Alveolar macrophage dysregulation in the pathogenesis of Gulf War respiratory illness

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Background: Over two decades following the Persian Gulf War, up to 250,000 veterans are still plagued by chronic conditions. Debilitating respiratory symptoms were neglected in initial studies. However, airway inflammation with abundant of alveolar macrophages has been discovered, along with diffuse constrictive bronchiolitis, possibly associated with deployment-related inhalation, but with no infectious etiology. Yet, only limited investigation into the underlying pathogenesis of Gulf War respiratory illness (GWRI) has been undertaken and the role of alveolar macrophages and the airway microbiome in GWRI remains unexplored. Our group has discovered severe alveolar macrophage dysfunction underlying the pathogenesis of COPD. Alveolar macrophages in COPD are dramatically hyporesponsive to bacterial antigens. Exacerbation-prone adults with COPD have significantly diminished pathogen-induced alveolar macrophage function. Moreover, COPD alveolar macrophages have a fundamental phagocytic defect for respiratory pathogens that is directly linked to progression of COPD. While impaired innate immune responses and decline in lung function are integral to COPD, they are not unique to COPD, but rather highlight the key potential contribution of alveolar macrophage dysfunction to progression of numerous inflammatory lung diseases. Hypothesis: Dynamic alveolar macrophage-microbial interactions are fundamental to the pathogenesis of Gulf War respiratory disease. Specific Aims: The following specific aims will be accomplished: Aim 1: Characterize the human airway microbiome of Gulf War Illness with and without respiratory disease. Aim 2: Elucidate the role of alveolar macrophage innate immune dysfunction in Gulf War respiratory illness and the relationship with airway microbiome composition. Aim 3: Elucidate the relationship of specific deployment exposures, demographics and respiratory disease in Gulf War Illness. Research Design: As GWRI is an exclusively human disease, these studies are designed using alveolar macrophages obtained from Gulf War participants. Four groups of volunteers will be recruited. Group 1: GWI with respiratory symptoms. Group 2: GWI without respiratory symptoms. Group 3: Gulf War veterans without any evidence of GWI. Group 4: non-Gulf War veterans. Groups 3 and 4 provide important controls for Gulf War exposures. Each participant will undergo bronchoalveolar lavage. Aim 1 will be the first investigation into the lung microbiome of GWRI. In Aim 2, differences in alveolar macrophage phagocytosis, TLR-2 and -4 regulation of inflammation and of transcriptome expression will be determined between groups, and will be integrated with results from Aim 1 to begin to explore the dynamic interplay between the airway microbiome and immune dysfunction in GWRI. In Aim 3, demographic and deployment exposures, and pulmonary function will be investigated and will be integrated with results of Aims 1 and 2. Impact: There are no established therapeutics for GWRI and no established benefit from antibiotics, bronchodilators or steroids. Studies of this proposal are directed at identifying taxa or combinations of taxa, associated not just with aberrant alveolar macrophage functions, but with select functions chosen from a broad immunologic array. This approach holds the promise of modulation of select alveolar macrophage function through transfer of lung microbiota, an approach that has revolutionized the treatment of C. difficile colitis. We anticipate results of this proposal will lead to regulation of alveolar macrophage function through microbiome restoration in GWRI, a completely novel approach aimed at interrupting the progression of disease. The overall goal of this research is to identify fundamental, modifiable regulatory innate defense mechanisms of alveolar macrophages in GWRI, to serve as therapeutic targets and improve clinical outcomes.