Prevention of adult respiratory distress syndrome with plasminogen activator in pigs

Hardaway, Robert M.; Williams, Charles H.; Marvasti, Miriam; Farias, Mary; Tseng, Albert; Pinon, I.; Yanez, Debra; Martinez, Marcos; Navar, Jamie

doi:10.1097/00003246-199012000-00021

Cited by 89 publications

(68 citation statements)

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“…However, the number of available complete hemodynamic measurements was lower (162) than in our study. Elevated pulmonary vascular resistance is well recognized in ARDS [25] and may be the result of hypoxic vasoconstriction [26], abnormal vascular reactivity [27], blood microclots [28], and histamine H 2 -receptor activation [29].…”

Section: Review Of Resultsmentioning

confidence: 99%

Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study

Squara

Jf²,

Artigas

et al. 1998

Intensive Care Medicine

125

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Section: Review Of Resultsmentioning

confidence: 99%

Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study

Squara

Jf²,

Artigas

et al. 1998

Intensive Care Medicine

125

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“…It is clear, however, that plasminogen activator inhibitor 1 (PAI-1), the major endogenous inhibitor of tPA and urokinase (uPA) (8,9), affects the outcome of pleural injury. An increased level of PAI-1 is a biomarker in a variety of serious pulmonary conditions, including acute respiratory distress syndrome and acute lung injury (10,11), empyema, and other forms of organizing pleural injury (7,(12)(13)(14). Increments of PAI-1 antigen have been reported to occur in inflammatory pleural effusions and empyema (15,16).…”

Section: Clinical Relevancementioning

confidence: 99%

Targeting of Plasminogen Activator Inhibitor 1 Improves Fibrinolytic Therapy for Tetracycline-Induced Pleural Injury in Rabbits

Florova

Azghani

Karandashova

et al. 2015

Am J Respir Cell Mol Biol

133

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Endogenous active plasminogen activator inhibitor 1 (PAI-1) was targeted in vivo with monoclonal antibodies (mAbs) that redirect its reaction with proteinases to the substrate branch. mAbs were used as an adjunct to prourokinase (single-chain [sc] urokinase [uPA]) intrapleural fibrinolytic therapy (IPFT) of tetracycline-induced pleural injury in rabbits. Outcomes of scuPA IPFT (0.25 or 0.0625 mg/kg) with 0.5 mg/kg of mouse IgG or mAbs (MA-33H1F7 and MA-8H9D4) were assessed at 24 hours. Pleural fluid (PF) was collected at 0, 10, 20, and 40 minutes and 24 hours after IPFT and analyzed for plasminogen activating (PA), uPA, fibrinolytic activities, levels of total plasmin/plasminogen, a-macroglobulin (aM), mAbs/IgG antigens, free active uPA, and aM/uPA complexes. Anti-PAI-1 mAbs, but not mouse IgG, delivered with an eightfold reduction in the minimal effective dose of scuPA (from 0.5 to 0.0625 mg/kg), improved the outcome of IPFT (P , 0.05). mAbs and IgG were detectable in PFs at 24 hours. Compared with identical doses of scuPA alone or with IgG, treatment with scuPA and anti-PAI-1 mAbs generated higher PF uPA amidolytic and PA activities, faster formation of aM/uPA complexes, and slower uPA inactivation. However, PAI-1 targeting did not significantly affect intrapleural fibrinolytic activity or levels of total plasmin/plasminogen and aM antigens. Targeting PAI-1 did not induce bleeding, and rendered otherwise ineffective doses of scuPA able to improve outcomes in tetracycline-induced pleural injury. PAI-1-neutralizing mAbs improved IPFT by increasing the durability of intrapleural PA activity. These results suggest a novel, well-tolerated IPFT strategy that is tractable for clinical development. Keywords: plasminogen activator inhibitor 1; fibrinolytic therapy; animal model; prourokinase; monoclonal antibodies Clinical RelevanceOrganizing pleural injury remains an important clinical problem for which fibrinolytic therapy has been used with variable results for children and adults. This study demonstrates, for the first time, that the targeting of active plasminogen activator inhibitor 1 enhances the ability of relatively low doses of intrapleural single-chain urokinase to clear pleural effusions after induction of organizing injury. This work defines a new, well-tolerated approach for intrapleural fibrinolytic therapy that is promising and tractable for clinical trial testing.The results of Multicenter Intrapleural Sepsis Trials 1 and 2 demonstrated that intrapleural fibrinolytic therapy (IPFT) with either streptokinase, or tissue-type plasminogen activator (tPA) alone were ineffective (1, 2). In contrast, there is a growing body of clinical reports demonstrating the successful use of IPFT, including tPA,. It is likely that the disparate results of IPFT trials, which are largely successful in children (2, 6) and variably effective in adults (6, 7), relate to the lack of formal toxicological and dose-escalation studies, resulting in empiric dosing. A further impediment to the field is an incomplete underst...

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“…FIBRINOLYSINS, INCLUDING tissue type (tPA) and urokinase (active two-chain enzyme; tcuPA), are plasminogen activators (PAs) that have long been used to treat a variety of thrombotic conditions including acute myocardial infarction (23; 44), deep vein thrombosis (33,40), ischemic stroke (1,3), acute respiratory distress syndrome (ARDS) (20,21), pulmonary emboli, and organizing pleural effusions (8,9,11,31,37,43). Although intrapleural fibrinolytic therapy (IPFT) has been in use for over 60 years, it has recently undergone reassessment in light of the disparate results seen in clinical trials (9,11,37).…”

mentioning

confidence: 99%

Active α-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids

Komissarov

Florova

Azghani

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

106

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Komissarov AA, Florova G, Azghani A, Karandashova S, Kurdowska AK, Idell S. Active ␣-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids. Am J Physiol Lung Cell Mol Physiol 305: L682-L692, 2013. First published August 30, 2013 doi:10.1152/ajplung.00102.2013.-Intrapleural processing of prourokinase (scuPA) in tetracycline (TCN)-induced pleural injury in rabbits was evaluated to better understand the mechanisms governing successful scuPA-based intrapleural fibrinolytic therapy (IPFT), capable of clearing pleural adhesions in this model. Pleural fluid (PF) was withdrawn 0 -80 min and 24 h after IPFT with scuPA (0 -0.5 mg/kg), and activities of free urokinase (uPA), plasminogen activator inhibitor-1 (PAI-1), and uPA complexed with ␣-macroglobulin (␣M) were assessed. Similar analyses were performed using PFs from patients with empyema, parapneumonic, and malignant pleural effusions. The peak of uPA activity (5-40 min) reciprocally correlated with the dose of intrapleural scuPA. Endogenous active PAI-1 (10 -20 nM) decreased the rate of intrapleural scuPA activation. The slow step of intrapleural inactivation of free uPA (t1/2 ␤ ϭ 40 Ϯ 10 min) was dose independent and 6.7-fold slower than in blood. Up to 260 Ϯ 70 nM of ␣M/uPA formed in vivo [second order association rate (kass) ϭ 580 Ϯ 60 M Ϫ1 ·s Ϫ1 ]. ␣M/uPA and products of its degradation contributed to durable intrapleural plasminogen activation up to 24 h after IPFT. Active PAI-1, active ␣2M, and ␣2M/uPA found in empyema, pneumonia, and malignant PFs demonstrate the capacity to support similar mechanisms in humans. Intrapleural scuPA processing differs from that in the bloodstream and includes 1) dose-dependent control of scuPA activation by endogenous active PAI-1; 2) two-step inactivation of free uPA with simultaneous formation of ␣M/uPA; and 3) slow intrapleural degradation of ␣M/uPA releasing active free uPA. This mechanism offers potential clinically relevant advantages that may enhance the bioavailability of intrapleural scuPA and may mitigate the risk of bleeding complications. fibrinolytic therapy; rabbit model; pleural injury; urokinase; ␣-macroglobulin; human FIBRINOLYSINS, INCLUDING tissue type (tPA) and urokinase (active two-chain enzyme; tcuPA), are plasminogen activators (PAs) that have long been used to treat a variety of thrombotic conditions including acute myocardial infarction (23; 44), deep vein thrombosis (33, 40), ischemic stroke (1, 3), acute respiratory distress syndrome (ARDS) (20, 21), pulmonary emboli, and organizing pleural effusions (8,9,11,31,37,43). Although intrapleural fibrinolytic therapy (IPFT) has been in use for over 60 years, it has recently undergone reassessment in light of the disparate results seen in clinical trials (9, 11, 37). The efficacy of IPFT in adults remains a subject of ongoing debate. Intrapleural streptokinase was ineffective in patients with complicated parapneumonic pleural effusions and empyema (EMP), whereas ...

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Prevention of adult respiratory distress syndrome with plasminogen activator in pigs

Cited by 89 publications

References 0 publications

Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study

Hemodynamic profile in severe ARDS: results of the European Collaborative ARDS Study

Targeting of Plasminogen Activator Inhibitor 1 Improves Fibrinolytic Therapy for Tetracycline-Induced Pleural Injury in Rabbits

Active α-macroglobulin is a reservoir for urokinase after fibrinolytic therapy in rabbits with tetracycline-induced pleural injury and in human pleural fluids

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