# Advancing Non-Invasive Diagnostics and Treatments of Deployment-Related Chronic Lung Disease in Gulf War Veterans

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2021 · —

## Abstract

Rationale. An increased incidence of respiratory complaints has been identified in Veterans of the Gulf War
(GW) [and post-9/11 conflicts. An inhalational injury is suspected given numerous potential exposures to airway
toxins. A landmark study (1) in 2011 described a cohort of post-9/11 soldiers with unexplained dyspnea and
impaired exercise tolerance that underwent surgical lung biopsy; findings showed evidence of chronic
inflammation surrounding thickened fibrotic bronchioles referred to as deployment related chronic bronchiolitis
(DR-CB) in this proposal. We performed a preliminary analysis of chest CT scans previously obtained on a
subset of these soldiers using parametric response mapping (PRM), a recently-developed CT analytic technique
that measures differential lung density between inspiratory and expiratory scans. Here we provide the first
evidence linking the histopathologic features of DR-CB with an abnormal radiographic signature indicative of
functional small airways disease (fSAD). We show that forced oscillation technique (FOT), a pulmonary function
test, may also non-invasively identify small airways disease in deployed Veterans. We provide additional data
demonstrating that key histopathologic features of DR-CB are recapitulated in a transgenic murine model of
inducible, specific, and sustained injury to progenitor club cells located within the airway epithelium. This finding
and additional associational evidence indicate that numerous airway toxins present during deployment mediate
their deleterious effects via a club cell injury pathway. We further implicate an increase in apoptotic club cells
and profibrotic macrophage accumulation in the pathogenesis of chronic bronchiolitis. Our collective data and
proposed studies address an urgent need to better understand, diagnose, and treat DR-CB.]
Hypothesis: [We hypothesize that the histopathologic features of DR-CB in Veterans are manifested as
increased functional small airways disease detectable by PRM and FOT. We further hypothesize that the
histopathologic features of chronic bronchiolitis induced by club cell injury in mice result from increased apoptotic
cell burden which triggers accumulation and profibrotic activation of lung macrophages.]
Aim 1: To determine whether PRM identifies an increase in fSAD as a radiographic surrogate [for the
histopathologic abnormalities that define] DR-CB. In this Aim, we will obtain comprehensive data sets (including
high resolution CT scans) on cohorts of GW and Post-9/11 Veterans that underwent clinically-indicated
evaluations for unexplained dyspnea at the Vanderbilt University Medical Center and the New Jersey War
Related Illness and Injury Study Center. We will first quantify PRM classifications in Veterans with
histopathologic evidence of DR-CB and identify a predictive threshold of PRMfSAD that may aid in the diagnosis
of this condition (Aim 1a). We will then use this threshold to compare cohorts of non-biopsied Gulf War and
Post-9/11 V...

## Key facts

- **NIH application ID:** 10125813
- **Project number:** 5I01BX004740-02
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** JOHN OSTERHOLZER
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10125813

## Citation

> US National Institutes of Health, RePORTER application 10125813, Advancing Non-Invasive Diagnostics and Treatments of Deployment-Related Chronic Lung Disease in Gulf War Veterans (5I01BX004740-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10125813. Licensed CC0.

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