Identification of novel therapeutics for chronic obstructive pulmonary disease

Research Doctorate - Doctor of Philosophy (PhD)Chronic obstructive pulmonary disease (COPD) is characterised by progressive decline in lung function that is caused by aberrant inflammatory responses, small airway remodelling and emphysema. The key risk factor of COPD is cigarette smoking. Current mainstay therapies of COPD only provide symptomatic relief and fail to limit the disease progression. Thus there is an urgent requirement for the development of new therapies. However this is hampered by the lack of understanding of the mechanisms that drive COPD pathogenesis. Therefore there is a need for the elucidation of the mechanisms that underpin the development of COPD. MicroRNAs (miRs) are evolutionarily conserved small noncoding RNAs that regulate the expression of their target genes at the post-transcriptional level. More than 1,000 human miRNAs have been identified and are known to regulate numerous biological processes such as cell differentiation and proliferation, apoptosis, and immune responses. Importantly, altered expression of miRs are implicated in the development of several cancers and inflammatory diseases including asthma. However, their role in the pathogenesis of COPD is limited. Thus, our studies were aimed to understand the roles of CS-induced dysregulated miRs and interrogate their potential for therapeutic targeting in experimental COPD. Using microarray-based miR profiling technique, we identified a range of dysregulated miRs in CS-induced experimental mouse model of COPD. Acute and chronic CS-exposure chronically upregulated the expression of four miRs (miR-9, -21, -135b and-146b) in the lungs. Using miR-specific antagomirs we inhibited the CS-induced miRs and demonstrated that targeting CS-induced miRs may be an effective therapy in COPD treatment. We showed that CS-induced miR-9 and miR-21 promote airway inflammation and small airway remodelling and worsened lung function in experimental COPD. Treatment with miR-9- and miR-21-specific antagomirs, Ant-9 and Ant-21 lead to reduced airway inflammation, suppressed small airway remodelling and improvement in impaired lung function. Thus indicating a potential pathogenic role for the miRs in the development of COPD. Our studies identified increased levels of oxidative stress responsive transcription factor NRF2 and restored levels of cytokine signalling suppressor protein, SOCS5 to play important roles reducing the COPD pathologies. We also identified a novel miR-21-dependent pro-inflammatory pathway in COPD pathogenesis. We demonstrated that CS-exposure induces a miR-21/SATB1/S100A9/NF-κB axis in the lungs and thus advances our understanding of the pro-inflammatory role of miR-21 in COPD pathogenesis. Our studies also demonstrated that CS-miR-135b promotes neutrophilic airway inflammation and showed reduced BMPR2 expression, a potential mediator of macrophage recruitment and may play a role in small airway remodelling in experimental COPD. We also demonstrated that treatment with Ant-135b and Ant-146b suppresses airway remodelling and emphysema-like alveolar enlargement. This indicates that miR-135b and miR-146b may play potentially overlapping roles in mediating COPD pathogenesis. We also showed that miR-135b and miR-146b may promote emphysema through VEGF and IRAK1 and TRAF6-dependent mechanisms. Furthermore our studies demonstrated for the first time that inhibition of combinations of CS-induced miRs, may have beneficial effects in reducing some features of COPD. Further we also showed that combined inhibition of CS-induced miR-21 and miR-146b may be more effective in suppressing key features of COPD. Collectively, these studies further extend our understanding of the pathogenesis of COPD and identifies CS-induced miRs as potential novel therapeutic strategies in the treatment of COPD. Therapeutic targeting of a CS-induced miR or in combination may be more beneficial as miRs regulate multiple pathogenic pathways. Further, exploration of the CS-induced miR-dependent mechanisms identified in our studies may assist in the development of miR-based therapeutic strategies for the treatment of COPD