scholarly journals Fibrin turnover and pleural organization: bench to bedside

2018 ◽  
Vol 314 (5) ◽  
pp. L757-L768 ◽  
Author(s):  
Andrey A. Komissarov ◽  
Najib Rahman ◽  
Y. C. Gary Lee ◽  
Galina Florova ◽  
Sreerama Shetty ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fibrinolytic Therapy ◽  
Mesothelial Cells ◽  
Plasminogen Activator Inhibitor 1 ◽  
Mesenchymal Transition ◽  
Pleural Injury ◽  
Activator Inhibitor ◽  
Intrapleural Administration

Recent studies have shed new light on the role of the fibrinolytic system in the pathogenesis of pleural organization, including the mechanisms by which the system regulates mesenchymal transition of mesothelial cells and how that process affects outcomes of pleural injury. The key contribution of plasminogen activator inhibitor-1 to the outcomes of pleural injury is now better understood as is its role in the regulation of intrapleural fibrinolytic therapy. In addition, the mechanisms by which fibrinolysins are processed after intrapleural administration have now been elucidated, informing new candidate diagnostics and therapeutics for pleural loculation and failed drainage. The emergence of new potential interventional targets offers the potential for the development of new and more effective therapeutic candidates.

scholarly journals Precision Targeting of the Plasminogen Activator Inhibitor-1 Mechanism Increases Efficacy of Fibrinolytic Therapy in Empyema

2020 ◽  
Author(s):  
Galina Florova ◽  
René A. Girard ◽  
Ali O. Azghani ◽  
Krishna Sarva ◽  
Ann Buchanan ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Therapeutic Dose ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activators ◽  
Fibrinolytic Therapy ◽  
Plasminogen Activator Inhibitor 1 ◽  
Chemically Induced ◽  
Pleural Injury ◽  
Activator Inhibitor ◽  
Pai 1

AbstractPlasminogen activator inhibitor-1 (PAI-1) is an endogenous irreversible inhibitor of tissue-type (tPA) and urokinase (uPA) plasminogen activators. PAI-1-targeted fibrinolytic therapy (PAI-1-TFT) is designed to decrease the therapeutic dose of tPA and uPA to attenuate the risk of bleeding and other complications. The docking site peptide (DSP) is a part of the PAI-1 reactive center loop, which interacts with plasminogen activators, thus affecting the PAI-1 mechanism. We used DSP for PAI-1-TFT in two rabbit models: chemically-induced pleural injury and Streptococcus pneumoniae induced empyema. PAI-1-TFT with DSP combined with single chain uPA or tPA resulted in an up to 8-fold decrease in the minimal effective therapeutic dose of plasminogen activator and induced no bleeding. An increase in the level of PAI-1 in infectious pleural injury, when compared to chemically-induced injury, coincided with an increase in the minimal effective dose of plasminogen activator and DSP. PAI-1 is a valid molecular target in S. pneumoniae empyema model in rabbits, which closely recapitulates key characteristics of empyema in humans. Low dose PAI-1-TFT is a novel precise interventional strategy that may improve fibrinolytic therapy of empyema in clinical practice.

scholarly journals Targeting plasminogen activator inhibitor-1 in tetracycline-induced pleural injury in rabbits

2018 ◽  
Vol 314 (1) ◽  
pp. L54-L68 ◽  
Author(s):  
Galina Florova ◽  
Ali O. Azghani ◽  
Sophia Karandashova ◽  
Chris Schaefer ◽  
Serge V. Yarovoi ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Fibrinolytic Therapy ◽  
Wild Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Sandwich Type ◽  
Pleural Injury ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Selection Of

Elevated active plasminogen activator inhibitor-1 (PAI-1) has an adverse effect on the outcomes of intrapleural fibrinolytic therapy (IPFT) in tetracycline-induced pleural injury in rabbits. To enhance IPFT with prourokinase (scuPA), two mechanistically distinct approaches to targeting PAI-1 were tested: slowing its reaction with urokinase (uPA) and monoclonal antibody (mAb)-mediated PAI-1 inactivation. Removing positively charged residues at the “PAI-1 docking site” (179RHRGGS184→179AAAAAA184) of uPA results in a 60-fold decrease in the rate of inhibition by PAI-1. Mutant prourokinase (0.0625–0.5 mg/kg; n = 12) showed efficacy comparable to wild-type scuPA and did not change IPFT outcomes ( P > 0.05). Notably, the rate of PAI-1-independent intrapleural inactivation of mutant uPA was 2 times higher ( P < 0.05) than that of the wild-type enzyme. Trapping PAI-1 in a “molecular sandwich”-type complex with catalytically inactive two-chain urokinase with Ser195Ala substitution (S195A-tcuPA; 0.1 and 0.5 mg/kg) did not improve the efficacy of IPFT with scuPA (0.0625–0.5 mg/kg; n = 11). IPFT failed in the presence of MA-56A7C10 (0.5 mg/kg; n = 2), which forms a stable intrapleural molecular sandwich complex, allowing active PAI-1 to accumulate by blocking its transition to a latent form. In contrast, inactivation of PAI-1 by accelerating the active-to-latent transition mediated by mAb MA-33B8 (0.5 mg/kg; n = 2) improved the efficacy of IPFT with scuPA (0.25 mg/kg). Thus, under conditions of slow (4–8 h) fibrinolysis in tetracycline-induced pleural injury in rabbits, only the inactivation of PAI-1, but not a decrease in the rate of its reaction with uPA, enhances IPFT. Therefore the rate of fibrinolysis, which varies in different pathologic states, could affect the selection of PAI-1 inhibitors to enhance fibrinolytic therapy.

Inhibitory Role of Plasminogen Activator Inhibitor-1 in Arterial Wound Healing and Neointima Formation

Circulation ◽  
1997 ◽  
Vol 96 (9) ◽  
pp. 3180-3191 ◽  
Author(s):  
Peter Carmeliet ◽  
Lieve Moons ◽  
Roger Lijnen ◽  
Stefaan Janssens ◽  
Florea Lupu ◽  
...  
Keyword(s):  
Wound Healing ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Neointima Formation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Inhibitory Role ◽  
Activator Inhibitor

Role of plasminogen activator inhibitor-1 in coronary pathophysiology

2018 ◽  
Vol 164 ◽  
pp. 54-62 ◽  
Author(s):  
Richard G. Jung ◽  
Trevor Simard ◽  
Alisha Labinaz ◽  
F. Daniel Ramirez ◽  
Pietro Di Santo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Activator Inhibitor

scholarly journals Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay

Blood ◽  
1988 ◽  
Vol 71 (1) ◽  
pp. 220-225 ◽  
Author(s):  
PJ Declerck ◽  
MC Alessi ◽  
M Verstreken ◽  
EK Kruithof ◽  
I Juhan-Vague ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Immunosorbent Assay ◽  
Healthy Subjects ◽  
Plasminogen Activator Inhibitor ◽  
Enzyme Linked Immunosorbent Assay ◽  
Plasminogen Activator Inhibitor 1 ◽  
Platelet Poor Plasma ◽  
Activator Inhibitor ◽  
Pai 1

An enzyme-linked immunosorbent assay for plasminogen activator inhibitor-1 (PAI-1) in biologic fluids was developed on the basis of two murine monoclonal antibodies raised against PAI-1 purified from HT- 1080 fibrosarcoma cells. The lower limit of sensitivity of the assay in plasma is 2 ng/mL. The assay is 12 times less sensitive toward the PAI- 1/human tissue-type plasminogen activator (t-PA) complex as compared with free PAI-1. The intraassay, interassay, and interdilution coefficients of variation are 5.2%, 8.0%, and 7.1%, respectively. The level of PAI-1 in platelet-poor plasma of healthy subjects is 18 +/- 10 ng/mL (mean +/- SD, n = 45). In platelet-rich plasma after freezing and thawing, 92% of PAI-1 antigen is released from platelets, whereas only 8% is found in the corresponding platelet-poor plasma. In platelet-poor plasma from healthy subjects, a linear correlation (r = 0.80) was found between PAI activity and PAI-1 antigen. In plasma approximately two thirds of the PAI-1 antigen was functionally active, whereas only 5% of the PAI-1 antigen released from platelets was active. During pregnancy a progressive increase of PAI-1 antigen levels up to three- to sixfold the control value was observed. In plasma of patients with recurrent deep vein thrombosis, PAI-1 levels were 44 +/- 20 ng/mL (mean +/- SD, n = 7), during a clinically silent phase. Four of these patients had a level above 38 ng/mL (mean +/- 2 SD of normal). The present assay, based on stable and reproducible reagents, allows the specific determination of PAI-1 antigen in biologic fluids. It may facilitate interlaboratory comparisons and be useful for further investigations of the role of PAI-1 in clinical conditions associated with impaired fibrinolysis and/or a tendency to thrombosis and investigations of the role of PAI-1 in platelets.

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