Pleural drainage is required for complicated parapneumonic effusions and empyema in up to 40,000 US patients annually. Intrapleural fibrinolytic therapy (IPFT), which enhances clearance of pleural loculation to augment pleural drainage, remains a therapeutic option that obviates the need for surgical drainage. However, current IPFT is limited by variable efficacy, uncertain dosing and safety concerns that are underscored by ttie disparate results of recent clinical trials. These are important clinical problems that mandate the search for better IPFT. Plasminogen activator inhibitor-1 (PAI-1) is strongly implicated in the pathogenesis of pleural loculation and inhibits tissue and urokinase plasminogen activators;tPA and uPA, which are currently used for IPFT. Our hypothesis that intrapleural neutralization of PAI-1 will further improve IPFT is strongly supported by published work and preliminary data. Our objective is to improve outcomes of treatment for organizing pleural injury using novel PAI-1-targeted interventions.
The Specific Aims are: 1) To determine if molecules that compete with fibrinolysins for PAI-1 enhance the ability of fibrinolysins (tPA or single chain urokinase) to clear pleural loculations. 2) To detennine if mAbs that potentiate inactivation of PAI-1 via latency or substrate pathway redirection increase the therapeutic potential of fibrinolysins. 3) To test the ability of PAI-1 targeted interventions to potentiate profibrinolytic responses of human and rabbit primary mesothelial cells and in human pleural fluids. We will also test the efficacy of PAI-1 targeted interventions in rabbit models of empyema and tetracycline- induced pleural injury enhanced with adenoviral delivery of human PAI-1. Our approach is innovative as intrapleural targeting of PAI-1 has never before been evaluated. We will meet milestones that can be accomplished by our multidisciplinary team within the two year funding period. At the end of this project, we will identify a prime interventional PAI-1 -targeted candidate and one or two backups. We will develop the most effective novel PAI-1- targeted therapeutics in CADET II for clinical trial testing. This project addresses a key gap in medical practice and could advance the field of IPFT through identification of more reliable, more effective and potentially safer treatment strategies for patients with pleural loculation.

Public Health Relevance

Intrapleural fibrinolytic therapy (IPFT) is often used as a less invasive alternative to surgery to treat patients with pleural loculation (scarring and fluid collections), but its efficacy remains controversial. We infer that outcomes of IPFT will be improved by PAI-1-targeting, a novel approach that addresses a critical mechanism of pleural injury. Ultimately, new interventions identified in this project could improve outcomes for thousands of afflicted US patients annually.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL107186-02
Application #
8259726
Study Section
Special Emphasis Panel (ZHL1-CSR-D (F1))
Program Officer
Harabin, Andrea L
Project Start
2011-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$424,780
Indirect Cost
$89,900
Name
University of Texas Health Center at Tyler
Department
None
Type
Organized Research Units
DUNS #
800772337
City
Tyler
State
TX
Country
United States
Zip Code
75708
Lee, Kristy; Hart, Matthew R; Briehl, Margaret M et al. (2014) The copper chelator ATN-224 induces caspase-independent cell death in diffuse large B cell lymphoma. Int J Oncol 45:439-47
Komissarov, Andrey A; Florova, Galina; Azghani, Ali et al. (2013) 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:L682-92
Karandashova, Sophia; Florova, Galina; Azghani, Ali O et al. (2013) Intrapleural adenoviral delivery of human plasminogen activator inhibitor-1 exacerbates tetracycline-induced pleural injury in rabbits. Am J Respir Cell Mol Biol 48:44-52
Komissarov, Andrey A; Florova, Galina; Idell, Steven (2011) Effects of extracellular DNA on plasminogen activation and fibrinolysis. J Biol Chem 286:41949-62