Introduction: Targeted lung denervation (TLD) is a novel bronchoscopic treatment for patients with Chronic Obstructive Pulmonary Disease (COPD). Increased parasympathetic drive causes inappropriate bronchoconstriction and mucus secretion in COPD. TLD involves the ablation of the pulmonary branches of the vagus nerve using radiofrequency energy, thereby reducing the release of neuronal acetylcholine (the principle parasympathetic neurotransmitter). The aim of this work is to further evaluate the mechanisms of TLD through analysis of its effects on airway epithelial gene expression.
Methods: This thesis includes data from 17 patients with moderate-to-severe COPD treated with TLD across three different multi-centre trials at the Royal Brompton Hospital: AIRFLOW 1 (n=5), AIRFLOW 2 (n=9) and AIRFLOW 3 (n=3). AIRFLOW-2 included a randomised, sham-controlled trial (TLD = 6, SHAM = 6), in which bronchial brush samples were taken for the primary analysis for this thesis: whole-genome RNA sequencing and transcriptomic pathway analysis. Secondary outcomes included measures of health-related quality-of-life, lung function, exercise capacity and airways inflammation.
Results: Only 16 genes were found to be differentially expressed after TLD, and no relevant mechanistic interpretation could be derived from these. However, the pathway analyses (Gene Set Enrichment Analysis and Overrepresentation Analysis) showed significant upregulation of gene sets related to the immune system in the TLD group. Upregulated pathways featured the anti-inflammatory cytokine IL-10, as well as interferons, which are important mediators in the immune response to viruses. No significant changes were seen in the secondary outcomes.
Conclusion: This thesis has demonstrated a potential anti-inflammatory and/or anti-viral effect of TLD in COPD. The full AIRFLOW-2 trial showed a protective effect of TLD against COPD exacerbations, and these results are suggestive of a possible immunological mechanism which has not been demonstrated to date. Changes in anti-inflammatory airway cytokines and interferons should be included in the mechanistic hypotheses for future TLD trials.