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...