Tumor necrosis factor (TNF) stimulates plasminogen activator inhibitor (PAI) production by endothelial cells and decreases blood fibrinolytic activity in the rat

Dosne, A.M.; Dubor, F.; Lutcher, F; Parant, M; Chedid, L

doi:10.1016/0049-3848(88)90160-0

Cited by 26 publications

(10 citation statements)

References 13 publications

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“…In accordance with the elevated PAI-activity the global fibrinolytic capacity of the circulating plasma was decreased (prolonged ECLT). Other investigators found an increase in PAI-activity in surgical patients (d'Angelo et al, 1985), in adult respiratory distress syndrome (Modig & Bagge, 1986) and in meningococcal disease (Engebretsen et al, 1986); an increase in PAI-activity could be induced by endotoxin in rabbits (Colucci et al, 1985) and by tumour necrosis factor in rats and in human endothelial cells (Dosne et at, 1988;van Hinsbergh et al, 1988). The increase in PAI-activity seems to be due to the PAI-1 from endothelial cells or platelets (Collen, 1986) since increased levels of PAI-2 have only been found in pregnancy (Kruithof et al, 1988).…”

Section: Resultsmentioning

confidence: 95%

Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit

et al. 1990

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Disseminated thrombotic processes in the microcirculation are considered to be an important cause of multiple organ failure in septic patients. Fibrinolysis is one endogenous mechanism protecting the circulation from overwhelming thrombosis. Therefore, we looked for alterations of fibrinolytic parameters (tissue plasminogen activator (t-PA), tissue plasminogen activator inhibitor (PAI), D-dimer, euglobulin-clot-lysis-time (ECLT), plasminogen, alpha 2-antiplasmin) and of some coagulation parameters (prothrombin time, fibrinogen, platelets, antithrombin III, protein C, factor XII) in clearly defined septic patients and for the relations of these values to the severity of the disease (APACHE II-score). An increase in D-dimer and t-PA-antigen was registered in all patients, while factor XII and plasminogen were decreased, indicating an activated fibrinolysis. In contrast the systemic fibrinolytic capacity of the blood was strongly inhibited: t-PA-activity was not detectable, PAI-function was elevated, the ECLT was prolonged and alpha 2-antiplasmin was normal. Coagulation was moderately activated: the platelets, antithrombin III and protein C were decreased, the prothrombin time was prolonged and fibrinogen was normal. The changes in t-PA-antigen, PAI-function, factor XII, prothrombin time and antithrombin III were significantly related to the APACHE II-score of the patients. We conclude that the activation of coagulation is accompanied by an activation of fibrinolysis in the microcirculation, but that systemically the increased inhibitors of fibrinolysis (PAI, alpha 2-antiplasmin) induce a decrease of the fibrinolytic capacity of the blood. The severity of the disease determines the extent of the alterations.

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Section: Resultsmentioning

confidence: 95%

Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit

et al. 1990

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“…Peritoneal adhesions induced by intestinal bacteria can be inhibited by TNF neutralization (12). In addition to experimental data, after surgical intra-abdominal manipulations in patients, higher grades of adhesions correlated with higher levels of TNF both in serum and peritoneal exudate (15).TNF has procoagulant and antifibrinolytic effects both in blood and on mesothelium (6,26,27). At higher TNF concentrations these properties might lead to disseminated intravascular coagulation (DIC), which is uniformly regarded as harmful during sepsis.…”

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confidence: 99%

“…TNF has procoagulant and antifibrinolytic effects both in blood and on mesothelium (6,26,27). At higher TNF concentrations these properties might lead to disseminated intravascular coagulation (DIC), which is uniformly regarded as harmful during sepsis.…”

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confidence: 99%

Tumor Necrosis Factor-Dependent Adhesions as a Major Protective Mechanism Early in Septic Peritonitis in Mice

Echtenacher¹,

Weigl²,

Lehn

et al. 2001

Infect Immun

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The occurrence of peritoneal adhesions in surgical patients is positively correlated with tumor necrosis factor (TNF) levels. In a model of septic peritonitis-cecal ligation and puncture-TNF neutralization prevented formation of peritoneal adhesions and increased mortality, most likely because localization of the septic focus was prevented. To discriminate between the coagulation-independent protective TNF effect and a potential protective procoagulant TNF effect, formation of peritoneal adhesions after CLP was inhibited with heparin, hirudin, or urokinase. Each treatment increased mortality and increased the number of bacteria in the peritoneal lavage fluid, kidney, and liver to various degrees. Under these experimental conditions, antibiotics prevented death. In coagulation-compromised mice, lethality was further enhanced by additional TNF neutralization. These findings demonstrate that peritoneal adhesions early in septic peritonitis are an important mechanism of innate immunity that prevents increased spread of bacteria and reduces mortality.Although tumor necrosis factor (TNF) was regarded for many years as the major cytokine causing morbidity and mortality in sepsis and septic shock (13), clinical studies testing TNF inhibitors in septic shock did not yield encouraging results (11,30). Besides the many sepsis/septic shock models demonstrating that TNF inhibitors protect animals from bolus injections with lipopolysaccharide (LPS) or bacteria, there are also reports concerning the use of TNF inhibitors in models of bacterial peritonitis where either no effect on survival (1, 10, 23) or even deleterious effects (7) were observed. The observation that mice treated with an anti-TNF monoclonal antibody after cecal ligation and puncture (CLP) show both increased mortality and reduced peritoneal adhesions raised the question of whether survival after CLP depends on adhesions (8). Peritoneal adhesions induced by intestinal bacteria can be inhibited by TNF neutralization (12). In addition to experimental data, after surgical intra-abdominal manipulations in patients, higher grades of adhesions correlated with higher levels of TNF both in serum and peritoneal exudate (15).TNF has procoagulant and antifibrinolytic effects both in blood and on mesothelium (6,26,27). At higher TNF concentrations these properties might lead to disseminated intravascular coagulation (DIC), which is uniformly regarded as harmful during sepsis. Therefore, prevention of coagulation might protect against sepsis (3). Antithrombin III or hirudin, indeed, ameliorated DIC and protected rats against sequelae of intravenous administration of LPS alone or injection of bacteria together with an antibiotic, whereas heparin plus antibiotic had no effect on survival in the latter model. This might be due to the fact that the anticoagulant function of heparin is indirect by accelerating antithrombin III binding to thrombin (4,5,19).The situation in bacterial peritonitis, however, is different since anticoagulant treatment may enhance the spread of bacter...

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“…To our knowledge, the molecular pathways underlying TNF-␣/TNFR1-stimulated coagulation have yet to be established in vivo. Prior observations suggest that TNF-␣ may promote fibrin deposition by stimulating vascular permeability (4,5,14), increasing expression of procoagulant molecules (3,6,37,45), decreasing expression of anticoagulant molecules (37,45), and/or suppressing fibrin degradation (9,32,56,57). Investigating the TNFR1 dependency of these events in the toxoplasmosis model should help to establish their in vivo relevance with regard to infection-associated fibrin deposition.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Alpha and Gamma Interferon, but Not Hemorrhage or Pathogen Burden, Dictate Levels of Protective Fibrin Deposition during Infection

et al. 2006

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While coagulation often causes pathology during infectious disease, we recently demonstrated that fibrin, a product of the coagulation pathway, performs a critical protective function during acute toxoplasmosis (L. L. Johnson, K. N. Berggren, F. M. Szaba, W. Chen, and S. T. Smiley, J. Exp. Med. 197:801-806, 2003). Here, we investigate the mechanisms regulating the formation of this protective fibrin. Through comparisons of Toxoplasma-infected wild-type and cytokine-deficient mice we dissociate, for the first time, the relative fibrin-regulating capacities of pathogen products, host cytokines, and infection-stimulated hemorrhage. Remarkably, neither the pathogen burden nor hemorrhage is a primary regulator of fibrin levels. Rather, two type 1 cytokines exert dominant and counterregulatory roles: tumor necrosis factor alpha (TNF-α), acting via the type 1 TNF-α receptor, promotes fibrin deposition, while gamma interferon (IFN-γ), acting via STAT1 and IFN-γ receptors expressed on radioresistant cells, suppresses fibrin deposition. These findings have important clinical implications, as they establish that cytokines known to regulate pathological coagulation also dictate levels of protective fibrin deposition. We present a novel model depicting mechanisms by which the immune system can destroy infected tissue while independently restraining hemorrhage and promoting tissue repair through the deliberate deposition of protective fibrin.

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Tumor necrosis factor (TNF) stimulates plasminogen activator inhibitor (PAI) production by endothelial cells and decreases blood fibrinolytic activity in the rat

Cited by 26 publications

References 13 publications

Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit

Activation and inhibition of fibrinolysis in septic patients in an internal intensive care unit

Tumor Necrosis Factor-Dependent Adhesions as a Major Protective Mechanism Early in Septic Peritonitis in Mice

Tumor Necrosis Factor Alpha and Gamma Interferon, but Not Hemorrhage or Pathogen Burden, Dictate Levels of Protective Fibrin Deposition during Infection

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