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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In vitro, nitric oxide (NO) decreases leukocyte adhesion to endothelium by attenuating endothelial adhesion molecule expression. In vivo, lipopolysaccharide-induced leukocyte rolling and adhesion was greater in inducible NO synthase (iNOS)-/- mice than in wild-type mice. The objective of this study was to assess E- and P-selectin expression in the microvasculature of iNOS-/- and wild-type mice subjected to acute peritonitis by cecal ligation and perforation (CLP). E- and P-selectin expression were increased in various organs within the peritoneum of wild-type animals after CLP. This CLP-induced upregulation of E- and P-selectin was substantially reduced in iNOS-/- mice. Tissue myeloperoxidase (MPO) activity was increased to a greater extent in the gut of wild-type than in iNOS-/- mice subjected to CLP. In the lung, the reduced expression of E-selectin in iNOS-/- mice was not associated with a decrease in MPO. Our findings indicate that NO derived from iNOS plays an important role in sepsis-induced increase in selectin expression in the systemic and pulmonary circulation. However, in iNOS-/- mice, sepsis-induced leukocyte accumulation is affected in the gut but not in the lungs.
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PMID:Endothelial E- and P-selectin expression in iNOS- deficient mice exposed to polymicrobial sepsis. 1120 53

Human protein C is a natural anticoagulant factor, and a recombinant activated form of the molecule (rhAPC) is completing clinical evaluation for treatment of severe sepsis. Because of the pathophysiologic role of endothelial dysfunction in severe inflammatory disease and sepsis, we explored the possibility that rhAPC might directly modulate endothelial function, independent of its anticoagulant activity. Using broad transcriptional profiling, we show that rhAPC directly modulates patterns of endothelial cell gene expression clustering into anti-inflammatory and cell survival pathways. rhAPC directly suppressed expression of p50 and p52 NFkappaB subunits, resulting in a functional decrease in NFkappaB binding at target sites. Further, rhAPC blocked expression of downstream NFkappaB regulated genes following tumor necrosis factor alpha induction, including dose-dependent suppression of cell adhesion expression and functional binding of intracellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin. Further, rhAPC modulated several genes in the endothelial apoptosis pathway, including the Bcl-2 homologue protein and inhibitor of apoptosis protein. These pathway changes resulted in the ability of rhAPC to inhibit the induction of apoptosis by the potent inducer, staurosporine. This new mechanistic understanding of endothelial regulation and the modulation of tumor necrosis factor-induced endothelial dysfunction creates a novel link between coagulation, inflammation, and cell death and provides insight into the molecular basis for the efficacy of APC in systemic inflammation and sepsis.
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PMID:Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. 1127 52

This article reviews recent advances in the knowledge of the role of L-selectin, an adhesion molecule that is expressed on the surface of circulating leucocytes, in animal and human physiology and pathophysiology. After a brief discussion on nomenclature and structure, it progresses through the evidence for expression and regulation of L-selectin, cell collection and purification, physiological function and roles. The special role of knock out mice and monoclonal antibodies in determining a role for L-selectin in inflammatory states is described before proceeding to discuss the importance of L-selectin ligands and shed L-selectin. A second section describes a role for L-selectin in pathophysiological states in animals and man, with special reference to trauma, systemic inflammatory syndromes and sepsis. The review concludes with a summary of the potential role of anti-inflammatory medication and L-selectin blockers in the management of inflammation.
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PMID:L-selectin in health and disease. 1184 80

Upon activation, polymorphonuclear leucocytes (PMN) release bactericidal/permeability-increasing protein, (BPI) from their azurophil granules. BPI selectively binds to the lipopolysaccharide (LPS) on gram-negative bacteria and induces their death. This study examined plasma BPI concentration levels in healthy newborns and in newborns with clinical sepsis, and the ability of PMN from preterm and term infants to release BPI. We also studied the release of myeloperoxidase (MPO), and the surface expression of adhesion molecule CD11b on PMN. In infants with clinical sepsis, plasma BPI concentration was higher, 27.8 microg/L [8.6-883; median (range)] (n = 11), than in healthy term infants 8.9 microg/L (3.9-179) (n = 17), and in adults 7.3 microg/L (0.7 -18.4) (n = 15); p = 0.014, Kruskal-Wallis. In preterm infants (n = 8), the ability of PMN to release BPI in vitro after stimulation with PMA was 8.8, in term infants it was 15.9 (n = 29; p > 0.05 vs. preterm infants) and in adults 23.4 ng/10(6) PMN (n = 15; p = 0.024 and p > 0.05 vs. preterm and term infants, respectively). The corresponding values of MPO were 20.0 ng/10(6) (11.3-46.7) in preterms, 19.0 ng/10(6) (2.2-223.7) in terms, and 27.8 ng/10(6) (9.1-80.7) in adults; p = 0.67 between groups. In infants with clinical sepsis, CD11b level was higher, 292 RFU (234-403) than the basal CD11b expression levels in healthy newborn infants, 116 RFU (76-145); P = 0.0001. FMLP-stimulated PMN CD11b expressions in preterm cord blood, 1071 RFU (552-1286) and in term cord blood, 918 (567-1472) were on the same level, but lower than that in adult blood, 1592 (973-1946); p < 0.001, ANOVA. Our findings suggest that in preterm infants the ability to release BPI is lower than in adults and term infants. These findings suggest that premature neonates have an impaired ability to mobilize BPI, possibly contributing to their marked susceptibility to infections with Gram-negative bacteria.
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PMID:Extracellular release of bactericidal/permeability-increasing protein in newborn infants. 1203 58

Systemic inflammation because of sepsis results in endothelial cell activation and microvascular injury. High-mobility group protein-1 (HMGB1), a novel inflammatory molecule, is a late mediator of endotoxin shock and is present in the blood of septic patients. The receptor for advanced glycation end products (RAGE) is expressed on endothelium and is a receptor for HMGB1. Here we examine the effects of HMGB1 on human endothelial cell function. Recombinant human HMGB1 (rhHMGB1) was cloned and expressed in Escherichia coli and incubated with human microvascular endothelium. rhHMGB1 caused a dose- and time-dependent increase in the expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and RAGE. rhHMGB1 induced the secretion of tumor necrosis factor-alpha (TNFalpha), interleukin 8 (IL-8), monocyte chemotactic protein-1 (MCP-1), plasminogen activator inhibitor 1 (PAI-1), and tissue plasminogen activator (tPA) (P <.01). rhHMGB1 stimulation resulted in transient phosphorylation of mitogen-activated protein (MAP) kinases, extracellular signal-related kinase (ERK), Jun N-terminal kinase (JNK), and p38, and in nuclear translocation of transcription factors NF-kappaB and Sp1. These effects are partially mediated by TNFalpha autocrine stimulation, as anti-TNFalpha antibodies significantly decrease chemokine and adhesion molecule responses (P </=.002). Thus, rhHMGB1 elicits proinflammatory responses on endothelial cells and may contribute to alterations in endothelial cell function in human inflammation.
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PMID:Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. 1245 6

Endotoxin-induced intercellular adhesion molecule-1 (ICAM-1) and interleukin 8 (IL-8) production in endothelial cells, which is mediated by Toll-receptor signaling, is essential for optimal neutrophil recruitment and migration during sepsis. Endotoxin also causes stress fiber polymerization that has recently been shown to affect intracellular signaling. However, the role of this polymerization process on endothelial-induced neutrophil adhesion and migration is unknown. Human umbilical vein endothelial cells (HUVEC) were stimulated with lipopolysaccharide (LPS). Selected cells were pretreated with cytochalasin D (CD) or lactrunculin A (LA), agents that disrupt actin polymerization. Cellular protein was extracted and analyzed by Westem blot for the phosphorylated form of IL-1-associated kinase (IRAK) and production of ICAM-1. Extracted nuclear protein was analyzed by Western blot and electrophoretic mobility shift assay (EMSA) for nuclear translocation and activity of NF-kappaB. IL-8 production was determined by enzyme-linked immunoabsorbant assay (ELISA). Neutrophil adhesion was assayed fluorometrically using calcein-AM-labeled neutrophils on treated endothelial cells. LPS treatment led to phosphorylation of IRAK, and subsequent NF-kappaB translocation and activation. This cellular signaling was followed by ICAM-1 expression and IL-8 production. Pretreatment of cells with CD or LA led to a significant inhibition of IRAK phosphorylation, and NF-kappaB nuclear translocation and activation. Actin depolymerization also significantly inhibited LPS-induced ICAM-1 and IL-8 production. HUVEC pretreated with CD or LA demonstrated significant inhibition of LPS-induced neutrophil adhesion. Endotoxin-induced actin polymerization is essential for optimal intracellular signaling through IRAK and NF-kappaB. Failure of these signaling events is associated with a marked reduction in adhesion molecule production, IL-8 production, and neutrophil adhesion. These findings support the necessity of stress fiber polymerization for optimal recruitment of neutrophils during sepsis.
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PMID:Endotoxin-induced endothelial cell proinflammatory phenotypic differentiation requires stress fiber polymerization. 1274 86

Polymorphonuclear neutrophils (PMNs) and macrophages are recognized to serve as the first line of defense against bacterial contamination during the perioperative period. Chemoattractants produced by macrophages cause PMN accumulation at the inflammatory site. Proinflammatory cytokines released by macrophages increase adhesion molecule expression on the surface of endothelial cells. P- and E-selectins produce leukocyte rolling, whereas beta 2-integrin-ICAM-1 interaction causes firm adhesion of leukocytes to the endothelium, followed by migration to the interstitium. Thus appropriate activation of the inflammatory cascade leads to leukocyte migration to the infectious focus. In particular, during the first several hours after the onset of bacterial contamination, massive exudation of PMNs is generally observed. PMNs and macrophages phagocytose the bacteria via opsonization and kill them with oxygen products or proteolytic enzymes. Malnutrition and the lack of enteral nutrition are assumed to impair PMN-macrophage-dependent host defense by derangement of adhesion molecule expression and the cytokine milieu. Recently, sticky PMNs before surgery have been reported to increase infectious morbidity after surgery. In addition, augmented alpha 4-integrin-VCAM-1 interaction has been demonstrated during sepsis, which is possibly a mechanism for increased PMN adhesion and resultant organ injury. Further study is needed to clarify the mechanisms of the disturbed function of PMNs and macrophages under various conditions.
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PMID:[Role of polymorphonuclear neutrophils and macrophages in the prevention of postoperative infections]. 1288 74

L-Selectin is an adhesion molecule shed from the surface of lymphocytes and granulocytes upon activation. Soluble L-selectin in the plasma can thus reflect immune activation and is elevated in several pathological states. Our objective was to evaluate plasma levels of L-selectin as an immune activation marker in neonates and to determine whether it can serve as a marker of infection, either neonatal or congenital, or if it is affected by the mode of delivery and obstetrical or perinatal complications. A solid-phase ELISA was used on 89 sera from neonates less than 2 days of age, according to the manufacturer's instructions. Levels of soluble L-selectin in the neonate were lower than those of older infants and children and comparable to the levels seen in adults. There was no difference between levels of soluble L-selectin of premature (median, 1172 ng/ml) and full-term babies (median, 1151 ng/ml) or between babies born via vaginal (median, 1233 ng/ml) or cesarean delivery (median, 1146 ng/ml). Conditions such as preeclampsia or administration of steroids to the mother did not affect the levels of L-selectin in the neonate. In contrast, the presence of maternal clinical chorioamnionitis resulted in an increase in levels of L-selectin in the neonate (median, 1377 vs 1072 ng/ml, p = 0.02), as did neonatal sepsis (median, 1331 vs 1149 ng/ml, p = 0.026). Soluble L-selectin, and thus immune activation level, is highest in neonates with neonatal infection and needs to be further evaluated as a surrogate marker for diagnosing sepsis in the neonate.
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PMID:Soluble L-selectin, a marker of immune activation, in neonatal infection. 1459 21

C5a-C5aR signaling plays an essential role in innate immunity of neutrophils. However, excessive interaction of C5a-C5aR results in harmful effects in these cells. In sepsis, robust generation of C5a occurs; blockade of either C5a or C5aR greatly improves survival in experimental sepsis following cecal ligation and puncture (CLP). The beneficial effects derived from C5a-C5aR interaction are associated with preservation of neutrophil innate immune functions (chemotaxis, phagocytosis, respiratory burst), attenuation of the inflammatory reaction, amelioration of coagulopathy, alteration in adhesion molecule expression, and modulation of apoptosis. Following CLP, C5aR expression is significantly elevated in organs, perhaps setting the stage for C5a-induced organ dysfunction. In contrast, C5aR content on neutrophils drops significantly at early stages of sepsis and progressively increases at later time points. Re-expression of C5aR on neutrophils during sepsis appears to be associated with the functional recovery of neutrophil innate immune functions. Following CLP, there is a positive correlation between C5aR content on blood neutrophils and survival of individual animals; high levels of C5aR on neutrophils are associated with survival, whereas low levels of C5aR on neutrophils predict mortality. These data suggest that in sepsis C5a-C5aR signaling is excessive, resulting in paralysis of neutrophil function. Interception of either C5a or C5aR dramatically improves survival during experimental sepsis.
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PMID:Role of C5a-C5aR interaction in sepsis. 1467 76

Binding of host inflammatory cells to the endothelium is a critical contributor to the vascular damage characteristic of severe meningococcal disease and is regulated by endothelial cell adhesion molecules such as ICAM-1, VCAM-1 and CD62E. Intact meningococci induce far higher levels of CD62E than lipopolysaccharide (LPS) alone, whereas LPS is at least as potent as meningococci at inducing both VCAM-1 and ICAM-1 expression. This suggests that meningococci possess additional factors other than LPS present in whole bacteria that result in differential adhesion molecule expression. To investigate this possibility, we studied the capacity of an LPS-deficient isogenic strain of serogroup B Neisseria meningitidis H44/76 (lpxA-) to induce endothelial cell adhesion molecule expression and translocation of the transcription factor NF-kappaB, and compared it to both parent and unencapsulated strains of both B1940 and H44/76 and purified LPS. Although the LPS-deficient isogenic mutant of strain H44/76 was found to be a poor inducer of NF-kappaB, it induced higher levels of CD62E expression than LPS alone. These data provide evidence that intact meningococci induce a range of signals in the endothelium that are distinct from those seen with purified LPS alone and that they occur in a LPS-dependent and LPS-independent manner. These signals may explain the potent effects of N. meningitidis on CD62E expression on vascular endothelium and provide a basis for the complex endothelial dysregulation seen in meningococcal sepsis.
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PMID:High-level endothelial E-selectin (CD62E) cell adhesion molecule expression by a lipopolysaccharide-deficient strain of Neisseria meningitidis despite poor activation of NF-kappaB transcription factor. 1467 68


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