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SummaryFibrin deposition, the primary step in the formation of post-surgical adhesions, is the result of a disbalance between the fibrinforming and the fibrin-dissolving capacity of the peritoneum. Literature data suggest a transient reduction in local plasminogen activator activity after peritoneal trauma, which results in a reduction of fibrinolysis and permits deposited fibrin to become organized into fibrous, permanent adhesions. In the present study, the fibrinolytic parameters tissue-type plasminogen activator (tPA; antigen and activity) and plasminogen activator inhibitor type-1 (PAI-1; antigen and activity) were measured in peritoneal fluid, in peritoneal biopsies and in plasma to establish the time course of changes in fibrinolytic activity.A standardized peritoneal adhesion model in the rat.Analysis, over a 72-h period following surgical trauma, of the main fibrinolytic parameters in peritoneal lavage, in biopsies of damaged and undamaged peritoneum, and in plasma, and determination of fibrin and fibrin(ogen)-degradation products in peritoneal lavage fluid.At all time intervals, tPA antigen was found to be about six-fold increased in peritoneal lavage after surgical trauma. This significant rise in tPA antigen was accompanied by a large increase in its main inhibitor PAI-1, resulting in tPA activity levels similar to, or slightly higher than, those found in control animals. tPA activity was lowest at 4 h and increased thereafter. Also in biopsies from damaged peritoneum, tPA antigen was significantly increased. Tissue tPA activity was also lowest at 4 h, after which it increased, significantly so at 24 and 72 h. Similar, though smaller, changes were seen in the biopsies from undamaged areas of the peritoneal wall in operated rats. PAI-1 (antigen and activity) was not detected in peritoneal biopsies. Fibrin-related material (especially fibrin monomer/fibrinogen, an indicator of forming fibrin) in peritoneal fluid was slightly increased at 4 h, and abundantly present at 16 and 24 h, returning to control levels at 72 h. Fibrin degradation products were always present. From 2 h onward, adhesions were found.In contrast to the view that adhesions are formed as a result of a reduced fibrinolytic activity, our results demonstrate that tPA activity remained unchanged or slightly increased after surgical trauma, and point to increased fibrin formation rather than diminished fibrinolytic activity as the main cause of fibrin deposition after peritoneal trauma. Therapies directed at prevention of adhesion formation should therefore aim at avoiding massive fibrin production and at promoting fibrinolytic activity during the early period after trauma.

SummaryFibrates are used to lower plasma triglycerides and cholesterol levels in hyperlipidemic patients. In addition, fibrates have been found to alter the plasma concentrations of fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and apolipoprotein A-I (apo A-I). We have investigated the in vitro effects of fibrates on fibrinogen, PAI-1 and apo A-I synthesis and the underlying regulatory mechanisms in primary monkey hepatocytes.We show that fibrates time- and dose-dependently increase fibrinogen and apo A-I expression and decrease PAI-1 expression in cultured cynomolgus monkey hepatocytes, the effects demonstrating different potency for different fibrates. After three consecutive periods of 24 h the most effective fibrate, ciprofibrate (at 1 mmol/l), increased fibrinogen and apo A-I synthesis to 356% and 322% of control levels, respectively. Maximum inhibition of PAI-1 synthesis was about 50% of control levels and was reached by 1 mmol/l gemfibrozil or ciprofibrate after 48 h. A ligand for the retinoid-X-receptor (RXR), 9-cis retinoic acid, and specific activators of the peroxisome proliferator-activated receptor-α (PPARα), Wy14,643 and ETYA, influenced fibrinogen, PAI-1 and apo A-I expression in a similar fashion, suggesting a role for the PPARα/RXRα heterodimer in the regulation of these genes. When comparing the effects of the various compounds on PPARα trans-activation activity as determined in a PPARα-sensitive reporter gene system and the ability of the compounds to affect fibrinogen, PAI-1 and apo A-I antigen production, a good correlation (r = 0.80; p

Oral Ethinyl Estradiol, but not Transdermal 17β-estradiol, Increases Plasma C-reactive Protein Levels in Men

Human foreskin microvascular endothelial cells synthesize and release tissue-type plasminogen activator (t-PA) in similar amounts as do endothelial cells from umbilical cord artery and vein. Human thrombin increases the production of t-PA by these cells, which could be visualized from 8 h after addition of 0.1-5 units/ml thrombin by fibrin autography after SDS polyacrylamide gel electrophoresis of the endothelial cell conditioned media. Thrombin also increased the secretion of t-PA antigen. Together with t-PA, human microvascular cells release urokinasetype plasminogen activator (u-PA) antigen and endothelial cell type PA inhibitor, PA inhibitor-1, which were both demonstrated by specific immunoprecipitation from radiolabeled endothelial cell conditioned medium. Thrombin increases the release of u-PA antigen, but no u-PA activity could be demonstrated. Thrombin induced a two-fold stimulation of the synthesis and secretion of PA inhibitor-1 antigen. At 0.1 unit/ml thrombin also an increase in PA inhibitor activity was found. At high concentrations of thrombin a decrease of PA inhibitor activity was found, due to the conversion of the active 46 kD PA inhibitor-1 into a 42 kD product without PA inhibitor activity. Our data indicate that interaction of thrombin with microvascular endothelial cells will shift the balance between t-PA, u-PA and PA inhibitor-1, and thus affects the regulation of fibrinolysis. Chemicals/CAS: plasminogen activator inhibitor, 105844-41-5; thrombin, 9002-04-4; Glycoproteins; Plasminogen Activators, EC 3.4.21.-; Plasminogen Inactivators; Thrombin, EC 3.4.21.5