Targeted lung denervation in sheep: durability of denervation and long-term histologic effects on bronchial wall and peribronchial structures

BACKGROUND: Targeted lung denervation (TLD), a novel bronchoscopic procedure which attenuates pulmonary nerve input to the lung to reduce the clinical consequences of neural hyperactivity, may be an important emerging treatment for COPD. While procedural safety and impact on clinical outcomes have recently been reported, the mechanism of action has not been reported. We explored the long-term pathologic and histopathologic effects in a sheep model of ablation of bronchial branches of the vagus nerve using a novel dual-cooled radiofrequency ablation catheter. METHODS: Nineteen sheep underwent circumferential ablation of both main bronchi with simultaneous balloon surface cooling using a targeted lung denervation system (Nuvaira, Inc., USA). Animals were followed over an extended time course (30, 365, and 640 days post procedure). At each time point, lung denervation (axonal staining in bronchial nerves), and effect on peribronchial structures near the treatment site (histopathology of bronchial epithelium, bronchial cartilage, smooth muscle, alveolar parenchyma, and esophagus) were quantified. One way analysis of variance (ANOVA) was performed to reveal differences between group means on normal data. Non-parametric analysis using Kruskal-Wallis Test was employed on non-normal data sets. RESULTS: No adverse clinical effects were observed in any sheep. Nerve axon staining distal to the ablation site was decreased by 60% at 30 days after TLD and efferent axon staining was decreased by >70% at 365 and 640 days. All treated airways exhibited 100% epithelial integrity. Effect on peribronchial structures was strictly limited to lung tissue immediately adjacent to the ablation site. Tissue structure 1 cm proximal and distal to the treatment area remained normal, and the pulmonary veins, pulmonary arteries, and esophagus were unaffected. CONCLUSIONS: The denervation of efferent axons induced by TLD therapy is durable and likely a contributing mechanism through which targeted lung denervation impacts clinical outcomes. Further, long term lung denervation did not alter the anatomy of the bronchioles or lung, as evaluated from both a gross and histologic perspective.