Immunology and Microbiology, School of Biomedical Science and Pharmacy, The University of Newcastle; Professor
Understanding pathogenesis to develop new treatments for respiratory diseases
Severe, steroid-resistant (SSR) asthma and COPD are two of the most important respiratory diseases but do not respond to current therapies. The development of new therapies has been hampered by the lack of mouse models that accurately recapitulate SSR asthma and COPD.
We developed novel mouse models of SSR asthma and COPD. We combined ovalbumin (OVA)-induced allergic airway disease (AAD) with respiratory infections or high fat diets associated with this form of asthma (Chlamydia, Haemophilus, influenza, RSV). This induces airway inflammation and airway hyperresponsiveness (wheezing) that are not suppressed by steroid treatment. We expose mice to chronic cigarette smoke for 8-12 weeks to induce persistent airway inflammation, airway fibrosis/remodelling, emphysema and impaired lung function.
In SSRAAD/asthma we show that each element in the NLRP3-IL-1-caspase-1 pathway is elevated and that suppression of each, including with a new NLRP3-specific inhibitor, inhibited SSR airway inflammation and AHR. To identify new targets we performed RNA-seq and are analysing the data and comparing to different human phenotypes. In COPD we have profiled the phenotypes of macrophages and changes in mmunometabolic processes. We have targeted them to reverse disease.
Thus, using mouse models of SSR asthma and COPD we can identify potential new therapeutics and targeting inflammasomes and immune metabolism may have therapeutic potential in these diseases.