# NOVEL PARACRINE MECHANISMS FOR CELL-BASED THERAPY OF INJURED LUNGS

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH CTR AT TYLER · 2020 · $372,859

## Abstract

TITLE: NOVEL PARACRINE MECHANISMS FOR CELL-BASED THERAPY OF INJURED LUNGS
SUMMARY. We have recently described a potentially paradigm-shifting signal pathway for repair of injured
alveolar epithelium by mesenchymal stem (stromal) cells (MSCs). In injured distal airspaces, increased PAI-1
levels depress local fibrinolytic activity. We demonstrated that MSC-released keratinocyte growth factor (KGF)
up-regulates fibrinolysins, which cleave epithelial sodium channels (ENaC). Based on our Preliminary Data, we
hypothesize that KGF-activated fibrinolysins in MSCs constitute a novel signal cascade for normalizing
alveolar fluid homeostasis and re-epithelialization in injured lungs. We propose that the
KGF/uPA/plasmin/ENaC pathway is critical in KGF-mediated edema fluid resolution. This hypothesis is
supported by a body of very recent observations: 1) MSC culture medium restores amiloride-inhibitable fluid re-
absorption in injured lungs; 2) KGF stimulates expression of uPA, a predominate fibrinolysin in MSCs, and
extracellular fibrinolytic activity during repair; 3) depolarization of epithelial cells improves wound healing by
facilitating migration, and this depolarization is mainly determined by ENaC activity; 4) knockout of mouse uPA
inhibits transepithelial fluid re-absorption; 5) both uPA and plasmin activate ENaC function by cleaving
substrate-like extracellular motifs of ENaC; and finally, 6) plasmin augments alveolar fluid clearance in human
lungs, and intratracheal delivery of uPA improves edema fluid resolution in acid aspiration injured mice. Aim 1
will test the beneficial role of this novel KGF/fibrinolysins/ENaC pathway in MSC-based repair. This aim
will utilize an in vitro 3D model of cytokine/hypoxia-challenged primary human alveolar epithelial type 2 cells
(AT2), acid injured mice, and ex vivo perfused human lungs infected with live bacteria; Aim 2 will determine
the molecular mechanisms by which the KGF/uPA/plasmin/ENaC pathway enhances reabsorption of
alveolar edema fluid. This aim will utilize a clinically relevant in vivo mouse lungs injured with acid, 3D primary
AT2 cultures exposed to cytomix plus hypoxia, and expression systems. We will test the hypotheses 1) that
MSC-derived KGF rebuilds the fibrinolytic niche for injured lung epithelium, 2) that elevated fibrinolysins cleave
ENaC proteolytically following physical intermolecular regulation, and 3) that extracellular cleavage sites in
ENaC proteins are identical to favorite catalytic substrates of fibrinolysins in sequence. This aim will also test if
the KGF/uPA/plasmin/ENaC pathway regulates proliferation, migration, and differentiation of AT2 cells. The
robust and unbiased results of these studies will identify novel mechanisms and causal relationships for MSC
and KGF-mediated restoration of normal alveolar fluid clearance in lung injury models, and determine how
fibrinolytic proteases activate ENaC function to improve edema fluid resolution. Our studies are both basic and
transla...

## Key facts

- **NIH application ID:** 9994349
- **Project number:** 5R01HL134828-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH CTR AT TYLER
- **Principal Investigator:** HONG-LONG JI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,859
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9994349

## Citation

> US National Institutes of Health, RePORTER application 9994349, NOVEL PARACRINE MECHANISMS FOR CELL-BASED THERAPY OF INJURED LUNGS (5R01HL134828-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9994349. Licensed CC0.

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