PROJECT SUMMARY More than 2.7 million military service members have deployed to Iraq or Afghanistan since 2001. Compared to non-deployed personnel, Veterans of these conflicts have a higher prevalence of exertional dyspnea and other respiratory symptoms which may relate to exposure to inhalational irritants during deployment. While many of these patients have asthma or other common respiratory conditions, approximately one-third remain undiagnosed with a traditional lung disease despite an extensive pulmonary evaluation. In a case series reported by our group in the New England Journal of Medicine in 2011, 38/49 such Veterans were diagnosed with constrictive bronchiolitis (CB) after surgical lung biopsy. Although more than a decade has passed since this initial report, no follow-up study has been performed to define the clinical evolution of disease in these Veterans. Further, no study has been performed to link development of constrictive bronchiolitis to specific exposures - either self-reported or quantified in lung tissue samples. Finally, although constrictive bronchiolitis was included in the recently passed PACT Act, there is currently no means of establishing this diagnosis outside of a surgical lung biopsy which is costly and carries significant morbidity and some mortality. Our published and preliminary data suggest that lung biopsies from Veterans with DR-CB have chronic activation of adaptive immunity which is associated with progressive airflow obstruction. Further, these findings occur in association with widespread deposition of polarizable and non-polarizable pigmented material containing foreign elements such as lead, silicon, strontium, and titanium. These data led us to hypothesize that persistent elemental species in the lungs of Veterans with DR-CB drive ongoing adaptive immune activation and progressive airflow obstruction. Further, we hypothesize that new imaging-based techniques can diagnose DR-CB without a surgical lung biopsy. To test these hypotheses, we will 1) identify and quantify trace elements in the lungs of Veterans with DR-CB, Veterans without DR-CB, and civilian controls, and correlate these levels with morphometric measurements of lung pathology and the surrounding immune response; 2) determine whether Veterans who were diagnosed with DR-CB have a higher prevalence of progressive cardiopulmonary disease than those without DR-CB; and 3) establish non-invasive, radiology-based methods of diagnosing DR-CB and monitoring for disease progression. Together, these studies will positively impact Veterans by advancing our understanding of factors which may promote DR-CB development, rigorously assessing cutting-edge diagnostic modalities which may improve our ability to diagnose DR-CB non-invasively, informing our understanding of disease progression, and creating new surrogate endpoints for future clinical trials.