# Coordinated regeneration of lung epithelial and endothelial compartments

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $543,560

## Abstract

Influenza alone kills as many as 500,000 people annually, and at least 4.5 million have died
from SARS-CoV-2 during this ongoing pandemic, with mortality from both respiratory viruses
largely due to viral pneumonia progressing to acute respiratory distress syndrome (ARDS).
Significant focus has been placed on regeneration of the epithelium after influenza, but relatively
little is known as to how the endothelium is repaired, a critical question since vascular
endothelial integrity is necessary to prevent ARDS-associated pulmonary edema, hypoxemia,
and mortality. We recently demonstrated that at least 20% of the lung's vascular endothelium is
regenerated by 1 month after infection, indicating a robust capacity for endothelial repair. We
therefore investigated signaling pathways which might modulate this regenerative functionality.
Somewhat unexpectedly given its role in promoting fibrosis, we observed that endothelial-
specific blockade of TGF-β signaling prevents effective repair of the lung endothelium and
results in inefficient physiologic recovery. Moreover, in order to achieve coordinated, functional
tissue repair, we reasoned that lung endothelial cells might influence repair of the adjacent
epithelium by release of angiocrine factors. In keeping with this notion, we identified a
matricellular protein, SPARCL1, which is secreted by injury-activated endothelial cells and
serves to enhance alveolar epithelial regeneration, at least in part by modulating TGF-β. Based
on our cumulative findings, we hypothesize that injury-activated endothelial cells engage
a TGF-β / SPARCL1 axis to coordinately regulate lung endothelial and epithelial repair.
The major objectives to address this hypothesis are 1) mechanistically define how TGF-β
promotes lung vascular repair and 2) determine whether and how SPARCL1 acts as an
angiocrine factor to promote alveolar epithelial regeneration. Successful completion of these
studies will inform approaches designed to enhance endothelial cell regenerative potential and
promote effective lung repair / prevent mortality in ARDS and viral pneumonia.

## Key facts

- **NIH application ID:** 10907512
- **Project number:** 5R01HL164350-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Andrew Vaughan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $543,560
- **Award type:** 5
- **Project period:** 2022-08-20 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907512

## Citation

> US National Institutes of Health, RePORTER application 10907512, Coordinated regeneration of lung epithelial and endothelial compartments (5R01HL164350-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10907512. Licensed CC0.

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