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

James P Hummel,Philip J Johnson,Steve Dimmer,Martin L Mayse

doi:10.1152/japplphysiol.00565.2018

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.

Highlights

Autonomic innervation of the lung is provided by the vagus nerve via the pulmonary plexus, which originates at the level of the main carina and extends nerve branches along each mainstem bronchi that terminate in distal airways
With the exception of the animal treated at low power, the Hering-Breuer reflex (HBR) was abolished or attenuated by the Targeted lung denervation (TLD) acutely (0 day) and at seven days postprocedure
The present study suggests that TLD produces an adequate lesion depth to reliably denervate pulmonary branches of the vagus and alter lung physiology

Summary

Introduction

Autonomic innervation of the lung is provided by the vagus nerve via the pulmonary plexus, which originates at the level of the main carina and extends nerve branches along each mainstem bronchi that terminate in distal airways. These nerves control airway relaxation and constriction using integrated networks of parasympathetic preganglionic neurons in the brainstem, postganglionic neurons in the lung, and sensory neurons in the nodose and jugular ganglia. Preganglionic efferent fibers coursing through these pulmonary branches of the vagal nerve provide signals to postganglionic neurons of bronchial ganglia via acetylcholine release. Longacting pharmacologic blockade of cholinergic nervous input (efferent input) has become a mainstay of treatment for COPD, resulting in marked improvements in dyspnea, frequency of exacerbations, and lung function [6, 30, 39]

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