# Proof of concept treatment interventions in a rodent model of the rare disease bronchiolitis obliterans

> **NIH NIH R21** · DUKE UNIVERSITY · 2020 · $241,500

## Abstract

Bronchiolitis obliterans (BO) is a poorly understood rare disease. Inhalation of flavoring chemicals used in
the food manufacturing industry directly contributes to the development and progression of the occupational
form of BO known as ‘popcorn lung’. BO is characterized by neutrophilic inflammation, altered lung function
and persistent airway fibrosis that can lead to reduced quality of life, increased health care costs and reduced
life expectancy. Because of its rarity, there have been no effective therapies developed for any form of BO.
 Critical impediments to the advancement of effective therapies for BO have been: 1) the lack of an
appropriate pre-clinical model for hypothesis driven proof of concept testing of candidate therapeutics; and, 2)
a poor understanding of basic disease mechanisms to guide hypothesis driven targeted interventions. We have
directly addressed these impediments as follows. First, we have recapitulated in rats the clinical observation
that workplace exposure to the artificial butter flavoring compound diacetyl (2-,3-butanedione; DA) causes BO
in humans1. Second, because epithelial injury is central to the development of other forms of fibrosis, we have
modeled DA vapor exposure of the human airway using primary human airway epithelial cells. Taken together
these represent the enabling advances by virtue of which this proposal was developed.
 Preliminary data from our in vitro model system shows that DA exposure induces persistent selective
phosphorylation of the epidermal growth factor receptor (EGFR) and the closely related co-receptor ErbB2.
Similarly, we show that the DA exposed airway epithelium secretes significantly increased quantities of
interleukin (IL) 8, hyaluronan (HA) and matrix metalloprotease (MMP) 9 in an EGFR dependent manner. IL-8,
HA and MMP9 are all pathognomonic of BO and have been plausibly linked with the development of airway
fibrosis in other animal models of disease. Consistent with this, we show significant increases in IL-8, HA, and
MMP9 in the DA-induced rodent model as BO develops and progresses. Therefore our hypothesis is that
blocking EGFR or ErbB2 using FDA approved small molecule inhibitors will prevent disease
development and progression in our rodent model of DA-induced occupational BO. To test our
hypothesis we have developed the following Specific Aims:
Aim 1: Determine the efficacy of prophylactic inhibition of the EGFR with the FDA approved specific inhibitor
Icotinib, or ErbB2 with the FDA approved specific inhibitor Trastuzumab in attenuating the development of
neutrophilic inflammation, altered lung function and persistent airway fibrosis observed in DA-induced BO both
in male and female rats.
Aim 2: Determine the efficacy of therapeutic intervention of the EGFR with Icotinib, or ErbB2 with Trastuzumab
in preventing the progression of previously established neutrophilic inflammation, altered lung function and
persistent airway fibrosis observed in DA induced BO in both male...

## Key facts

- **NIH application ID:** 10040120
- **Project number:** 1R21TR003037-01A1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Scott M Palmer
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $241,500
- **Award type:** 1
- **Project period:** 2020-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10040120

## Citation

> US National Institutes of Health, RePORTER application 10040120, Proof of concept treatment interventions in a rodent model of the rare disease bronchiolitis obliterans (1R21TR003037-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10040120. Licensed CC0.

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