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)

We investigate the regulation of plasminogen activator inhibitor-2 (PAI-2) in murine macrophages. PAI-2 mRNA was inducible by bacterial lipopolysaccharide (LPS) in primary cells and macrophage-like cell lines. Evidence is presented for a role for autocrine factors, including cyclooxygenase products but not the cytokines tumor necrosis factor alpha or interferon-beta (IFN-beta). PAI-2 mRNA levels generally varied inversely from those of its target, urokinase-type plasminogen activator (uPA), and the macrophage growth factor CSF-1, which induces uPA, inhibited PAI-2 expression in cells treated subsequently with LPS. Expression of PAI-2 was distinct from that of other LPS-inducible genes in terms of induction time course, LPS dose response, and sensitivity to co-stimulation with IFN-gamma. Induction of PAI-2 mRNA in subclones of the cell line RAW 264 was not uniform, reflecting heterogeneous expression in the parent line. The expression pattern of PAI-2 is discussed in terms of a possible role in LPS-induced pathology such as septicemia.
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PMID:Regulation of the plasminogen activator inhibitor-2 (PAI-2) gene in murine macrophages. Demonstration of a novel pattern of responsiveness to bacterial endotoxin. 1041 Oct 6

Proteins influencing plasminogen activation to plasmin, namely plasminogen activators tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA) and their principal inhibitors, plasminogen activator inhibitor 1 (PAI-1) and PAI-2, were measured in the plasma, the polymorph and mononuclear cell fractions taken from patients with major sepsis who were entering a general intensive care unit. The purpose of this study was to elucidate the factors favouring the persistence of fibrin in the microvasculature and thus contributing to multiple organ failure. Levels of u-PA antigen in plasma rose in sepsis and u-PA activity, not detectable in normal plasma, appeared. Levels of u-PA antigen in the cell fractions fell concomitantly. t-PA antigen in plasma and in the mononuclear cell fraction rose in sepsis, but t-PA activity was not detectable. Plasma PAI-1 antigen levels were strikingly raised in sepsis, presumably accounting for the complete neutralization of t-PA activity. PAI-2 antigen, not normally detected in plasma, appeared in the plasma of some patients, whereas it disappeared from the cellular fractions. Appearance of PAI-2 in plasma was associated with non-survival of the patient. The observations indicate that all the agents involved in plasminogen activation are released into the plasma in major sepsis. The levels of PAI-1 reached were quantitatively sufficient to suppress all activity of the released t-PA, but the inhibitors did not prevent expression of u-PA activity in the circulation. Circulating active u-PA and PAI-2 in the plasma of patients with severe sepsis may represent material originating from leucocytes. Leucocyte release of these agents within fibrin deposits may influence the persistence of fibrin and thus the development of multiple organ failure.
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PMID:Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. 1084 22

A 29-year-old male patient with Crohn's disease of the terminal ileum and previous abdominal surgery was admitted because of severe abdominal pain and signs of bacterial sepsis. The diagnosis of portal vein thrombosis and multiple liver abscesses due to Streptococcus intermedius septicaemia was made and antibiotic therapy was instituted immediately. As high-dose heparin therapy was ineffective, urokinase was administered intravenously over a total of 7 days. Within 2 days, the patient's symptoms completely subsided. Colour duplex ultrasonography revealed complete recanalization of the main stem of the portal vein; the right branch of the portal vein, however, remained occluded. Other case reports on thrombolytic therapy in patients with portal vein thrombosis are reviewed.
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PMID:Thrombolytic therapy in patients with portal vein thrombosis: case report and review of the literature. 1105 61

Lipopolysaccharide-containing outer membrane vesicles (OMV-LPS) which are spontaneously released from Neisseria meningitidis during logarithmic growth were studied for their ability to induce procoagulant (tissue factor), profibrinolytic (urokinase-type plasminogen activator) and antifibrinolytic (plasminogen activator inhibitor-2) factors in purified human monocytes. Cell-associated tissue factor was 5.0-fold (n=5) increased, peaking after 8 h, in the presence of OMV-LPS (1 microg/ml, final concentration). Plasminogen activator inhibitor-2 release from monocytes was maximal after 24 h OMV-LPS (1 microg/ml) stimulation and 13.7-fold (n=5) increased compared to controls; whereas urokinase-type plasminogen activator antigen in culture medium remained uninfluenced by OMV-LPS. In conclusion, these OMV-induced imbalances favor fibrin deposition in the monocyte microenvironment and is probably of great importance in the development of disseminated intravascular coagulation, microthrombosis and organ dysfunction related to fulminant meningococcal septicemia.
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PMID:Outer membrane vesicles from Neisseria meningitidis: effects on tissue factor and plasminogen activator inhibitor-2 production in human monocytes. 1136 30

Infection, mainly related to vascular access, is one of the main causes of morbidity and a preventable cause of death in hemodialysis patients. From January 1994 to April 1998 we conducted a prospective study to assess the incidence and risk factors of catheter-related bacteremia. One hundred and twenty-nine tunneled dual-lumen hemodialysis catheters were inserted percutaneously into the internal jugular vein in 89 patients. Bacteremia (n = 56) occurred at least once with 37 (29%) of the catheters (an incidence of 1.1/1,000 catheter-days); local infection (n = 45, 1/1,000 catheter-days) was associated with bacteremia in 18 cases. Death in 1 case was directly related to Staphylococcus aureus (SA) septic shock, and septicemia contributed to deaths in 2 additional cases. Catheters were removed in 48% of the bacteremic episodes. Treatment comprised intravenous double antimicrobial therapy for 15-20 days. Bacteriological data of bacteremia showed 55% involvement of SA. Nasal carriage of SA was observed in 35% of the patients with catheters. Bacteremic catheters were more frequently observed in patients with diabetes mellitus (p = 0.03), peripheral atherosclerosis (p = 0.001), a previous history of bacteremia (p = 0.05), nasal carriage of SA (p = 0.0001), longer catheter survival time (p = 0.001), higher total intravenous iron dose (p = 0.001), more frequent urokinase catheter infusion (p < 0.01), and local infection (p < 0.001) compared with non-bacteremic catheters. Monovariate survival analysis showed that significant initial risk factors for bacteremia were nasal carriage of SA (p = 0.00001), previous bacteremia (p = 0.0001), peripheral atherosclerosis (p = 0.005), and diabetes (p = 0.04). This study confirms the relatively high incidence of bacteremia with tunneled double-lumen silicone catheters and its potential complications. Possible preventive actions are discussed according to the risk factors.
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PMID:Risk factor analysis for long-term tunneled dialysis catheter-related bacteremias. 1211 69

Fibrin persistence in the vasculature is an important complication of sepsis that can often lead to mortality. We have previously established that polymorphonuclear leukocytes (PMN) from healthy individuals have the capacity to degrade fibrin via urokinase-type plasminogen activator (u-PA). We have also demonstrated an increase in u-PA antigen in the plasma of patients suffering from septic shock. In this study, we investigate the hypothesis that PMN from patients with sepsis have lost their fibrinolytic ability and that this might contribute to the persistence of fibrin deposits. We show here that PMN from these patients do not express any u-PA activity, despite retaining some u-PA antigen. Additionally, thrombi prepared from the whole blood of the patients exhibit reduced endogenous lysis compared with those from healthy individuals. These data indicate that loss of fibrinolytic activity from PMN may be a contributing factor in fibrin persistence in the microvasculature in sepsis.
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PMID:Polymorphonuclear leukocytes from patients with severe sepsis have lost the ability to degrade fibrin via u-PA. 1527 68

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

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

Plasminogen activator inhibitor type-1 (PAI-1) is a major inhibitor of fibrinolysis by virtue of its capacity to inhibit urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Systemic inflammation is invariably associated with elevated circulating levels of PAI-1, and during human sepsis plasma PAI-1 concentrations predict an unfavorable outcome. Knowledge about the functional role of PAI-1 in a systemic inflammatory response syndrome is highly limited. In this study, we determined the role of endogenous PAI-1 in cytokine release induced by administration of LPS or staphylococcal enterotoxin B (SEB). Both LPS and SEB elicited secretion of PAI-1 into the circulation of normal wild-type (Wt) mice. Relative to Wt mice, PAI-1 gene-deficient (PAI-1(-/-)) mice demonstrated strongly elevated plasma IFN-gamma concentrations after injection of either LPS or SEB. In addition, PAI-1(-/-) splenocytes released more IFN-gamma after incubation with LPS or SEB than Wt splenocytes. Both PAI-1(-/-) CD4+ and CD8+ T cells produced more IFN-gamma upon stimulation with SEB. LPS-induced IFN-gamma release in mice deficient for uPA, the uPA receptor, or tPA was not different from IFN-gamma release in LPS-treated Wt mice. These results identify a novel function of PAI-1 during systemic inflammation, where endogenous PAI-1 serves to inhibit IFN-gamma release by a mechanism that does not depend on its interaction with uPA/uPA receptor or tPA.
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PMID:Plasminogen activator inhibitor type-1-deficient mice have an enhanced IFN-gamma response to lipopolysaccharide and staphylococcal enterotoxin B. 1711 93

Dual-lumen cuffed central venous catheter proved an important alternative vascular access compared to conventional arteriovenous (Cimino-Brescia) shunt in a selected group of patients on regular dialysis treatment. Typically, these catheters are used as bridging access, until fistula or graft is ready for use, or as permanent access when an arteriovenous fistula or graft is not planned (NKF-DOQI). We conducted a prospective study on IJV permanent catheter insertion and its related earlier and long-term complications. From February 1991 to February 2001 we inserted in 124 patients in end stage renal disease 135 cuffed catheters (130 in the right IJV and 5 in the left IJV), 92 of which were Permcath, 27 Vascath, and 16 Ash-Split. We performed the insertion of catheters by puncturing the IJV under ultrasonographic guid-ance in the lower side of the Sedillot triangle and checking the accurate position of the tip by endocavitary electrocardiography (EC-ECG). The duration of catheter use was from 60 to 1460 days, mean 345 days. The actuarial survival rate at 1 year was 82%, at 2 years 56%, at 3 years 42% and at 4 years 20%. The exit site infection and septicemia rates were 5.2 and 2.86 per 1000 catheter days respectively. Catheter sepsis was implicated in the death of three patients, all of whom had multiple medical problems. Several episodes of thrombosis (6% of dialyses) occurred which required urokinase treatment, and catheter replacement in 12 patients (9.6%). In 3 cases the catheters were displaced and correct repositioning was performed. Two catheters (Ash-Split) were replaced due to accidental damage of the external portion of catheters (alcoholic disinfectant). Catheter tip embolism occurred on one occasion during elective catheter exchange over guide-wire. One of the common problems encountered with cuffed tunneled catheters is poor blood flow, most often secondary to the formation of a fibrin sheath around the lumen. Even if we conducted a non-randomized study, in our experience, the higher rate of malfunctioning catheters was in the group with no anticoagulation therapy. Therefore, we suggest anticoagulation treatment in all patients wearing central vascular catheters with no contraindication. Just one year ago, we followed NKF-DOQI clinical practice guidelines for vascular access that indicated that for patients who have a primary AV fistula maturing, but need im-mediate hemodialysis, tunneled cuffed catheters are the access of choice and the preferred insertion site is the right IJV. Considering recent reports of permanent central venous stenosis or occlusion after IJV can-nulation, currently, our first choice is femoral vein cannulation with smooth silicone rubber catheters, tunneled if long-term utilization is needed (more the 3-4 weeks). In our opinion, the right IJV puncture is to be avoided as much as the venipuncture of arm veins suitable for vascular access placement, particularly the cephalic vein of the non-dominant arm. Our data confirm that permanent venous catheters might rep-resent an effective long-term vascular access for chronic hemodialysis, particularly for older patients with cardiovascular disease and for cancer patients.
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PMID:Implantation of permanent jugular catheters in patients on regular dialysis treatment: ten years' experience. 1763 64


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