Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Mortality of severe sepsis remains at 40% to 50%. Intensive efforts over the past two decades have only marginally improved outcome. Improving outcome in sepsis depends on understanding its pathophysiology, which involves triggers, responses of the organism, and dysfunction. Stress, injury, or infection trigger host responses, including local and systemic orchestrated mechanisms. Dysfunction and outcome depend on both trigger and response. Blood coagulation, inflammation, immunity, and fibrinolysis are critical components of the organism's responses. Understanding their role in sepsis pathophysiology is the key to effective treatment. Relevant studies were identified by a systematic literature search, complemented by manual search of individual citations. Using PubMed, 'sepsis' yields more than 62,000 references, 'plasminogen activators' more than 21,000. The selection of citations was guided by preference for reviews that expand important threads of argumentation. Single original studies were included when relevant to critical points. This analytical review describes the essential elements of pathophysiology and the current status of sepsis treatment. Based on this context, an emerging therapeutic option will be discussed: plasminogen activators.
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PMID:Plasminogen activators in inflammation and sepsis. 1216 68

Urokinase plasminogen activator (uPA) is a serine protease that catalyzes the conversion of plasminogen to plasmin. Although increased circulating levels of uPA are present in endotoxemia and sepsis, conditions in which activated neutrophils contribute to the development of acute organ dysfunction, the ability of uPA to participate directly in LPS-induced neutrophil activation has not been examined. In the present experiments, we show that uPA can enhance activation of neutrophils exposed to submaximal stimulatory doses of LPS. In particular, uPA increased LPS-induced activation of intracellular signaling pathways, including Akt and c-Jun N-terminal kinase, nuclear translocation of the transcriptional regulatory factor NF-kappa B, and expression of proinflammatory cytokines, including IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha. There was no effect of uPA on LPS-induced activation of p38 mitogen-activated protein kinase in neutrophils. Transgenic mice unable to produce uPA (uPA(-/-)) were protected from endotoxemia-induced lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, lung IL-1 beta, macrophage-inflammatory protein-2, and TNF-alpha cytokine levels. These results demonstrate that uPA can potentiate LPS-induced neutrophil responses and also suggest that such effects are sufficiently important in vivo to play a major contributory role in neutrophil-mediated inflammatory responses, such as the development of acute lung injury.
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PMID:Urokinase-type plasminogen activator potentiates lipopolysaccharide-induced neutrophil activation. 1275 45

Plasminogen activator inhibitor-1 (PAI-1) is the major inhibitor of plasminogen activation and likely plays important roles in coronary thrombosis and arteriosclerosis. Tumor necrosis factor-alpha (TNFalpha) is one of many recognized physiological regulators of PAI-1 expression and may contribute to elevated plasma PAI-1 levels in sepsis and obesity. Although TNFalpha is a potent inducer of PAI-1 expression in vitro and in vivo, the precise location of the TNFalpha response site in the PAI-1 promoter has yet to be determined. Transient transfection studies using luciferase reporter constructs containing PAI-1 promoter sequence up to 6.4 kb failed to detect a response to TNFalpha. Moreover, TNFalpha failed to induce expression of enhanced green fluorescent protein under the control of a 2.9-kb human PAI-1 promoter in transgenic mice, although endogenous murine PAI-1 was strongly induced. These data suggested that the TNFalpha response element in the PAI-1 gene is remote from the proximal promoter region. In this study, seven candidate regulatory regions were identified using cross-species sequence homology analysis as well as DNase I-hypersensitive site analysis. We identified a 5' distal TNFalpha-responsive enhancer of the PAI-1 gene located 15 kb upstream of the transcription start site containing a conserved NFkappaB-binding site that mediates the response to TNFalpha. This newly recognized site is fully capable of binding NFkappaB subunits p50 and p65, whereas overexpression of the NFkappaB inhibitor IkappaB prevents TNFalpha-induced activation of this enhancer element.
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PMID:Tumor necrosis factor alpha activates the human plasminogen activator inhibitor-1 gene through a distal nuclear factor kappaB site. 1496 43

To evaluate the predictive value of protein C as a marker of severity in patients with diffuse peritonitis and abdominal sepsis, protein C levels were repeatedly determined and compared with serum levels of antithrombin III, plasminogen, alpha(2)-antiplasmin, Plasminogen activator inhibitor, D-dimer, C1-inhibitor, high molecular weight kininogen, and the C5a, C5b-9 fragments of the complement system. We carried out a prospective study from 44 patients with severe peritonitis confirmed by laparotomy and 15 patients undergoing elective ventral hernia repair who acted as controls. Analyzed biochemical parameters were determined before operations and on days 1, 2, 3, 5, 7, 10, and 14 after operations. For the study group, preoperative average protein C level was significantly lower in the patients who developed septic shock in the late course of the disease, with lethal outcome, than in the patients with severe peritonitis and sepsis who survived (p = 0.0001). In non-survivors, protein C activity remained decreased below 70%, whereas the course of survivors was characterized by increased values that were significantly higher (p < 0.03) at every time point than in those patients who died. Protein C was of excellent predictive value and achieved a sensitivity of 80% and a specificity of 87.5% in discriminating survivors from non-survivors within the first 48 hours of the study (AUC-0.917; p < 0.001), with a "cut-off" level of 66.0%. As for the control group, throughout the study period, protein C activity was permanently maintained within the range of normal, with significant differences with reference to the study group (p < 0.01). These results suggest that protein C represents a sensitive and early marker for the prediction of severe septic complications during diffuse peritonitis, and of outcome.
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PMID:Protein C as an early marker of severe septic complications in diffuse secondary peritonitis. 1588 Feb 75

Urokinase-type plasminogen activator (uPA) is a serine protease that not only displays fibrinolytic function but also modulates innate and adaptive immune responses. In the present study, we assessed whether uPA acts as an endogenous antibiotic. It has been demonstrated that uPA inhibits growth of Staphylococcus aureus both in vivo and in vitro. Importantly, the bactericidal properties of uPA are associated with the serine protease domain of the molecule but are not dependent on its plasminogen-activation potential and cannot be inhibited by plasminogen activator inhibitor type 1 (PAI-1). In a murine infection model, uPA treatment alleviated staphylococcal sepsis by inhibiting bacterial growth. To further evaluate the changes in uPA levels during the course of staphylococcal infection, total uPA and active uPA levels were analyzed in plasma and in kidney homogenates. Expression of total uPA was constant, but PAI-1 levels were dramatically increased in plasma and in kidney homogenates during the course of staphylococcal infection. After infection with staphylococci, the level of metabolically active uPA was unaltered in plasma but was significantly decreased in kidney homogenates. Active uPA levels were inversely related to PAI-1 levels and to bacterial loads in kidney homogenates. In conclusion, we report that uPA acts as an endogenous antibacterial substance that might constitute the first line of host defense against staphylococcal infection. The decreased active uPA levels in infected organs might be due to the dramatically increased PAI-1 production during S. aureus infection.
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PMID:Urokinase-type plasminogen activator, an endogenous antibiotic. 1599 56

Staphylokinase is a 136 aa long bacteriophage encoded protein expressed by lysogenic strains of Staphylococcus aureus. Present understanding of the role of staphylokinase during bacterial infection is based on its interaction with the host proteins, alpha-defensins and plasminogen. alpha-Defensins are bactericidal peptides originating from human neutrophils. Binding of staphylokinase to alpha-defensins abolishes their bactericidal properties, which makes staphylokinase a vital tool for staphylococcal resistance to host innate immunity. Complex binding between staphylokinase and plasminogen results in the formation of active plasmin, a broad-spectrum proteolytic enzyme facilitating bacterial penetration into the surrounding tissues. We have recently shown high levels of staphylokinase expression in clinical isolates of skin and mucosal origin and relative low levels in isolates invading internal organs. These findings are supported by sepsis studies using isogenic S. aureus strains demonstrating increased bacterial load in the absence of staphylokinase production. Our observations indicate that staphylokinase favours symbiosis of staphylococci with the host that makes it an important colonization factor.
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PMID:Staphylococcus aureus: Staphylokinase. 1611 12

Plasminogen activator inhibitor type 1 (PAI-1) is a 50-kilodalton glycoprotein of the serine protease inhibitor family. The primary role of PAI-1 in vivo is the inhibition of both tissue- and urokinase-type plasminogen activators. In addition to this function, PAI-1 acts as an acute-phase protein during acute inflammation. PAI-1 is a pivotal player in the pathogenesis of sepsis, a complex clinical syndrome that results from a systemic inflammatory response. In patients with sepsis, the levels of PAI-1 are positively related to poor outcome, increased severity of disease, and increased levels of various cytokines, acute-phase proteins, and coagulation parameters. The 4G/5G insertion/deletion promoter polymorphism, which leads to differences in PAI-1 production, has been demonstrated to affect the risk of developing severe complications and dying from sepsis during meningococcal infection and multiple trauma.
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PMID:Plasminogen activator inhibitor type 1 gene polymorphism and sepsis. 1623 47

Indications for fresh frozen plasma (FFP), once used routinely in the support of critically ill infants and children, have become more specific as evolving evidence has confirmed or disproved the efficacy of plasma in various circumstances. FFP is currently indicated to treat the coagulopathies of massive hemorrhage, liver failure and disseminated intravascular coagulation and sepsis. Whole blood reconstituted from FFP and packed red cells is the product of choice for exchange transfusion, as well as for circuit priming. In the US, FFP remains the only approved source of factors V, XI, protein C, protein S and plasminogen. Cryoprecipitate is used chiefly as a source of fibrinogen, factor VIII and factor XIII in consumptive coagulopathy; recombinant or viral inactivated plasma derivatives are preferred for congenital deficiencies of factor VIII and von Willebrand factor. Recombinant and highly purified, viral inactivated, plasma-derived proteins are preferred over FFP for congenital and acquired deficiencies. This chapter reviews evidence to support the use of plasma and plasma derivatives for pediatric patients.
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PMID:Pediatric hemostasis and use of plasma components. 1637 47

Sepsis is associated with enhanced production of tissue-type plasminogen activator (tPA). We investigated the function of endogenous tPA in the immune responses to Escherichia coli-induced abdominal sepsis using tPA gene-deficient (tPA(-/-)) and normal wild-type (WT) mice. tPA(-/-) mice demonstrated an impaired defense against E. coli peritonitis as indicated by higher bacterial loads at the primary site of the infection, enhanced dissemination, and reduced survival. The protective function of tPA was independent of plasmin since plasminogen gene-deficient (Plg(-/-)) mice were indistinguishable from WT mice. Relative to WT mice, tPA(-/-) mice demonstrated similar neutrophil counts in the peritoneal cavity despite much higher bacterial loads and higher local concentrations of neutrophil attracting chemokines, suggesting a reduced migratory response. In line, tPA(-/-) mice demonstrated a reduced thioglycolate-induced neutrophil influx into the peritoneal cavity and i.p. injection of WT mice with a replication-defective adenoviral vector expressing tPA caused an enhanced cell migration to the peritoneal cavity during E. coli peritonitis. These findings identify a novel protective function of tPA in abdominal sepsis caused by E. coli that seems independent of its role in the generation of plasmin.
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PMID:Endogenous tissue-type plasminogen activator is protective during Escherichia coli-induced abdominal sepsis in mice. 1681 77

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are associated with high mortality rates despite therapeutic advances. The pathogenesis of ALI and ARDS is similar to that of sepsis, as these disease states involve uncontrolled host defense responses that lead to inflammation, endothelial damage, enhanced coagulation, diminished fibrinolysis, and fibroproliferation. Recent studies of anticoagulants have shown positive outcomes in patients with severe sepsis. In addition, emerging evidence suggests that the use of anticoagulants, such as tissue factor pathway inhibitor, antithrombin, thrombomodulin, heparin, activated protein C, and fibrinolytics (plasminogen activators and particularly tissue plasminogen activator), may be useful in the treatment of ALI and ARDS. Data from experimental models of sepsis, ALI, and ARDS indicate that some of these agents improve lung function and oxygenation. Although clinical data are less convincing than these findings, results from clinical trials may influence the design of future studies.
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PMID:Emerging role of anticoagulants and fibrinolytics in the treatment of acute respiratory distress syndrome. 1754 69


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