# Fibrinolytic Proteases, meso-mesenchymal transition and pleural remodeling

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2021 · $362,500

## Abstract

Pleural injury often resolves with remodeling of the pleural surfaces, which in severe cases leads to pleural
fibrosis (PF) and fibrothorax. These sequellae are associated with respiratory impairment, reduced quality of
life and increased mortality. PF with lung restriction is often seen in medical practice but current treatment is
unsatisfactory and effective pharmacotherapy is not available. PF is characterized by aberrant local fibrin
deposition and proliferation of alpha-smooth muscle actin (α-SMA) expressing myofibroblasts. The expansion
of myofibroblasts is largely due to mesenchymal transition (MT) of resident pleural mesothelial cells (PMC),
termed MesoMT. These motile, matrix-producing cells are largely responsible for thickening of the pleura;
pleural rind formation. MesoMT and PF are linked to fibrinolytic pathways, as proteases involved in fibrin
degradation induce MesoMT. We recently reported that deficiency of plasminogen activator inhibitor (PAI)-1,
the principal inhibitor of urokinase plasminogen activator (uPA) and tissue PA (tPA), increases plasmin activity
and significantly worsens pleural injury. We also found that uPA and plasmin potently induce MesoMT. uPA-
and plasmin-mediated MesoMT involves activation of glycogen synthase kinase (GSK)-3β, a new and
promising target for the treatment of PF. Further, our preliminary studies show that GSK-3β inhibition with a
novel inhibitor, 9ING41, significantly attenuates the progression of pleural injury and remodeling. Based on
these observations and strong preliminary data, we strongly infer that uPA and plasmin and their activation of
GSK-3β, substantively contribute to the progression of PF. In this project, we will test the central hypothesis
that fibrinolysin-mediated changes and activation of GSK-3β are important steps that regulate PMC phenotype
and pleural injury outcomes including PF. Our objective is to determine the mechanism by which fibrinolytic
proteases, including uPA and plasmin, induce MesoMT and define their contribution to fibrosing pleural injury.
We will also define the contribution of increased GSK-3β signaling to the progression of PF. Our specific aims
are: 1) to define protease-receptor interactions by which the fibrinolytic system regulates MesoMT and pleural
remodeling, 2) to determine the mechanism by which GSK-3β signaling is regulated in uPA and plasmin-
induced MesoMT and 3) to determine the contribution of GSK-3β to the progression of pleural injury. We will
use new models of fibrosing pleural injury and empyema, mice with mesothelial labelling for fate-mapping
analyses, molecular, biochemical, histology and immunohistochemical techniques with which we have
expertise, state of the art CT imaging and pulmonary function analyses to accomplish these aims. We will test
whether new therapeutic agents including inhibitors of GSK-3β signaling effectively block the development of
PF. These studies will address gaps in our understanding of the pathogenesis of PF a...

## Key facts

- **NIH application ID:** 10084709
- **Project number:** 5R01HL130133-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** Torry Alle Tucker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $362,500
- **Award type:** 5
- **Project period:** 2017-01-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10084709

## Citation

> US National Institutes of Health, RePORTER application 10084709, Fibrinolytic Proteases, meso-mesenchymal transition and pleural remodeling (5R01HL130133-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10084709. Licensed CC0.

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