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)

Neutrophil-specific granule deficiency (SGD) is a rare, congenital disease characterized by atypical neutrophil structure and function, resulting in recurrent bacterial infections from early infancy. Homozygous recessive mutations in the CCAAT/enhancer-binding protein epsilon (C/EBPepsilon) gene were described in two of five SGD patients, indicating loss of C/EBPepsilon function as the primary genetic defect in this disease. C/EBPepsilon is expressed in murine and human macrophages. Macrophages from the C/EBPepsilon-deficient mice show impaired differentiation, phagocytic activity, and transcription of macrophage-specific genes. To determine if monocyte/macrophage cells are impacted in SGD, we analyzed phenotypic features of peripheral blood (PB) monocytes in a SGD individual lacking functional C/EBPepsilon. Flow cytometric analysis of PB leukocytes revealed aberrant expression of CD45, CD11b, CD14, CD15, and CD16 on cells from the SGD individual. Also, the PB CD14(+) cells from this individual, weakly stained for the monocyte-specific enzyme, nonspecific esterase, and electron microscopic examination, indicated morphologic differences between the SGD cells and those from normal controls. Serum interleukin (IL)-6 levels in the SGD individual during a severe bacterial infection were lower compared with levels in other non-SGD individuals with sepsis. In contrast, serum IL-8 levels were markedly elevated in the SGD individual compared with those of non-SGD individuals in sepsis. PB CD14(+) cells from the SGD individual expressed higher IL-8 mRNA levels compared with normal controls in response to lipopolysaccharide and interferon-gamma. These phenotypic and functional alterations of PB monocytes in the SGD individual suggest that C/EBPepsilon plays a critical role in monocyte/macrophage development of humans and is consistent with observations in the murine system. This study implicates abnormalities in monocytes/macrophages and neutrophils in the onset and development of SGD.
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PMID:Phenotypic and functional alterations of peripheral blood monocytes in neutrophil-specific granule deficiency. 1457 62

Hydroxyethyl starch (HES) has been shown to be beneficial in several inflammatory situations, but the mechanisms are unclear. The present study tested the hypothesis that HES has effects on nuclear factor kappa B (NF-kappaB) activation and the expression of inflammatory mediators induced by lipopolysaccharide. Sepsis was induced in male Wistar rats by injection of lipopolysaccharide (LPS, 6 mg/kg, i.p.). At 1 min after the LPS challenge, HES was infused via the right external jugular vein at the following doses: 3.75, 7.5, 15, or 30 ml/kg. NF-kappaB activation in peripheral blood mononuclear cells and neutrophils, plasma concentrations of tumor necrosis factor (TNF)-alpha, cytokine-induced neutrophil chemoattractant (CINC), expression of CD11b on the blood neutrophil cell surface, and neutrophil sequestration in multiple organs were examined 2 or 4 hr after the LPS challenge. Treatment of rats with HES (3.75 and 7.5 ml/kg) prevented LPS-induced NF-kappaB activation, and inhibited, in a dose-related manner, LPS-induced TNF-alpha and CINC expression. The 4 graded doses of HES decreased CD11b expression in a dose-dependent manner. HES significantly reduced neutrophil sequestration in lung, heart, and liver. These results suggest that HES has an anti-inflammatory effect in endotoxic rats. This effect is mediated by inhibition in the production pathways for inflammatory mediators, including NF-kappaB activation.
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PMID:Hydroxyethyl starch inhibits NF-kappaB activation and prevents the expression of inflammatory mediators in endotoxic rats. 1458 60

Fulminant meningococcal sepsis has been termed the prototypical lipopolysaccharide (LPS)-mediated gram-negative septic shock. Systemic inflammation by activated complement and cytokines is important in the pathogenesis of this disease. We investigated the involvement of meningococcal LPS in complement activation, complement-dependent inflammatory effects, and cytokine or chemokine production. Whole blood anticoagulated with lepirudin was stimulated with wild-type Neisseria meningitidis H44/76 (LPS+), LPS-deficient N. meningitidis H44/76lpxA (LPS-), or purified meningococcal LPS (NmLPS) at concentrations that were relevant to meningococcal sepsis. Complement activation products, chemokines, and cytokines were measured by enzyme-linked immunosorbent assays, and granulocyte CR3 (CD11b/CD18) upregulation and oxidative burst were measured by flow cytometry. The LPS+ and LPS- N. meningitidis strains both activated complement effectively and to comparable extents. Purified NmLPS, used at a concentration matched to the amount present in whole bacteria, did not induce any complement activation. Both CR3 upregulation and oxidative burst were also induced, independent of LPS. Interleukin-1beta (IL-1beta), tumor necrosis factor alpha, and macrophage inflammatory protein 1alpha production was predominantly dependent on LPS, in contrast to IL-8 production, which was also markedly induced by the LPS- meningococci. In this whole blood model of meningococcal sepsis, complement activation and the immediate complement-dependent inflammatory effects of CR3 upregulation and oxidative burst occurred independent of LPS.
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PMID:Complement activation and complement-dependent inflammation by Neisseria meningitidis are independent of lipopolysaccharide. 1515 39

Late-onset hospital-acquired sepsis is common in extremely low birth-weight (<1000 g) (ELBW) infants. The diagnosis is difficult since, at early stages of sepsis, routine laboratory tests are neither specific nor sensitive. In term infants with sepsis neutrophil surface expression of CD11b/CD18, a beta2-integrin, is significantly increased. Here we studied whether increased CD11b/CD18 density on blood neutrophils and monocytes serves as an early sepsis marker in ELBW infants. Blood samples were obtained from 30 ELBW infants on a daily basis for 3-4 postnatal weeks, and neutrophil and monocyte CD11b/CD18 expression was determined by flow-cytometry. Patients were assigned one of 3 groups: 1) an infected group, comprised of infants who had blood culture-positive sepsis and/or necrotizing enterocolitis, 2) a non-infected group, and 3) a potentially infected group, comprised of infants in whom infection was suspected but could not be confirmed microbiologically. One patient had blood culture contamination and was excluded from the analysis. In the infected group, CD11b expression gradually increased during the three days preceding sampling for blood culture. At the day of sampling, median expression of CD11b in neutrophils and monocytes was higher in the infected group than in the control group. For neutrophils the sensitivity and specificity were 1.00 and 0.56, respectively, and for monocytes, 0.86 and 0.94, respectively. From these data, we conclude that determination of CD11b/CD18 density on neutrophils and monocytes may improve diagnosis of late-onset sepsis in ELBW infants.
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PMID:Increased CD11b-density on circulating phagocytes as an early sign of late-onset sepsis in extremely low-birth-weight infants. 1558 84

Neutropenia is a common sequela of neonatal sepsis. Recent clinical trials have shown the beneficial effects of colony-stimulating factors (CSFs) on outcome in this group, but the exact mechanism remains unknown. Neonates and mothers who were at high-risk for infection were recruited for cord blood sampling in a university tertiary referral maternity hospital. Neonatal and adult neutrophils were evaluated for their ability to combat bacterial infection by examining their functional activity (CD11b and reactive oxygen intermediates) and their persistence at inflammatory sites (apoptosis). The mechanism for altered apoptotic responses was assessed by caspase activation assays, X chromosome-linked inhibitor of apoptosis protein expression, and cytosolic cytochrome c release. Although granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly delayed neutrophil apoptosis in normal adults, only G-CSF had a similar effect in normal neonates. Neutrophils from neonates who are at high risk for infection are unresponsive to the antiapoptotic effects of G-CSF or GM-CSF, unlike maternal neutrophils, which have delayed apoptosis in response to GM-CSF. However, CD11b expression and reactive oxygen intermediate production were significantly increased in normal neonatal neutrophils that were incubated with GM-CSF versus controls but not G-CSF or lipopolysaccharide. Decreased cytosolic cytochrome c release and caspases 3 and 9 activity are associated with the CSF-mediated delay in apoptosis in adults but not in newborns. The antiapoptotic X chromosome-linked inhibitor of apoptosis protein is up-regulated in neonates compared with adults and may mediate their differential spontaneous apoptosis. These results have important implications for the use of CSFs in neonatal sepsis, as responses differ from those seen in adults. Further delineation of neonatal neutrophil responses to CSFs may improve their therapeutic potential.
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PMID:Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor have differential effects on neonatal and adult neutrophil survival and function. 1571 63

To inactivate chronically the beta2-integrin CD11b (Mac-1), we made a transgenic model in mice in which we expressed the CD11b antagonist polypeptide neutrophil inhibitory factor (NIF). Using these mice, we determined the in vivo effects of CD11b inactivation on polymorphonuclear leukocyte (PMN) function and acute lung injury (ALI) induced by Escherichia coli septicemia. In wild-type PMNs, CD11b expression was induced within 1 h after E. coli challenge, whereas this response was significantly reduced in NIF(+/+) PMNs. Coimmunoprecipitation studies showed that NIF associated with CD11b in NIF(+/+) PMNs. To validate the effectiveness of CD11b blockade, we compared PMN function in NIF(+/+) and Mac-1-deficient (Mac-1(-/-)) mice. Adhesion of both Mac-1(-/-) and NIF(+/+) PMNs to endothelial cells in response to LPS was reduced in both types of PMNs and fully blocked only by the addition of anti-CD11a monoclonal antibody. This finding is indicative of intact CD11a function in the NIF(+/+) PMNs but the blockade of CD11b function. CD11b inactivation in NIF(+/+) mice interfered with lung PMN infiltration induced by E. coli and prevented the increase in lung microvessel permeability and edema formation, with most of the protection seen in the 1-h period after the E. coli. Thus our results demonstrate that CD11b plays a crucial role in mediating lung PMN sequestration and vascular injury in the early phase of gram-negative septicemia. The NIF(+/+) mouse model, in which CD11b is inactivated by binding to NIF, is a potentially useful model for in vivo assessment of the role of PMN CD11b in the mechanism of vascular inflammation.
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PMID:Inactivation of CD11b in a mouse transgenic model protects against sepsis-induced lung PMN infiltration and vascular injury. 1583 44

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

Treatments targeting complement receptors have been demonstrated to improve outcome in experimental sepsis. The regulation of the complement receptors in sepsis is not clear. Lipopolysaccharide (LPS) stimulation of granulocytes ex vivo has been shown to reduce C5a receptor (CD88) expression and to increase CD35 and CD11b/CD18 expressions in whole blood but not on isolated cells, indicating an indirect effect mediated via factors in the blood. With the aim to study whether these effects could be attributed to C5a, tumour necrosis factor (TNF)-alpha and interleukin (IL)-8, whole blood or isolated granulocytes and monocytes from healthy individuals were investigated. After incubation with C5a in a dose range of 1 x 10(-9)-1 x 10(-7) mol/l, and TNF-alpha and IL-8 at doses of 1-100 ng/ml, the expressions of the complement receptors CD88, CD35, CD11b/CD18 were analysed by flow cytometry. Incubation with C5a reduced granulocyte CD88 expression by 44+/-6.9% and 82+/-4.2%, whereas monocyte CD88 expression decreased by 21+/-4.0 and 30+/-17% (whole blood and isolated cells). IL-8 and TNF-alpha incubation of granulocytes induced similar results. Granulocyte CD35 expression was significantly increased by 367, 175 and 336% by C5a, TNF-alpha, IL-8, respectively; CD11b expression was similarly increased. Consistent with findings in septic patients and after LPS incubation, it is concluded that all stimuli reduced granulocyte CD88 expression, whereas CD35 and CD11b were increased.
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PMID:C5a, interleukin-8 and tumour necrosis factor-alpha-induced changes in granulocyte and monocyte expression of complement receptors in whole blood and on isolated leukocytes. 1649 74

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

Recent literature indicates that females are more resistant to shock-, trauma-, and sepsis-induced immune dysfunction and organ injury than are males. Consequently, using trauma-hemorrhagic shock (T/HS) and burn models, we tested whether the neutrophil response to trauma occurred in a sexually dimorphic fashion and, if so, the role of sex hormones. Neutrophil activation, as reflected by CD11b expression and respiratory burst activity, was increased to a greater extent in male rats than in female rats after T/HS or burn injury. Testosterone appeared to potentiate neutrophil activation, because castration reduced neutrophil activation, whereas ovariectomy had little effect. Mechanistically, this sexually dimorphic neutrophil response appeared to be due to both cellular and humoral factors. Evidence for a cellular difference between male and female neutrophils is based on the observation that naive female neutrophils were more resistant to activation by burn or T/HS plasma and lymph than naive male neutrophils and that this resistance varied over the estrus cycle. Additionally, the humoral environment was more neutrophil activating in male rats, because burn and T/HS plasma and lymph from male rats activated naive male neutrophils to a greater extent than comparable samples from females. Last, on the basis of in vitro experiments examining the effects of estrogen on calcium signaling, it appears that estrogen limits trauma-induced neutrophil activation, at least in part, by limiting the entry of calcium into the cell via store-operated calcium entry mechanisms. In conclusion, there is a striking sexual dimorphism in neutrophil responses after trauma, and these changes reflect both cellular resistance to activation as well as a less activating humoral environment.
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PMID:Neutrophil activation is modulated by sex hormones after trauma-hemorrhagic shock and burn injuries. 1661 33


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