# Oxidative Stress and Regional Airway Remodeling and Fibrosis in Obese Asthma

> **NIH NIH R01** · DUKE UNIVERSITY · 2022 · $752,964

## Abstract

ABSTRACT
Obesity, a major comorbidity and a potential modulator of asthma, affects nearly 40% of asthmatics in the U.S.,
and increases its severity. Obese asthmatics do not respond as well to conventional anti-inflammatory therapies
and new biologics targeting asthma are less effective in obese asthmatics compared to lean. Very little research
has been conducted in obese animals or obese asthmatics, resulting in a major knowledge deficit.
 A key feature of asthma is airway remodeling and fibrosis, broadly defined as a change in distribution,
thickness, composition, mass or volume of structural components of the airway wall of patients relative to healthy
patients. Airway remodeling is difficult to diagnose in obese patients as mechanical changes in chest wall
compliance can contribute to the physiological changes seen. Classically, evidence of airway remodeling and
fibrosis are revealed as fixed airway obstruction on spirometry. However, spirometry is not only insensitive to the
peripheral airways, where airway remodeling occurs, but is fundamentally incapable of localizing the sites of
remodeling and fibrosis. Thus, a critical research limitation in the study of airway remodeling and fibrosis in
asthma is defining regions of disease activity to explore disease-specific mechanisms. To understand the nature
of airway remodeling and fibrosis in obese asthma and to rapidly screen for novel therapies requires translation
between preclinical models and patients, while using advanced imaging. Recent work in asthma using 3D
functional imaging with 129Xe MRI has revealed the location of both reversible and fixed ventilation defects
(defined based on bronchodilator responsivity). Several studies suggest that fixed defects represent sites of
airway remodeling and fibrosis, but to date, this has been inferred indirectly from sputum analyses and CT scans.
Our central hypothesis is that sites of abnormal ventilation on 129XeMRI represent areas of airway remodeling
and fibrosis and are enriched with fibroblasts that are invasive, proliferative and fibrogenic. We further
hypothesize that regional alterations in oxidant stress driving the production of transforming growth factor-beta
(TGF-β) direct pro-remodeling fibroblast functions. Lastly, we hypothesize that 129XeMRI will be a sensitive and
specific biomarker of airway remodeling and fibrosis in obese asthmatics and rat models of obese asthma. By
leveraging our excellence in clinical asthma, bronchoscopy, and translational expertise in cell function/signaling
and 3D MR imaging in both patients and animal models, we will conduct both ex vivo cell-specific mechanistic
studies and in vivo animal model studies to uncover the mechanisms of molecular and cellular function through
the following Specific Aims: Aim 1) Identify the pathology, structural cell profile (airway fibroblast and epithelial
cell) and redox status corresponding to regional areas of fixed and reversible post-bronchodilator defects (BD)
in obese...

## Key facts

- **NIH application ID:** 10463661
- **Project number:** 5R01HL153641-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Loretta G Que
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $752,964
- **Award type:** 5
- **Project period:** 2020-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10463661

## Citation

> US National Institutes of Health, RePORTER application 10463661, Oxidative Stress and Regional Airway Remodeling and Fibrosis in Obese Asthma (5R01HL153641-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10463661. Licensed CC0.

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