Source: International Congress 2016 – Asthma: mechanisms and biomarkers that promote clinical understanding
Disease area: Airway diseases

Abstract

Introduction: Steroid-insensitive (SI) asthma is of considerable clinical and economic significance and improved therapies are urgently required, however, the development of therapies has been hampered by a lack of understanding of the processes that underpin disease. Aim: To develop experimental models of SI asthma that represent different subtypes of clinical disease and use these models to elucidate universal drivers of SI asthma. Methods: Mouse models of Chlamydia, Haemophilus, influenza and respiratory syncytial virus (RSV) lung infections were superimposed with a model of steroid-sensitive ovalbumin (Ova)-induced allergic airways disease (AAD). The effects of infection on AAD and response to dexamethasone (DEX) treatment were examined. Results: We show that Chlamydia and Haemophilus infections drive neutrophil-dominated inflammation, while influenza and RSV infections drive eosinophil-dominated inflammation, in AAD. DEX does not suppress inflammation or airways hyper-responsiveness in all four models. These models of SIAAD represent neutrophil and eosinophil-enriched subtypes of SI asthma. Using gene expression and microRNA (miR) array analyses of these models we identified several factors that are universally dysregulated in SIAAD. Significantly, we show that suppression of miR-21 is effective for restoring steroid sensitivity in all four models. Conclusion: We have developed unique models of SI asthma and used these models to identify factors that are universally dysregulated in SI disease. These factors may represent novel targets for therapies that are broadly effective for the treatment of different subtypes of SI asthma in humans.


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Jay Horvat (Newcastle, Australia), Jay Horvat, Richard Kim, James Pinkerton, Brittany Rae, Malcolm Starkey, Ama-Tawiah Essilfie, Jemma Mayall, Bernadette Jones, Tatt Jhong Haw, Hiep Nguyen, Simon Keely, Joerg Mattes, Ian Adcock, Paul Foster, Philip Hansbro. Identification of therapeutic targets for steroid-insensitive asthma using models that represent different clinical subtypes of disease. Eur Respir J 2016; 48: Suppl. 60, 563

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