Physiologic and histopathologic effects of targeted lung denervation in an animal model

Abstract

Parasympathetic efferent innervation of the lung is the primary source of lung acetylcholine. Inhaled long-acting anticholinergics improve lung function and symptoms in patients with chronic obstructive pulmonary disease. Targeted lung denervation (TLD), a bronchoscopic procedure intended to disrupt pulmonary parasympathetic inputs, is an experimental treatment for chronic obstructive pulmonary disease. The physiologic and histologic effects of TLD have not previously been assessed. Eleven sheep and two dogs underwent circumferential ablation of the main bronchi with simultaneous balloon surface cooling using a lung denervation system (Nuvaira, Inc., Minneapolis, MN). Changes in pulmonary air flow resistance were monitored before and following TLD. Four animals were assessed for the presence or abolishment of the sensory axon-mediated Hering-Breuer reflex before and following TLD. Six sheep were histologically evaluated 30 days post-TLD for the extent of lung denervation (axonal staining) and effect on peribronchial structures near the treatment site. No adverse clinical effects were seen in any treated animals. TLD produced a ~30% reduction in pulmonary resistance and abolished the sensory-mediated Hering-Breuer reflex. Axonal staining was consistently decreased 60% at 30 days after TLD. All treated airways exhibited 100% epithelial integrity. Damage to other peribronchial structures was minimal. Tissue 1 cm proximal and distal to the treatment was normal, and the esophagus and periesophageal vagus nerve branches were unaffected. TLD treatment effectively denervates the lung while protecting the bronchial epithelium and minimizing effects on peribronchial structures.NEW & NOTEWORTHY The feasibility of targeted lung denervation, a new minimally invasive therapy for obstructive lung disease, has been demonstrated in humans with preliminary clinical studies demonstrating improvement in symptoms, pulmonary function, and exercise capacity in patients with chronic obstructive pulmonary disease. This preclinical animal study demonstrates the ability of targeted lung denervation to disrupt vagal inputs to the lung and details its physiologic and histopathologic effects.

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

“…Disruption of efferent input was confirmed by a decrease in airway resistance, and loss of sensory input was confirmed by loss of the Herring-Brewer reflex. Acute preservation of the bronchial mucosa at TLD treatment sites, and prevention of excessive collateral damage to other critical peribronchial structures (e.g., esophagus, major blood vessels, heart, and lung) was reported out to 30 days in these earlier studies [20]. The current manuscript details the pathologic and histopathologic effects of TLD in a sheep model, with animals followed out to 640 days after the procedure.…”

“…Nineteen sheep (37 airways) underwent the TLD procedure in both main bronchi with simultaneous balloon surface cooling using a lung denervation system (Nuvaira, Inc., USA), as previously described in detail [20]. All studies were conducted under the guidance of an Institutional Animal Care and Use committee.…”

“…ChAT analysis, which allowed for the lowest number of animals sacrificed. The TLD treatment effect has been previously shown to be distal to the ablation zone, with proximal locations outside the zone of tissue ablation representative of healthy control tissue [20]. At each time point, gross evaluation of tissue, surface protection at the treatment site (histopathology of bronchial epithelium), effect on bronchial and peribronchial structures near the treatment site (histopathology of bronchial cartilage, vasculature, smooth muscle, alveolar parenchyma, and esophagus) and lung denervation (axonal staining in bronchial nerves) were quantified at the treatment site, distal to the treatment site, and proximal to the treatment site with the proximal site serving as a control for each animal.…”

“…This change likely confounds inhaled therapy distribution and may contribute to the continued incidence of exacerbations reported in up to 70% of patients on optimal inhaled triple therapy [16]. Surgical denervation of pulmonary vagal inputs has resulted in marked decreases in airway resistance [6,[17][18][19][20][21][22]; however, the high morbidity and mortality associated with surgical denervation due to difficulty in approaching the pulmonary branches of the vagus nerve [23] has limited the utility of this approach. A less invasive and safer way to reliably ablate the pulmonary inputs of the vagus would therefore represent a promising novel therapeutic strategy in COPD.…”

“…Targeted Lung Denervation (TLD) seeks to ablate the bronchial vagal nerve fibers to denervate the lung, via a minimally invasive procedure which has been described in detail elsewhere [20]. Denervation decreases basal smooth muscle tone in the airways, may also reduce inflammation and mucous secretion [24], and blunts airway hyperresponsiveness [25][26][27] .…”