Defective cell migration as a mechanism of dysregulated asthmatic airway repair

Anthony Kicic, Stephen Stick

Our research group has previously demonstrated in primary tissue samples from a paediatric population that dysregulated wound repair is a feature of asthmatic epithelium (Stevens et al. 2008, Kicic et al. 2010). Aberrant wound repair of asthmatic epithelium has been confirmed by others in adult primary tissue and minimally transformed asthmatic cell lines (S Randell, personal communication). We believe that a failure of the epithelium to repair appropriately in asthma is an important component of an asthma endotype that renders the epithelium susceptible to injurious environmental triggers such as viruses and that can contribute to a chronic inflammatory response and remodelling in the airways.

Our group has made the exciting discovery that epithelial cells from young children with asthma display inherent biochemical and functional differences compared to similar cells from non-asthmatic children (Kicic et al. 2006, Stevens et al. 2008, Kicic et al. 2010). Further analysis by our group has revealed that asthmatic epithelial cells exhibit dysregulated responses to injury (Stevens et al. 2008). Furthermore, our recent discoveries have provided the basis for our overarching hypothesis that dysregulated repair is an innate feature of asthmatic epithelial cells. Our most recent findings demonstrate that the dysregulated repair in asthmatic epithelium is caused by a defective migratory capacity. Findings generated from this study are contributing to a fundamental shift in our approach to asthma, specifically, from one that focuses on the responses to injury to one addressing prevention of injury, restitution of normal repair and maintenance of epithelial integrity.

This project uses primary airway epithelial cells (pAEC), obtained by gently brushing the main airway of children (unselected population of mild asthmatics and non-asthmatics) undergoing non-respiratory elective surgery (e.g. tonsillectomy) at Princess Margaret Hospital and St. John of God Subiaco. Cells are grown in the laboratory and then wounding experiments are conducted to assess their migration patterns and reparative capacity in vitro. In order to measure responses to wounding; we are using established methods as well as RNA-Sequencing analysis coupled with systems biology that assesses global gene expression. Systems biology allows us to map all the genes in the pathways involved in cell migration response and identify which particular genes in asthmatic pAEC are associated with the observed dysfunctional repair. We will then screen for known drugs or natural products that are able to target these genes with the hope of identifying new therapeutic targets to aid in the effective restitution of the asthmatic airway epithelial layer and prevent subsequent lung inflammation and remodeling.

Plain Language summary

The findings from this study show that in children with asthma this protective barrier is different from children without asthma. It is leakier making it easier for viruses and toxins to enter the cells. Viral infections makes this leakiness worse. We also observed that the cells did not fully repair after injury, due to a lack of specific growth compound and the abnormal production of anchoring protein that helps the cell move. We also compared how these repair responses changed with age and severity of asthma, by comparing cells sampled from children and young adults. We have shown that this failure to repair happened very early in asthma and was sustained in adulthood.

Funder: NHMRC

External collaborators:

• Clinical Professor Francis Lannigan; Head of Paediatrics, SJOG
• Prof Darryl Knight, University of Newcastle, NSW
• Associate Prof Paul Rigby, CMCA, WA