Respiratory innate immune factors regulate steroid-resistant airway hyperreactivity and asthma

Research Doctorate - Doctor of Philosophy (PhD)Asthma is a chronic inflammatory disease of the airways and a combination of genetic and environmental factors underpin the pathogenesis. The clinical symptoms of asthmatics most mild to moderate, allergic asthma patients can be effectively managed by combination therapy with broad-spectrum anti-inflammatory agents and bronchodilators (typically inhaled glucocorticoids and long acting β-agonists). Indeed, glucocorticoids remain the forefront therapeutical approaches for the treatment of asthma. However, 5-10% of asthmatics who have severe asthma do not respond to treatment, and these patients account for almost 50% of asthma-related healthcare costs. Thus it is essential to understand the pathogenesis of steroid resistance in severe asthma for the development of more efficient therapies for those patients. With well-established animal models of steroid resistant airway hyper-responsiveness (AHR, a hallmark feature of asthma) and in vitro culture systems of pulmonary macrophages, the underlying mechanisms regulating steroid resistance and exacerbation of asthma have been thoroughly investigated, particularly on the causative roles of innate immune factors. This thesis consists of three publications. The first publication identifies changes in the expression of key innate immune molecules and their signalling pathways in a mouse model of steroid-resistant AHR and demonstrates the central role of pulmonary macrophages in the induction of steroid-resistant AHR The second publication investigates the expression of olfactory receptors in the respiratory system and on immune cells in response to innate immune activation, and identifies a potential role of olfactory receptors in regulating the function of pulmonary macrophages. The final publication discusses the modulation of small non-coding RNAs, microRNA, expression by innate immune activation in a steroid-resistant mouse model of asthma and evaluates the role of key microRNAs involved in the induction of steroid-resistant AHR by regulating the activity of a critical phosphatase, protein phosphatase-2A, which further affected the function of glucocorticoid