The Role of Serine Peptidase Inhibitor Gene Variants in Asthma Development

Instruction Bronchial asthma is a chronic inflammatory airway disease caused by a complex interaction between an individualʼs genetic make-up and the environment. Along this line, genetic studies have shown that variants in the serine peptidase inhibitor gene (serpin) scca1 are associated with asthma. However, the functional role of these variants (GV) is unknown.
Aim Therefore, we aim at deciphering the pathophysiological role of scca1 GV in asthma. To achieve this, we are exploring whether ssca1 GV increase the susceptibility towards common risk factors (hypoxia, tobacco smoke) and whether they affect airway epithelial barrier functions (structure, integrity and immune defence).
Methods The flyʼs orthologous of scca1 have been identified based on amino acid similarity and the presence of one serine protease inhibitor domain. By using the Gal4/UAS system, fly models (overexpression/RNAi models) dysexpressing scca1 in the airway epithelium were successfully established. To figure out if scca1 dysregulation affects airway morphology, the number and length of secondary branches in 1st and 3rd instar larvae were assessed. 3rd instar larvae were then exposed to hypoxia (5% O₂) for two hours. Larval crawling activity (a measure for hypoxic stress) was determined every ten minutes during hypoxia. Developmental period and mortality were assessed by counting the number of pupae and adult flies at different time points after HE.
Results Airway-specific overexpression of scca1 led to an increased number of secondary branches whereas its downregulation caused an increase in airway length. Moreover, dysexpression of scca1 resulted in a high vulnerability towards hypoxic stress within the first 30 minutes of exposure. Additionally, an exposure to acute hypoxia significantly increased adult but not pupal mortality of animals with reduced scca1 expression. While scca1 dysexpressing animals generally showed a developmental delay of pupae as well as adults, additional exposure to hypoxia does not affect the developmental period of both stages. In summary, we developed a Drosophila model for scca1, which is characterised by an altered airway structure. These airway alterations could be responsible for an impaired adaptability towards environmental stressors. Upcoming experiments will cover a more detailed analysis of molecular mechanisms underlying pathophysiological alterations of the airways due to scca1 dysregulation.