# Delivery of PAI-1-targeted intrapleural fibrinolytic therapy for empyema

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2020 · $352,311

## Abstract

Summary
Approximately 65,000 patients in the United States alone develop empyema (EMP) or
complicated parapneumonic pleural effusions each year. The incidence of EMP is increasing
worldwide. EMP is associated with serious morbidity, a mortality of about 20%, and annual
patient care costs of roughly $500 million. Intrapleural fibrinolytic therapy (IPFT) has been used
for over sixty years to expedite pleural drainage and prevent lung restriction, but its efficacy and
safety profile, especially in adults, remains uncertain. Bleeding occurs in up to 15% of patients.
Current IPFT protocols use empirically dosed, off-label interventions and reflect rudimentary
knowledge about the regulation of IPFT in EMP and its pathogenesis. These gaps have slowed
the development of more reliable and safer IPFT for patients with EMP or other forms of
loculated pleural injury and form the scientific premise for our project. Our preliminary data
validates active plasminogen activator inhibitor 1 (PAI-1) as a biomarker and therapeutic target
for IPFT. We provide proof of concept and show that three mechanistically different forms of
PAI-1 targeted IPFT effectively reverse tetracycline-induced pleural organization in rabbits.
These interventions allow for up to an 8-fold reduction of the dose of fibrinolysin in IPFT, thereby
mitigating bleeding risk. We designed a companion diagnostic test; the Fibrinolytic Potential
Assay (FPA), to monitor outcomes of PAI-1-targeted or other forms of IPFT. Our hypothesis is
that PAI-1 targeted IPFT can effectively clear intrapleural organization in EMP. We also posit
that FPA can predict outcomes of PAI-1-targeted IPFT and ultimately be used to select the
subjects most likely to benefit. To test this hypothesis, we developed and characterized a new
S. pneumoniae rabbit EMP model which simulates key features of human EMP from an acute
(96h) to an organized chronic (7-21 days) phase with multiloculation-like organization and
significant pleural thickening. Our objective is to test the efficacy and safety of PAI-1 targeted
IPFT in the S. pneumoniae EMP model and determine if the FPA predicts pleural injury
outcomes. This hypotheses will be tested in four Specific Aims, which are to: 1. Improve the
efficacy of IPFT in rabbit EMP using PAI-1 targeted delivery; 2. Determine the molecular
mechanisms governing intrapleural fibrinolysis in EMP and the effects of high levels of
extracellular DNA on PAI-1 targeted IPFT; 3. Select the single most effective form of PAI-1
targeted IPFT in EMP, develop and validate the companion FPA test using EMP fluids from the
model and patients; and 4. Optimize the structure and co-formulation of a novel IPFT for EMP
and evaluate its safety and efficacy. A range of state-of-the-art biochemical, physiologic, tissue
analysis, and imaging techniques will be used to accomplish the work. Our unique
multidisciplinary team includes leading experts in the fields of fibrinolysis, pleural injury, as well
as drug formulation...

## Key facts

- **NIH application ID:** 9850620
- **Project number:** 5R01HL130402-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** Galina Florova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,311
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850620

## Citation

> US National Institutes of Health, RePORTER application 9850620, Delivery of PAI-1-targeted intrapleural fibrinolytic therapy for empyema (5R01HL130402-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9850620. Licensed CC0.

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