The interaction of asthma risk genes with cigarette smoke and their influence on airway morphology, physiology and signaling pathways in Drosophila melanogaster

Asthma bronchiale is a chronic inflammatory airway disease with no intervention method or cure available. Its early life development is influenced by both host and environmental factors, which act independently but can also interact with each other. Genetic studies identified ORMDL3 and Scca1 as asthma risk genes associated with asthma development. Additionally, cigarette smoke (CS) exposure is a known environmental risk factor for asthma development in early life.

In this study, the interaction of ORMDL and Scca1 with CS exposure was investigated in the airway epithelium of Drosophila melanogaster. Therefore, flies with airway-specific knockdown (KD) or overexpression (OE) of the gene orthologues of ORMDL3 and Scca1 were generated. Changes in larval tracheal morphology, larval and adult physiology and in the transcriptome of the airways were characterized.

Results show that OE and KD of ORMDL cause mild morphological changes in the airway structure and influence physiological parameters. In interaction with CS exposure ORMDL OE led to massive changes in the airway epithelium. ORMDL KD interacted with CS exposure, which was reflected in sex-dependent changes in adult longevity. Scca1 KD caused only mild changes in interaction with CS exposure. Scca1 OE induced sex-dependent modifications of airway structure and had a strong impact on developmental traits. In interaction with CS exposure, morphology of airways was changed in males, while physiology was influenced in both sexes. The transcriptome of Scca1 OE flies was prone in a direction of inflammatory and stress signaling pathways at baseline. In interaction with CS, Scca1 OE caused the dysregulation of genes associated with inflammatory traits and airway remodeling.

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