Advanced Phenotyping Improves Diagnostic, Longitudinal Assessment, and Treatment Strategies for Deployment-Related Respiratory Disease
Abstract
Background: An increase in respiratory complaints including shortness of breath with activity, cough, and chest pain has been identified in military personnel (MP), including Veterans, returning from service in the first Gulf War and subsequent Post-9/11 conflicts. Exposures to airborne hazards, including burn pit smoke, sand and dust storms, fuel fumes, and other inhaled toxins may have caused these symptoms. A group of these MP whose symptoms were unexplained, despite extensive testing, underwent surgical lung biopsy. Review of the biopsies revealed evidence of a disease of the small airways called constrictive bronchiolitis (CB). Subsequent studies have shown evidence of additional types of injury and scarring in the small airways and more distal air spaces. In accordance with recent recommendations, MP that developed respiratory symptoms and evidence of lung injury post-deployment are described as having deployment related respiratory disease (DRRD). An urgent priority of the Toxic Exposure Research Program (TERP) is to identify tests that can diagnose DRRD without requiring a surgical lung biopsy and to determine whether this condition worsens over time. We developed a technique called Parametric Response Mapping (PRM), which analyzes high resolution chest CT scans of the lungs to both identify and quantify different types of lung damage. Using this technique, we have shown evidence of increased small airway damage in MP diagnosed with CB. Another urgent priority for the TERP is to better understand and treat DRRD. Our research group has developed two mouse models that mimic the injury to the airways (murine CB model; mCB) and distant air spaces of the lung (murine pulmonary fibrosis model; mPF) observed in DRRD. Our data suggest that a technique called Digital Spatial Profiling (DSP) can identify molecular pathways that contribute to fibrosis in distinct regions of the lung. We also show that PRM, and two new tests, called X-ray velocimetry (XV) and forced oscillation technique (FOT), may detect these injury and fibrosis patterns in mice and could be used to monitor disease and responses to treatment. Our findings suggest that mice with these injury patterns may be effectively treated by two drugs, roflumilast and pirfenidone, that are already approved by the U.S. Food and Drug Administration for use in other lung diseases. Hypotheses: We hypothesize that new advanced testing techniques, including PRM, will be able to identify disease progression in DRRD. These techniques will also improve our ability to characterize and categorize specific patterns, or subtypes of DRRD, and allow us to better understand and connect exposures with these subtypes. We also hypothesize that treatment with roflumilast and pirfenidone will be effective at preventing lung fibrosis in mouse models and that clinically relevant techniques, including PRM, XV, and FOT, will be able to detect and monitor these distinct injury patterns. Research Plan: In Aim 1, we will evaluate Veterans suspected of having DRRD using a panel of new diagnostic tests, including PRM, at enrollment and after 1 year, to look for evidence of disease progression and to identify distinct subtypes of disease to study how they change over time. In Aim 2, we will use our mouse models DSP to evaluate molecular pathways central to the development of scar tissue in mCB and mPF and to assess whether new diagnostic tests can identify each type of lung injury (Aim 2A). We will also investigate whether the drugs roflumilast or pirfenidone protect against lung fibrosis in mCB, and whether the new diagnostics can monitor response to treatment (Aim 2B). Impact: Our proposed studies will directly impact the respiratory health of current and former military personnel from both Gulf War and Post 9/11 conflicts by determining whether DRRD worsens over time. In addition, our studies will aid in the diagnosis of DRRD, provide insights on exposures and symptom
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310697
Entities
People
- John J Osterholzer
Organizations
- United States Army
- University of Michigan