# A Novel PAI-1 Function Drives Lung Fibrosis

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $695,226

## Abstract

Project Summary
 Progressive scarring of the lung interstitium is a common feature of many systemic and primary lung
diseases including Idiopathic Pulmonary Fibrosis (IPF). IPF is a common disorder, and patients diagnosed with
this disorder experience substantial morbidity and a median survival of 3-5 years. Although recently approved
therapies slow the rate of disease progression, more efficacious interventions that interfere with precise
disease mechanisms are desperately needed. Plasminogen activator inhibitor-1 (PAI-1) holds substantial
promise as a therapeutic target for lung fibrosis as experiments in multiple complementary animal models
reveal a direct correlation between the activity of this molecule and the severity of scarring. These studies
substantiate PAI-1 as a critical down-stream mediator of prominent pro-fibrotic stimuli including TGF-β and
matrix stiffness. Despite the large amount of data implicating PAI-1 as a critical pro-fibrotic protein, the
mechanism by which it promotes fibrosis remains elusive.
 PAI-1 is a multifunctional protein with inhibitory activity against the plasminogen activators through
which it regulates fibrinolysis and wound healing. PAI-1 also interacts with non-protease ligands including the
provisional matrix protein vitronectin (VTN). Using mutant proteins lacking specific functions and transgenic
mice, we demonstrated that the pro-fibrotic action of PAI-1 is largely independent of its plasminogen activator
inhibitory activity and that vitronectin is not required for PAI-1 to fully promote scarring of the lung. These
results led us to perform an unbiased proteomic study to identify novel PAI-1 binding partners within the injured
lung. With this approach, we identified sortilin related receptor-1 (SorlA) as the most enriched protein.
 SorlA is a multi-domain receptor implicated in the uptake and intracellular sorting of proteins. Our
preliminary data confirm that PAI-1 binds to SorlA and that this interaction is prevented by mutations that
suppress the profibrotic activity of PAI-1. We further find that PAI-1 is taken up by key cellular constituents of
the fibrotic lesion. Importantly, we also identify a previously unrecognized and potent role for SorlA in lung
fibrosis, and using human cells, we find that SorlA expression is upregulated in fibrotic epithelial cells and
fibroblasts. These preliminary data motivate our hypothesis that PAI-1 promotes lung fibrosis through an
interaction with SorlA that leads to cell uptake, cytosolic localization, and a profibrotic alteration in cell
phenotype. To interrogate this hypothesis, we have designed a multifaceted approach incorporating molecular
biology techniques, in vitro experiments with cells from patients and mice (as well as cell lines), and in vivo
experiments using transgenic mice, mutant PAI-1 proteins, and complementary models of lung fibrosis. To
accomplish our proposed studies, we have brought together a synergistic investigative team with expertise i...

## Key facts

- **NIH application ID:** 10753561
- **Project number:** 5R01HL163870-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel A Lawrence
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $695,226
- **Award type:** 5
- **Project period:** 2022-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10753561

## Citation

> US National Institutes of Health, RePORTER application 10753561, A Novel PAI-1 Function Drives Lung Fibrosis (5R01HL163870-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10753561. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*