# The Role of PON2 in the Development of Non-Allergic Asthma in Obesity

> **NIH NIH F32** · DUKE UNIVERSITY · 2022 · $80,746

## Abstract

Project Abstract
 Asthma is a common disease characterized by airway hyperresponsiveness (AHR) and a heterogenous
inflammatory profile. In patients with asthma, comorbid obesity is associated with worse asthma control and
decreased efficacy of therapy. The inflammatory profile in patients with comorbid obesity and asthma is typified
by less eosinophilic inflammation and more oxidative and nitrosative (oxo-nitrosative) stress than lean patients
with asthma. The mechanism of this observation is not known. However, patients with comorbid obesity and
asthma have lower levels of paraoxonase 2 (PON2) in their airway epithelium than lean patients with asthma.
Furthermore, PON2 levels are modulated by peroxisome proliferator-activated receptor gamma (PPAR) in
multiple tissues. This proposal examines the role of changes in PON2 and PPAR in contributing to oxo-
nitrosative stress in patients with comorbid obesity and asthma. Using a murine model of diet induced obesity
and ozone exposure as a model of inhaled oxidative stress, this proposal will address three questions. First,
what is the relationship between Pon2 expression and oxo-nitrosative stress under the condition of obesity? This
question will be answered by using a high fat, high sugar diet to induce obesity and an acute ozone exposure as
an exogenous oxidative insult. Pon2 expression, markers of oxo-nitrosative stress, and airway physiology will
be assessed in lean and obese mice to determine if there is an association between Pon2 levels and airway
oxo-nitrosative stress. These findings will be compared to Pon2-/- mice under the same conditions to isolate the
effect of PON2. To isolate the precise role of the pulmonary epithelium in this process, cultured human airway
epithelial cells will be exposed to ozone and assessed for oxo-nitrosative stress. Second, how does Pon2
expression changes affect the development of airway fibrosis after chronic exposure to an oxidative stressor?
This question will be addressed by feeding mice either a high fat, high sugar or a control diet and then chronically
exposing them to ozone for 6 weeks. At the end of six weeks, airway physiology will be measured and lung tissue
will be assessed for the development of fibrosis. Third, does PPAR activation abrogate the effect of obesity on
PON2 expression, AHR and markers of oxo-nitrosative stress? This question will be addressed by treating mice
with the PPAR agonist, pioglitazone, and repeating the high fat, high sugar diet and acute ozone exposures
from our first question. Airway physiology, PON2 levels and oxo-nitrosative stress will then be assessed.

## Key facts

- **NIH application ID:** 10533862
- **Project number:** 1F32HL165697-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Matthew McCravy
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $80,746
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10533862

## Citation

> US National Institutes of Health, RePORTER application 10533862, The Role of PON2 in the Development of Non-Allergic Asthma in Obesity (1F32HL165697-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10533862. Licensed CC0.

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