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 Veterans for radiographic evidence of DR-CB (Aim 1b) and assess relationships between PRMfSAD and FOT (Aim 1c).] Aim 2: To determine whether [histopathologic features of murine chronic bronchiolitis caused by sustained club cell injury can be prevented and (or) ameliorated by disrupting profibrotic macrophage responses to apoptotic cells. Using our murine model, we will first identify relationships between club cell injury, apoptotic cell burden, oxidative stress, and lung macrophage phenotype (Aim 2a) and thereafter determine whether CD36 blockade (Aim 2b) or azithromycin (Aim 2c) can prevent and (or) resolve chronic bronchiolitis in mice.] Benefit to Veterans: [The application of PRM and FOT technology will significantly improve our ability to safely diagnose DR-CB and thus advance assessment of its prevalence amongst deployed Veterans, including those with Gulf War Veterans Illness. Our focused investigation on club cell injury will enhance our understanding of DR-CB pathogenesis in response to numerous respiratory hazards and expedite the development of preventative or active treatments for this debilitating condition.]
An increase in unexplained persistent respiratory complaints in Gulf War [and Post-9/11 Veterans] has led to mounting concerns that region or conflict specific inhalational hazards cause occult lung injury resulting in chronic small airways inflammation and fibrosis, referred to as deployment-related chronic bronchiolitis (DR-CB) in this proposal. [At present, DR-CB is difficult to diagnose without resorting to surgical lung biopsy. This study will determine whether parametric response mapping, a new CT scan analytical technique, can substantially advance our ability to non-invasively diagnose DR-CB and assess its prevalence in symptomatic SW Asia- deployed Veterans, including those with Gulf War Veterans Illness. The pathogenesis of DR-CB is poorly understood and no treatments for this disorder have been tested in humans or animal models. This proposal utilizes a novel murine model of chronic bronchiolitis to elucidate critical pathologic pathways and potential treatments for this disorder.]
