during sepsis.
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PMID:Modulation of adhesion molecule expression on endothelial cells after induction by lipopolysaccharide-stimulated whole blood. 1514 53

Excessive activation of calpains has been implicated in the pathophysiology of inflammation, trauma, and ischemia reperfusion injury. Here, we investigated the effects of calpain inhibition on myocardial dysfunction and inflammation induced by endotoxin in rats. Rats were treated i.v. with endotoxin (10 mg/kg) or endotoxin plus calpain inhibitors and were then prepared after 4 h for myocardial contractility assessment, detection of endothelium leukocyte interactions, and plasma TNF-alpha, nitrite/nitrate, and endocan levels. Compared with vehicle-treated rats, hearts from endotoxin-treated rats had reduced systolic performance that was partially prevented by calpain inhibitors, i.e., acetyl-leucyl-leucyl-arginal (leupeptin), carbobenzoxy-valyl-phenylalanial (calpain inhibitor III), and N-acetyl-leucinyl-leucinyl-norleucinal (ALLN). Leupeptin and calpain inhibitor III reduced plasma TNF-alpha levels in endotoxin-treated rats. ALLN reduced plasma TNF-alpha and nitrite/nitrate levels in endotoxin-treated rats. Endotoxin treatment increased mesenteric venule leukocyte rolling (10 +/- 3 leukocytes/min vs. 44 +/- 10 leukocytes/min; P < 0.01) and adhesion (2 +/- 2 leukocytes/min vs. 15 +/- 3 leukocytes/min; P < 0.01), which was reduced by calpain inhibitors. Attenuation of leukocyte endothelium interactions observed in calpain inhibitor-treated rats with sepsis was associated with increases in plasma anti-adhesion molecule endocan. In conclusion, calpain inhibitors improved endotoxin-induced cardiac dysfunction, which may be attributed to the modulation of endothelium leukocyte interactions in the inflamed vasculature.
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PMID:Calpain inhibitors improve myocardial dysfunction and inflammation induced by endotoxin in rats. 1517 36

The lung is frequently the first failing organ during the sequential development of multiple organ dysfunction under both septic or non-septic conditions. The present study compared polymorphisms of tumor necrosis factor (TNFalpha), monocyte chemoattractant protein-1 (MCP-1), and adhesion molecule (AM) expression on circulating, recruited, and migrating leukocytes in the development of lung injury after induction of acute pancreatitis (AP) or abdominal sepsis by cecal ligation and puncture (CLP). Pulmonary alveolar barrier and endothelial barrier permeability dysfunction were measured. The expression of AMs (CD11b, CD11b/c, CD31, CD54 and CD62L) on leukocytes isolated from blood, lung tissue, and bronchoalveolar space were measured by flowcytometry. Plasma exudation to the interstitial tissue and the bronchoalveolar space significantly increased 1 and 3 hours after induction of pancreatitis and to the bronchoalveolar space from 6 hours after sepsis. Bronchoalveolar levels of MCP-1 significantly increased earlier than plasma exudation to the alveoli in both pancreatitis and sepsis. Alterations in expression of adhesion molecules on bronchoalveolar lavage (BAL) leukocytes can represent a marker reflecting leukocyte activation in the lung tissue, since both BAL and lung tissue leukocytes showed similar patterns of changes. Expression of adhesion molecules on circulating leukocytes increased 1 hour after induction of pancreatitis. Activating phenotypes of circulating, lung tissue and bronchoalveolar leukocytes may thus be responsible for the-development and severity of secondary lung injury.
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PMID:Alterations of adhesion molecule expression and inflammatory mediators in acute lung injury induced by septic and non-septic challenges. 1602 13

Fractalkine is a unique chemokine that functions as a chemoattractant as well as an adhesion molecule on endothelial cells activated by proinflammatory cytokines. Alpha-lipoic acid (LA), a naturally occurring dithiol compound, is an essential cofactor for mitochondrial bioenergetic enzymes. LA improves glycemic control, reduces diabetic polyneuropathies, and mitigates toxicity associated with heavy metal poisoning. The effects of LA on processes associated with sepsis, however, are unknown. We evaluated the antiinflammatory effect of LA on fractalkine expression in a lipopolysaccharide-induced endotoxemia model. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) significantly induced fractalkine mRNA and protein expression in endothelial cells. LA strongly suppressed TNF-alpha- or IL-1beta-induced fractalkine expression in endothelial cells by suppressing the activities of nuclear factor-kappaB and specificity protein-1. LA also decreased TNF-alpha- or IL-1beta-stimulated monocyte adhesion to human umbilical vein endothelial cells. As shown by immunohistochemistry, fractalkine protein expression was markedly increased by treatment with lipopolysaccharide in arterial endothelial cells, endocardium, and endothelium of intestinal villi. LA suppressed lipopolysaccharide-induced fractalkine protein expression and infiltration of endothelin 1-positive cells into the heart and intestine in vivo. LA protected against lipopolysaccharide-induced myocardial dysfunction and improved survival in lipopolysaccharide-induced endotoxemia. These results suggest that LA could be an effective agent to reduce fractalkine-mediated inflammatory processes in endotoxemia.
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PMID:Protective effect of alpha-lipoic acid in lipopolysaccharide-induced endothelial fractalkine expression. 1616 54

Experimental studies in ischemia-reperfusion and sepsis indicate that activated protein C (APC) has direct anti-inflammatory effects at a cellular level. In vivo, however, the mechanisms of action have not been characterized thus far. Intravital multifluorescence microscopy represents an elegant way of studying the effect of APC on endotoxin-induced leukocyte-endothelial-cell interaction and nutritive capillary perfusion failure. These studies have clarified that APC effectively reduces leukocyte rolling and leukocyte firm adhesion in systemic endotoxemia. Protection from leukocytic inflammation is probably mediated by a modulation of adhesion molecule expression on the surface of leukocytes and endothelial cells. Of interest, the action of APC and antithrombin in endotoxin-induced leukocyte-endothelial-cell interaction differs in that APC inhibits both rolling and subsequent firm adhesion, whereas antithrombin exclusively reduces the firm adhesion step. The biological significance of this differential regulation of inflammation remains unclear, since both proteins are capable of reducing sepsis-induced capillary perfusion failure. To elucidate whether the action of APC and antithrombin is mediated by inhibition of thrombin, the specific thrombin inhibitor hirudin has been examined in a sepsis microcirculation model. Strikingly, hirudin was not capable of protecting from sepsis-induced microcirculatory dysfunction, but induced a further increase of leukocyte-endothelial-cell interactions and aggravated capillary perfusion failure when compared with nontreated controls. Thus, the action of APC on the microcirculatory level in systemic endotoxemia is unlikely to be caused by a thrombin inhibition-associated anticoagulatory action.
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PMID:Microcirculatory alterations in ischemia-reperfusion injury and sepsis: effects of activated protein C and thrombin inhibition. 1616 73

This study investigated the effects of arginine (Arg) on cellular adhesion molecules and intracellular Th1/Th2 cytokine expressions in mice with polymicrobial sepsis. Myeloperoxidase activity in organs was also analyzed to identify the extent of tissue injury resulting from neutrophil infiltration. Mice were randomly assigned to a normal group (NC), a control group, or an Arg group. The NC group was fed a standard chow diet. The control group was fed a common semipurified diet, and in the Arg group, part of the casein was replaced by Arg, which provided 2% of the total calories. After 3 weeks, sepsis was induced by cecal ligation and puncture (CLP) in the control and Arg groups. Mice in the experimental groups were sacrificed at 0, 6, 12, and 24 h after CLP, whereas mice in the NC group were sacrificed when the CLP was performed. Blood and organ samples were immediately collected for further analysis. Results showed that compared with the control group, plasma intracellular adhesion molecule-1 levels were significantly higher in the Arg group 12 and 24 h after CLP. Lymphocyte interferon-gamma expression in the Arg groups was significantly lower, whereas interleukin (IL)-4 expression was higher than the control group at various time points after CLP. The expression of lymphocyte CD11a/CD18 was significantly higher in the Arg group 6, 12, and 24 h after CLP than those of the corresponding control group and the NC group. PMN expressions of CD11b/CD18 in the Arg groups were higher than those in the control group at 12 and 24 h after CLP. The Arg group had higher IL-6 levels at 6 and 12 h in the kidney and intestine and 12 h in the lung after CLP. Higher myeloperoxidase activities were observed in the Arg groups at 24 h after CLP than those in the control group in various organs. These findings suggest that pretreatment with an Arg-supplemented diet enhances adhesion molecule and inflammatory cytokine expression during sepsis, which may aggravate the inflammatory reaction and increase neutrophil infiltration into tissues. In addition, Arg supplementation reduced intracellular interferon-gamma and enhanced IL-4 expression. This change may promote the Th2-type response and suppress the cellular immune response in gut-derived sepsis.
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PMID:Dietary arginine enhances adhesion molecule and T helper 2 cytokine expression in mice with gut-derived sepsis. 1652 54

Fractalkine is a unique endothelial cell-derived chemokine that functions both as a chemoattractant and as an adhesion molecule. Recent findings suggest that fractalkine plays an important role in inflammatory diseases by modulating leucocyte endothelial cell interactions. A modulating effect on the immune system in severe sepsis has been suggested for recombinant human activated protein C (rhAPC). However, a little is known about the effect of rhAPC on the endothelial release of soluble fractalkine. The effect of rhAPC (50 ng/ml to 10 microg/ml) and protein C (in equimolar concentrations) on the synthesis of fraktalkine-mRNA and release of soluble protein in human umbilical vein endothelial cells (HUVEC) was determined by reverse transcription-polymerase chain reaction and by an enzyme-linked immunosorbent assay. rhAPC at supra-pharmacological concentrations (1-10 microg/ml) stimulated fractalkine-messenger RNA-gene transcription and release of soluble fractalkine in a time- and dose-dependent manner, whereas the zymogen protein C was ineffective. As shown by experiments using monoclonal antibodies against the thrombin receptor, protease-activated receptor-1 (PAR-1), PAR-2 and against the endothelial protein C receptor (EPCR), the effect of rhAPC on fractalkine upregulation was mediated by binding to the EPCR-receptor and signalling via PAR-1. These in vitro data demonstrate that induction of fractalkine release is an important response of HUVEC to stimulation with rhAPC and may lead to a better understanding of the molecular pathways involved in the mode of action of rhAPC. Further clinical trials are needed to confirm the in vivo relevance of these data.
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PMID:Recombinant human activated protein C upregulates the release of soluble fractalkine from human endothelial cells. 1668 44


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