# S-glutathionylation chemistry in fibrotic lung remodeling

> **NIH NIH R35** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2022 · $927,889

## Abstract

PROJECT SUMMARY
It is increasingly recognized that oxidative stress is an important feature in pathophysiology of chronic pulmonary
diseases, including asthma, COPD and pulmonary fibrosis. Yet, in spite of some successes in animal studies,
clinical trials using antioxidants have been largely ineffective in improving lung function in patients with lung
disease, and have not yielded new drugs. Despite these negative clinical trials, it has now become well accepted
that oxidants are molecules that carry out important biological functions. My laboratory has discovered that
protein S-glutathionylation (PSSG), a redox-based modification of reactive cysteines, plays a critical role in
airways remodeling and lung fibrosis. We identified that this process is catalyzed by glutathione S transferase P
(GSTP), and reversed by the deglutathionylating enzyme, glutaredoxin-1 (Glrx1) induced de-glutathionylation.
The intriguing observations around the GSTP-PSSG-Glrx1 redox axis have formed the foundation for a number
of research directions that will be pursued herein. We propose to do so in the setting of interstitial fibrosis and
fibrotic remodeling associated with allergic airways disease. The conceptual framework for this R35 over the
next seven years consists of five separate goals that include: 1) Identification of redox scaffolds and redox-relay
circuits harnessed by scaffolding complexes that encompass peroxiredoxin-4 (Prdx4), GSTP and client proteins
that are S-glutathionylated via a redox relay, 2) Avenues to combat protein S-glutathionylation (PSSG) in a
target-specific manner by focusing on new avenues for inhibition of GSTP, 3) Understanding mechanisms of
cellular uptake/secretion of Glrx1, approaches to modify stability of and deliver Glrx1 to specific cellular
compartments to enhance its de-glutathionylating function, 4) Address whether altered inflammatory/immune
responses contribute to the diminished fibrogenic response upon attenuation of S-glutathionylation, and 5)
Elucidate targets for PSSG in epithelial cells from asthmatics and lung tissues from patients with IPF and address
whether strategies to attenuate PSSG diminish pro-inflammatory/pro-remodeling responses in epithelial cells
from patients with asthma: The project areas identified have the strong potential to advance our knowledge of
how biological oxidations, specifically PSSG, are controlled, with the goal to identify strategies to intervene with
protein cysteine oxidations in a target- or compartment-specific manner. The anticipated outcomes will be
molecules that are therapeutically applicable and overcome the lack of efficacy observed with the use of non-
specific generic antioxidants in the treatment of pulmonary diseases. This research program has the potential to
be paradigm-shifting as it changes conventional thinking of how oxidants contribute to lung disease (oxidative
stress) toward a paradigm wherein oxidants transduce signals via highly scaffolded “electrical circuits”.

## Key facts

- **NIH application ID:** 10320789
- **Project number:** 5R35HL135828-06
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Yvonne M. W. Janssen-Heininger
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $927,889
- **Award type:** 5
- **Project period:** 2017-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320789

## Citation

> US National Institutes of Health, RePORTER application 10320789, S-glutathionylation chemistry in fibrotic lung remodeling (5R35HL135828-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10320789. Licensed CC0.

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