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

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2024 · $524,404

## Abstract

Empyema is a bacterial infection of the pleural space, a serious complication of pneumonia that carries a
mortality rate of up to 20%, the incidence of which continues to increase worldwide. Intrapleural fibrinolytic
therapy (IPFT) involving the delivery of plasminogen activators has been used to expedite drainage of loculated
pleural effusions, including empyema. Using a new model of Streptococcus pneumoniae-induced empyema in
rabbits we developed a single-dose IPFT with a plasminogen activator inhibitor 1 (PAI-1)-targeted adjunct, which
is 8-fold more effective than PA alone for treatment acute empyema. We also validated the ability of our
Fibrinolytic Potential Assay (FPA) to predict the success of IPFT in patients with empyema. Interestingly, the
efficacy of IPFT in our model of advanced-stage empyema is decreased by 40-50%, similar to what has been
observed in patients. This is, in part, due to a significant decrease in the rate of intrapleural fibrinolysis. To
mitigate the risk of bleeding complications associated with an increase in the dose of PA, we propose multiple
injections of low-dose PAI-1-targeted IPFT to treat advanced-stage empyema. Our objective is to identify
effective PAI-1-targeted IPFT for advanced-stage empyema. Our hypothesis is that successful IPFT in
advanced-stage empyema requires fibrinolytic activity sustained over a longer period of time and neutralization
of PAI-1. The hypothesis will be tested in four Specific Aims: 1. Maximize the efficacy of IPFT in advanced-
stage empyema in rabbits by targeting both the slow rate of fibrinolysis and PAI-1, 2. Develop novel PAI-1
targeting peptides to optimize IPFT in advanced-stage empyema, 3. Determine the mechanisms that result in
increased resistance to IPFT in advanced-stage empyema, and 4. Using the Fibrinolytic Potential Assay to
identify candidates for IPFT prior to treatment. We will select a dosing schedule and use two validated PAI-1
targeting adjuncts (monoclonal antibodies (mAbs), and a docking site peptide) to decrease the dose of PA, test
these mechanisms for additivity in PAI-1 targeting to maximize efficacy, and test the efficacy of PAI-1 targeting
peptides selected using phage display technology. We will use the FPA to analyze samples from Phase 2 Clinical
Trial “A Study to Evaluate LTI-01 in Patients with Infected, Non-draining Pleural Effusions” (ClinicalTrials.gov;
NCT04159831). We will use state of the art biochemical techniques to analyze pleural fluid and plasma from
human patients and our unique model of empyema to investigate the molecular interactions of fibrinolysis of
advanced-stage empyema. Our team has the biochemical, pulmonary and technical expertise to successfully
accomplish the proposed work. The project addresses key gaps in our current understanding of the pathogenesis
of pleural organization, optimization of IPFT and development of a new diagnostic approach to predict outcomes
of IPFT. This project is positioned to shift the paradigm of tre...

## Key facts

- **NIH application ID:** 10833091
- **Project number:** 5R01HL130402-08
- **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:** 2024
- **Award amount:** $524,404
- **Award type:** 5
- **Project period:** 2017-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10833091

## Citation

> US National Institutes of Health, RePORTER application 10833091, Delivery of PAI-1-targeted intrapleural fibrinolytic therapy for empyema (5R01HL130402-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10833091. Licensed CC0.

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