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

Abstract

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. Nonparametric 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.

New bronchoscopic treatment modalities for patients with chronic bronchitis

“…In this study, efferent axon staining was decreased by >70% at 365 and 640 days. Furthermore, tissue structure 1 cm proximal and distal to the treated area remained normal and there were no serious effects in the pulmonary veins and arteries and the oesophagus [34].…”

“…Pre-clinical studies Before patient testing, multiple bench and animal studies were performed, two using the same system and power used in the clinical trials [33,34]. The first study was performed in 11 sheep and two dogs and showed that the treatment reduced pulmonary airway resistance, abolished the Hering-Breuer reflex and consistently resulted in bronchial wall fibrosis to a depth which engulfed nearly all pulmonary branches of the vagal nerve [33].…”

Bronchoscopic Targeted Lung Denervation in Patients with Severe Asthma: Preliminary Findings

“…TLD could have the advantage over pharmacologic treatments that it targets the nerve directly, but still it is questionable whether all nerve branches can be reached and what the sustainability of the treatment is, with regard to, for example, nerve regeneration. Recently, an animal study with efferent neuron staining showed absence of regeneration up to 640 days after TLD treatment [19]. Interestingly, the bronchodilator response to LAMA was maintained after TLD in COPD patients, and therefore TLD could be considered an add-on treatment instead of replacement of LAMA therapy [20].…”

Bronchoscopic interventions for chronic bronchitis

“…Following TLD, studies have shown a decrease in the axonal staining by approximately 60% to 70%, distal to the ablation site at 30 days, while effectively protecting peri-bronchial structures and the perioesophageal vagal nerve branches. This effect on efferent axon staining was demonstrated at 365 and 640 days, indicating a durable effect [41]. Transcriptomic analyses of airway mucosal brush samples collected at 3-month post-TLD, have shown a reduced expression of acetylcholine related genes [42 && ].…”