# Nuclear Heparan Sulfate Mediates Fibroblast Activation in Indiopathic Pulmonary Fibrosis

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2021 · $51,036

## Abstract

PROJECT SUMMARY/ABSTRACT
 Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive lung disease characterized by fibrosis of
the peribronchiolar interstitium. There is increasing appreciation that IPF represents the chronic consequence
of a maladaptive response to acute lung injury. Accordingly, known mediators of acute lung injury and the
acute respiratory distress syndrome (ARDS) may have direct relevance to IPF pathogenesis.
 The laboratory of my mentor, Dr. Eric Schmidt (University of Colorado), has previously demonstrated
the importance of heparanase to the onset of ARDS. Heparanase specifically degrades heparan sulfate (HS),
a cell-surface glycosaminoglycan essential for homeostatic lung function. Heparanase-mediated degradation of
endothelial HS leads to ARDS; however, the relevance of HS degradation to pulmonary fibroblasts and chronic
lung injury is relatively unexplored.
 In preliminary experiments, we observed increased expression of heparanase in lung explants from
patients with severe IPF. Heparanase co-localized with activated pulmonary fibroblasts and was associated
with loss of cell-surface HS in pulmonary fibroblasts isolated from human IPF explants. This loss of cell-surface
HS is profibrotic, as experimental degradation of HS from normal human lung fibroblasts induced expression of
pro-fibrotic genes. Intriguingly, this fibroblast activation was associated with nuclear localization of HS
fragments released from the degraded cell surface. Nuclear HS translocation was sufficient to induce pro-
fibrotic gene expression, as nucleofection of normal mouse lung fibroblasts (MLFs) similarly induced
expression of profibrotic genes transforming growth factor β, collagen 1A1, and ɑ Smooth Muscle Actin. As
nuclear HS has been previously implicated as an inhibitor of histone acetyltransferases, the observed
profibrotic activation of pulmonary fibroblasts after degradation of cell-surface HS may reflect the epigenetic
consequence of nuclear HS translocation.
 Based upon these preliminary studies, I hypothesize that injury-induced expression of pulmonary
heparanase cleaves fibroblast cell-surface HS, leading to nuclear internalization of HS fragments.
Nuclear HS in turn suppresses histone acetyltransferase activity, inducing pro-fibrotic gene
expression in IPF. These studies represent a novel, high-impact investigation with robust preliminary data,
providing me with a unique and high-yield opportunity for training in diverse field such as glycosaminoglycan
biology, lung injury and repair, and state-of-the-art molecular biology techniques. Furthermore, the proposed
studies have translational relevance, representing a novel opportunity to therapeutically target lung fibrosis via
either the prevention of HS degradation (and release of HS fragments) or the augmentation of histone
acetylation.

## Key facts

- **NIH application ID:** 10199011
- **Project number:** 5F31HL143873-04
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Wells B LaRiviere
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2018-07-13 → 2022-07-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10199011

## Citation

> US National Institutes of Health, RePORTER application 10199011, Nuclear Heparan Sulfate Mediates Fibroblast Activation in Indiopathic Pulmonary Fibrosis (5F31HL143873-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10199011. Licensed CC0.

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