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Integrated Genomics Approaches Identify Mediators of Transcriptional and Epigenetic Responses to Afghan Desert Particulate Matter in Small Airway Epithelial Cells (PRO-Seq)

ABSTRACT: New respiratory diseases in personnel deployed to Southwest Asia after September 11th raise major concerns about the impacts of airborne particulate matter. Although regulations exist, the knowledge about how particulates influence disease states is limited, precluding the appropriate recognition, prevention and treatment of deployment-related lung diseases. We applied two genomics assays, Precision Run-on sequencing (PRO-seq) and the assay for transposase accessible chromatin with sequencing (ATAC-seq), to characterize the small airway epithelial cell response to Afghan desert particulate matter (APM).

ORGANISM(S): Homo sapiens

PROVIDER: GSE201150 | GEO | 2022/04/27

REPOSITORIES: GEO

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Project description:Upon returning from deployment to Afghanistan, increasing numbers of United States service personnel are reporting symptoms consistent with an asthma-like airways disease, thought to be caused by prolonged inhalation of toxic desert particulate matter. Deployment Related Lung Disease (DRLD) symptoms persist in the post-deployment setting, where soldiers are then exposed to common household allergens. The goal of this study was to define the transcriptomic responses of leukocytes found in the airway lumen and airspace in a post-deployment setting, mimicked by inhalation of Afghanistan desert particulate matter (APM) and subsequent challenge with house dust mite (HDM) in mice. C57BL/6 mice (n=15/group) were exposed to filtered air or aerosolized APM for 6 hours per day for 12 consecutive days using a whole body exposure system, followed by intranasal PBS or HDM allergen challenges. One day after the last HDM challenge, mice were euthanized to collect bronchoalveolar lavage (BAL) cells for single cell RNA sequencing (scRNAseq) using the 10x Genomics Platform and assessment of inflammation and airway hyperresponsiveness (AHR). Unsupervised clustering of BAL cell scRNAseq data revealed a unique monocyte population induced only by both APM and allergen treatments. This population of monocytes is characterized by expression of genes involved in allergic asthma, including ALOX15, which is involved in airway obstruction and promoting the inflammatory response. We validated ALOX15 expression in monocytes via immunohistochemistry and immunofluorescence staining of lung tissue. APM pre-exposure, followed by HDM challenge lead to significantly increased total respiratory system resistance compared to filtered air controls. Using this post-deployment mimic in mice, we demonstrated that inhalation of desert PM while on deployment to Afghanistan may prime airways to be more responsive to allergen exposure after returning home. DRLD symptoms in post deployment setting may involve induction of a unique lung monocyte population that has the ability to regulate AHR and inflammation, possibly through increased expression of ALOX15.

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Integrated Genomics Approaches Identify Mediators of Transcriptional and Epigenetic Responses to Afghan Desert Particulate Matter in Small Airway Epithelial Cells (PRO-Seq)

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