Absence of sympathetic innervation hampers the generation of tertiary lymphoid structures upon acute lung inflammation.

Tertiary lymphoid structures (TLS) are lymphoid organs present in inflammatory non-lymphoid tissues. Studies have linked TLS to favorable outcomes for patients with cancers or infectious diseases, but the mechanisms underlying their formation are not fully understood. In particular, secondary lymphoid organs innervation raises the question of sympathetic nerve fibers involvement in TLS organogenesis. We established a model of pulmonary inflammation based on 5 daily intranasal instillations of lipopolysaccharide (LPS) in immunocompetent mice. In this setting, lung lymphoid aggregates formed transiently, evolving toward mature TLS and disappearing when inflammation resolved. Sympathetic nerve fibers were then depleted using 6-hydroxydopamine. TLS quantification by immunohistochemistry showed a decrease in LPS-induced TLS number and surface in denervated mouse lungs. Although a reduction in alveolar space was observed, it did not impair overall pulmonary content of transcripts encoding TNF-α, IL-1ß and IFN-γ inflammation molecules whose expression was induced by LPS instillations. Immunofluorescence analysis of immune infiltrates in lungs of LPS-treated mice showed a drop in the proportion of CD23+ naive cells among CD19+ B220+ B cells in denervated mice whereas the proportion of other cell subsets remained unchanged. These data support the existence of neuroimmune crosstalk impacting lung TLS neogenesis and local naive B cell pool.

A vagal reflex evoked by airway closure.

Airway integrity must be continuously maintained throughout life. Sensory neurons guard against airway obstruction and, on a moment-by-moment basis, enact vital reflexes to maintain respiratory function1,2. Decreased lung capacity is common and life-threatening across many respiratory diseases, and lung collapse can be acutely evoked by chest wall trauma, pneumothorax or airway compression. Here we characterize a neuronal reflex of the vagus nerve evoked by airway closure that leads to gasping. In vivo vagal ganglion imaging revealed dedicated sensory neurons that detect airway compression but not airway stretch. Vagal neurons expressing PVALB mediate airway closure responses and innervate clusters of lung epithelial cells called neuroepithelial bodies (NEBs). Stimulating NEBs or vagal PVALB neurons evoked gasping in the absence of airway threats, whereas ablating NEBs or vagal PVALB neurons eliminated gasping in response to airway closure. Single-cell RNA sequencing revealed that NEBs uniformly express the mechanoreceptor PIEZO2, and targeted knockout of Piezo2 in NEBs eliminated responses to airway closure. NEBs were dispensable for the Hering-Breuer inspiratory reflex, which indicated that discrete terminal structures detect airway closure and inflation. Similar to the involvement of Merkel cells in touch sensation3,4, NEBs are PIEZO2-expressing epithelial cells and, moreover, are crucial for an aspect of lung mechanosensation. These findings expand our understanding of neuronal diversity in the airways and reveal a dedicated vagal pathway that detects airway closure to help preserve respiratory function.

Impaired hypoxic ventilatory drive induced by diabetic autonomic neuropathy, a cause of misdiagnosed severe cardiac events: brief report of two cases.

BACKGROUND: Sudden cardiac deaths are twice more frequent in diabetic patients with cardiac autonomic neuropathy. Sudden cardiac death etiologies remain unclear and no recommendations are made to identify factors associated with cardiorespiratory arrest in diabetic patients. We hypothesized, from two clinical cases, that impaired hypoxic ventilatory drive, induced by diabetic autonomic neuropathy, is a cause of misdiagnosed severe cardiac events. CASE PRESENTATION: We describe the cases of two patients with isolated low blood saturation on pulse oximeter during the systematic nurse check-up (77% and 85% respectively) contrasting with the absence of any complaint such as dyspnea, polypnea or other respiratory insufficiency signs observed during the clinical examination. Arterial blood gas measurements subsequently confirmed that blood oxygen saturation was low and both patients were indeed hypoxemic. Patient 1 suffered from vascular overload complicated by cardiac arrest caused by hypoxemia in light of the quick recovery observed after ventilation. Pulmonary edema was diagnosed in patient 2. The common denominator of these 2 cases described in this brief report is the absence of respiratory failure clinical signs contrasting with the presence of confirmed hypoxemia. Also, in both cases, such absence of precursory signs seems to be induced by an impaired ventilatory drive to hypoxemia. This appears to be related to the autonomic diabetic neuropathy encountered in those 2 patients. CONCLUSIONS: Therefore, we describe, in this brief report, cardiac autonomic neuropathy as a cause of impaired hypoxic ventilatory drive involved in severe acute cardiorespiratory events in two type 1 diabetic patients. We assume that altered response to hypoxemia due to cardiac autonomic neuropathy and non-functional central neurological breathing command could play a key role in sudden deaths among diabetic patients. An important point is that hypoxemia can be easily missed since no clinical signs of respiratory failure are reported in these two clinical cases. Systematic screening of cardiac autonomic neuropathy in diabetic patients and proactive detection of impaired hypoxic ventilatory drive for early management (e.g. treatment of hypoxemia) should be systematically undertaken in diabetic patients to prevent its dramatic consequences such as cardiorespiratory arrest and death.

Safety of denervation following targeted lung denervation therapy for COPD: AIRFLOW-1 3-year outcomes.

BACKGROUND: Targeted lung denervation (TLD) is a novel bronchoscopic therapy that disrupts parasympathetic pulmonary nerve input to the lung reducing clinical consequences of cholinergic hyperactivity. The AIRFLOW-1 study assessed safety and TLD dose in patients with moderate-to-severe, symptomatic COPD. This analysis evaluated the long-term impact of TLD on COPD exacerbations, pulmonary function, and quality of life over 3 years of follow up. METHODS: TLD was performed in a prospective, energy-level randomized (29 W vs 32 W power), multicenter study (NCT02058459). Additional patients were enrolled in an open label confirmation phase to confirm improved gastrointestinal safety after procedural modifications. Durability of TLD was evaluated at 1, 2, and 3 years post-treatment and assessed through analysis of COPD exacerbations, pulmonary lung function, and quality of life. RESULTS: Three-year follow-up data were available for 73.9% of patients (n = 34). The annualized rate of moderate to severe COPD exacerbations remained stable over the duration of the study. Lung function (FEV1, FVC, RV, and TLC) and quality of life (SGRQ-C and CAT) remained stable over 3 years of follow-up. No new gastrointestinal adverse events and no unexpected serious adverse events were observed. CONCLUSION: TLD in COPD patients demonstrated a positive safety profile out to 3 years, with no late-onset serious adverse events related to denervation therapy. Clinical stability in lung function, quality of life, and exacerbations were observed in TLD treated patients over 3 years of follow up.

REsidual Neuromuscular Block Prediction Score Versus Train-of-Four Ratio and Respiratory Outcomes: A Retrospective Cohort Study.

BACKGROUND: Residual neuromuscular blockade is associated with an increased incidence of postoperative respiratory complications. The REsidual neuromuscular block Prediction Score (REPS) identifies patients at high risk for residual neuromuscular blockade after surgery. METHODS: A total of 101,510 adults undergoing noncardiac surgery under general anesthesia from October 2005 to December 2018 at a tertiary care center in Massachusetts were analyzed for the primary outcome of postoperative respiratory complications (invasive mechanical ventilation requirement within 7 postoperative days or immediate postextubation desaturation [oxygen saturation {Spo2} <90%] within 10 minutes). The primary objective was to assess the association between the REPS and respiratory complications. The secondary objective was to compare REPS and train-of-four (TOF) ratio <0.90 on the strength of their association with respiratory complications. RESULTS: A high REPS (≥4) was associated with an increase in odds of respiratory complications (adjusted odds ratio [OR], 1.13 [95% confidence interval {CI}, 1.06-1.21]; P < .001). In 6224 cases with available TOF ratio measurements, a low TOF ratio (<0.9) was associated with respiratory complications (adjusted OR, 1.43 [95% CI, 1.11-1.85]; P = .006), whereas a high REPS was not (adjusted OR, 0.96 [95% CI, 0.74-1.23]; P = .73) (P = .018 for comparison between ORs). CONCLUSIONS: The REPS may be implemented as a screening tool to encourage clinicians to use quantitative neuromuscular monitoring in patients at risk of residual neuromuscular blockade. A positive REPS should be followed by a quantitative assessment of the TOF ratio.

Functional evidence of low-pressure cardiopulmonary baroreceptor reinnervation 1 year after heart transplantation.

PURPOSE: Heart transplantation (HTx) implies denervation of afferent neural connections. Reinnervation of low-pressure cardiopulmonary baroreceptors might impact the development and treatment of hypertension, but little is known of its occurrence. The present prospective study investigated possible afferent reinnervation of low-pressure cardiopulmonary baroreceptors during the first year after heart transplantation. METHODS: A total of 50 heart transplant recipients (HTxRs) were included and were evaluated 7-12 weeks after transplant surgery, with follow-up 6 and 12 months later. In addition, a reference group of 50 healthy control subjects was examined once. Continuous, non-invasive recordings of cardiovascular variables were carried out at supine rest, during 15 min of 20° head-up tilt, during Valsalva maneuver and during 1 min of 30% maximal voluntary handgrip. In addition, routine clinical data including invasive measurements were used in the analyses. RESULTS: During the first year after HTx, the heart rate (HR) response to 20° head-up tilt partly normalized, a negative relationship between resting mean right atrial pressure and HR tilt response developed, low-frequency variability of the RR interval and systolic blood pressure at supine rest increased, and the total peripheral resistance response to Valsalva maneuver became stronger. CONCLUSION: Functional assessments suggest that afferent reinnervation of low-pressure cardiopulmonary receptors occurs during the first year after heart transplantation, partially restoring reflex-mediated responses to altered cardiac filling.

Macrophage-derived netrin-1 drives adrenergic nerve-associated lung fibrosis.

Fibrosis is a macrophage-driven process of uncontrolled extracellular matrix accumulation. Neuronal guidance proteins such as netrin-1 promote inflammatory scarring. We found that macrophage-derived netrin-1 stimulates fibrosis through its neuronal guidance functions. In mice, fibrosis due to inhaled bleomycin engendered netrin-1-expressing macrophages and fibroblasts, remodeled adrenergic nerves, and augmented noradrenaline. Cell-specific knockout mice showed that collagen accumulation, fibrotic histology, and nerve-associated endpoints required netrin-1 of macrophage but not fibroblast origin. Adrenergic denervation; haploinsufficiency of netrin-1's receptor, deleted in colorectal carcinoma; and therapeutic α1 adrenoreceptor antagonism improved collagen content and histology. An idiopathic pulmonary fibrosis (IPF) lung microarray data set showed increased netrin-1 expression. IPF lung tissues were enriched for netrin-1+ macrophages and noradrenaline. A longitudinal IPF cohort showed improved survival in patients prescribed α1 adrenoreceptor blockade. This work showed that macrophages stimulate lung fibrosis via netrin-1-driven adrenergic processes and introduced α1 blockers as a potentially new fibrotic therapy.

Disrupted local innervation results in less VIP expression in CF mice tissues.

Vasoactive Intestinal Peptide (VIP) is the major physiological agonist of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) chloride channel activity. VIP functions as a neuromodulator and neurotransmitter secreted by neurons innervating all exocrine glands. VIP is also a potent vasodilator and bronchodilator that regulates exocrine gland secretions, contributing to local innate defense by stimulating the movement of water and chloride transport across intestinal and tracheobronchial epithelia. Previous human studies have shown that the rich intrinsic neuronal networks for VIP secretion around exocrine glands could be lost in tissues from patients with cystic fibrosis. Our research has since confirmed, in vitro and in vivo, the need for chronic VIP exposure to maintain functional CFTR chloride channels at the cell surface of airways and intestinal epithelium, as well as normal exocrine tissues morphology [1]. The goal of the present study was to examine changes in VIP in the lung, duodenum and sweat glands of 8- and 17-weeks old F508del/F508del mice and to investigate VIPergic innervation in the small intestine of CF mice, before important signs of the disease development. Our data show that a low amount of VIP is found in CF tissues prior to tissue damage. Moreover, we found a specific reduction in VIPergic and cholinergic innervation of the small intestine. The general innervation of the primary and secondary myenteric plexus was lost in CF tissues, with the presence of enlarged ganglionic cells in the tertiary layer. We propose that low amount of VIP in CF tissues is due to a reduction in VIPergic and cholinergic innervation and represents an early defect that constitutes an aggravating factor for CF disease progression.

Activation of cholinergic anti-inflammatory pathway involved in therapeutic actions of α-mangostin on lipopolysaccharide-induced acute lung injury in rats.

INTRODUCTION: Alpha-mangostin (MAN) possesses a wide variety of pharmacological effects. In this study, we investigated its effect on cholinergic anti-inflammatory pathway (CAP), and tested if CAP regulation was involved in the therapeutic action on acute lung injury (ALI). METHODS: Male Sprague Dawley rats were pre-treated with MAN (40 mg/kg) for 3 days and ALI was induced with an intraperitoneal injection of lipopolysaccharide (LPS). Certain rats received monolateral vagotomy or sham surgery. The effects on inflammatory reactions and relevant pathways in ALI rats or LPS pre-treated RAW 264.7 cells were investigated by histological, immunohistochemical, immunoblotting, RT-qPCR, and immunofluorescence assays, while levels of proinflammatory cytokines, acetylcholine (Ach) and the enzymatic activity of acetylcholinesterase (AchE) were determined by corresponding quantitative kits. RESULTS: Oral administration of MAN reduced the severity of ALI, while vagotomy surgery antagonized this effect. MAN restored the decline in α7 nicotinic acetylcholine receptor (α7nAchR) in the lungs of ALI rats, and promoted the expression of α7nAchR and choline acetyltransferase (CHAT) in RAW 264.7 cells. Although AchE expression was barely affected by MAN at 5 µg/ml, its catalytic activity was reduced by almost 95%. Extracellular rather than intracellular Ach was notably raised shortly after MAN treatment. Furthermore, MAN at 5 µg/ml effectively inhibited LPS-induced increase in phosphorylation and nucleus translocation of p65 subunit, and secretion of TNF-α and IL-1ß, which was then offset by methyllycaconitine citrate hydrate. CONCLUSION: MAN activated CAP by increasing peripheral Ach and up-regulating α7nAchR expression, which eventually led to NF-κB inhibition and remission of acute inflammations.

Heart rate variability and pulmonary dysfunction in rats subjected to hemorrhagic shock.

BACKGROUND: The activity of autonomic nervous system and its association with organ damage have not been entirely elucidated in hemorrhagic shock. The aim of this study was to investigate heart rate variability (HRV) and pulmonary gas exchange in hemorrhagic shock during unilateral subdiaphragmatic vagotomy. METHODS: Male Sprague Dawley rats were randomly assigned into groups of Sham, vagotomized (Vag), hemorrhagic shock (HS) and Vag + HS. HS was induced in conscious animals by blood withdrawal until reaching to mean arterial blood pressure (MAP) of 40 ± 5 mmHg. Then, it was allowed to MAP returning toward the basal values. MAP and heart rate (HR) were recorded throughout the experiments, HRV components of low (LF, sympathetic index), high (LH, parasympathetic index), and very low (VLF, injury index) frequencies and the LF/HF ratio calculated, and the lung histological and blood gas parameters assessed. RESULTS: In the initial phases of HS, the increase in HR with no change in MAP were observed in both HS and Vag + HS groups, while LF increased only in the HS group. In the second phase, HR and MAP decreased sharply in the HS group, whereas, only MAP decreased in the Vag + HS group. Meanwhile, LF and HF increased relative to their baselines in the HS and Vag + HS groups, even though the values were much pronounced in the HS group. In the third phase, HR, MAP, LF, HF, and the LF/HF ratio were returned back to their baselines in both HS and Vag + HS groups. In the Vag + HS group, the VLF was lower and HR was higher than those in the other groups. Furthermore, blood gas parameters and lung histology indicated the impairment of gas exchange in the Vag + HS group. CONCLUSIONS: The sympathetic activity is predominant in the first phase, whereas the parasympathetic activity is dominant in the second and third phases of hemorrhagic shock. There is an inverse relationship between the level of VLF and lung injury in vagotomized animals subjected to hemorrhagic shock.

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.

Feasibility, effectiveness, and safety of a novel cryo-balloon targeted lung denervation technique in an animal model.

BACKGROUND AND OBJECTIVE: Targeted lung denervation (TLD) is a pulmonary interventional procedure for COPD that aims to disrupt parasympathetic nerve input to the lung to reduce the clinical consequences of cholinergic hyperactivity. TLD has been proven to be a safe procedure and effectively alleviate symptoms and reduce the onset of exacerbation. In the present study, we developed a novel cryo-balloon TLD system and evaluated its feasibility, safety, and effectiveness. METHODS: A preclinical study was performed on twelve sheep, four were tested for airway resistance alterations before and after TLD, two were tested for the Hering-Breuer reflex (HBR) and the remaining six sheep were evaluated for 28 days to assess the safety and effectiveness of the procedure. RESULTS: After an observation period of 28 days, significant disruption of vagal innervation to the lung could be validated by both histological and physiological assessments. The operation time was shorter than traditional procedure, with minimal adjacent tissue injury and no device-related adverse events. CONCLUSIONS: The novel cryo-balloon TLD procedure was feasible, safe, and effective. In comparison with the traditional procedure, this treatment system required shorter operation time and caused less denervation-induced damage to adjacent tissues.

DT-0111: a novel drug-candidate for the treatment of COPD and chronic cough.

BACKGROUND: Extracellular adenosine 5'-triphosphate (ATP) plays important mechanistic roles in pulmonary disorders in general and chronic obstructive pulmonary disease (COPD) and cough in particular. The effects of ATP in the lungs are mediated to a large extent by P2X2/3 receptors (P2X2/3R) localized on vagal sensory nerve terminals (both C and Aδ fibers). The activation of these receptors by ATP triggers a pulmonary-pulmonary central reflex, which results in bronchoconstriction and cough, and is also proinflammatory due to the release of neuropeptides from these nerve terminals via the axon reflex. These actions of ATP in the lungs constitute a strong rationale for the development of a new class of drugs targeting P2X2/3R. DT-0111 is a novel, small, water-soluble molecule that acts as an antagonist at P2X2/3R sites. METHODS: Experiments using receptor-binding functional assays, rat nodose ganglionic cells, perfused innervated guinea pig lung preparation ex vivo, and anesthetized and conscious guinea pigs in vivo were performed. RESULTS: DT-0111 acted as a selective and effective antagonist at P2X2/3R, that is, it did not activate or block P2YR; markedly inhibited the activation by ATP of nodose pulmonary vagal afferents in vitro; and, given as an aerosol, inhibited aerosolized ATP-induced bronchoconstriction and cough in vivo. CONCLUSIONS: These results indicate that DT-0111 is an attractive drug-candidate for the treatment of COPD and chronic cough, both of which still constitute major unmet clinical needs. The reviews of this paper are available via the supplementary material section.

Safety and Dose Study of Targeted Lung Denervation in Moderate/Severe COPD Patients.

RATIONALE: Targeted lung denervation (TLD) is a novel bronchoscopic treatment for the disruption of parasympathetic innervation of the lungs. OBJECTIVES: To assess safety, feasibility, and dosing of TLD in patients with moderate to severe COPD using a novel device design. METHODS: Thirty patients with COPD (forced expiratory volume in 1 s 30-60%) were 1:1 randomized in a double-blinded fashion to receive TLD with either 29 or 32 W. Primary endpoint was the rate of TLD-associated adverse airway effects that required treatment through 3 months. Assessments of lung function, quality of life, dyspnea, and exercise capacity were performed at baseline and 1-year follow-up. An additional 16 patients were enrolled in an open-label confirmation phase study to confirm safety improvements after procedural enhancements following gastrointestinal adverse events during the randomized part of the trial. RESULTS: Procedural success, defined as device success without an in-hospital serious adverse event, was 96.7% (29/30). The rate of TLD-associated adverse airway effects requiring intervention was 3/15 in the 32 W versus 1/15 in the 29 W group, p = 0.6. Five patients early in the randomized phase experienced serious gastric events. The study was stopped and procedural changes made that reduced both gastrointestinal and airway events in the subsequent phase of the randomized trial and follow-up confirmation study. Improvements in lung function and quality of life were observed compared to baseline values for both doses but were not statistically different. CONCLUSIONS: The results demonstrate acceptable safety and feasibility of TLD in patients with COPD, with improvements in adverse event rates after procedural enhancements.

Prolongation of bronchopulmonary C-fiber-mediated apnea by prenatal nicotinic exposure in rat pups: role of 5-HT3 receptors.

Prenatal nicotinic exposure (PNE) reportedly sensitizes bronchopulmonary C-fibers (PCFs) and prolongs PCF-mediated apnea in rat pups, contributing to the pathogenesis of sudden infant death syndrome. Serotonin, or 5-hydroxytryptamine (5-HT), induces apnea via acting on 5-HT receptor 3 (5-HT3R) in PCFs, and among the 5-HT3R subunits, 5-HT3B is responsible for shortening the decay time of 5-HT3R-mediated currents. We examined whether PNE would promote pulmonary 5-HT secretion and prolong the apnea mediated by 5-HT3Rs in PCFs via affecting the 5-HT3B subunit. To this end, the following variables were compared between the control and PNE rat pups: 1) the 5-HT content in bronchoalveolar lavage fluid, 2) the apneic response to the right atrial bolus injection of phenylbiguanide (a 5-HT3R agonist) before and after PCF inactivation, 3) 5-HT3R currents and the stimulus threshold of the action currents of vagal pulmonary C-neurons, and 4) the immunoreactivity (IR) and mRNA expression of 5-HT3A and 5-HT3B in these neurons. Our results showed that PNE up-regulated the pulmonary 5-HT concentration and strengthened the PCF 5-HT3R-mediated apnea. PNE significantly facilitated neural excitability by shortening the decay time of 5-HT3R currents, lowering the stimulus threshold, and increasing 5-HT3B IR. In summary, PNE prolongs the apnea mediated by 5-HT3Rs in PCFs, likely by increasing 5-HT3B subunits to enhance the excitability of 5-HT3 channels.-Zhao, L., Gao, X., Zhuang, J., Wallen, M., Leng, S., Xu, F. Prolongation of bronchopulmonary C-fiber-mediated apnea by prenatal nicotinic exposure in rat pups: role of 5-HT3 receptors.

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

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.

Vagotomy decreases the neuronal activities of medulla oblongata and alleviates neurogenic inflammation of airways induced by repeated intra-esophageal instillation of HCl in guinea pigs.

Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex.

Low-dose oral cadmium increases airway reactivity and lung neuronal gene expression in mice.

Inhalation of cadmium (Cd) is associated with lung diseases, but less is known concerning pulmonary effects of Cd found in the diet. Cd has a decades-long half-life in humans and significant bioaccumulation occurs with chronic dietary intake. We exposed mice to low-dose CdCl2 (10 mg/L in drinking water) for 20 weeks, which increased lung Cd to a level similar to that of nonoccupationally exposed adult humans. Cd-treated mice had increased airway hyperresponsiveness to methacholine challenge, and gene expression array showed that Cd altered the abundance of 443 mRNA transcripts in mouse lung. In contrast to higher doses, low-dose Cd did not elicit increased metallothionein transcripts in lung. To identify pathways most affected by Cd, gene set enrichment of transcripts was analyzed. Results showed that major inducible targets of low-dose Cd were neuronal receptors represented by enriched olfactory, glutamatergic, cholinergic, and serotonergic gene sets. Olfactory receptors regulate chemosensory function and airway hypersensitivity, and these gene sets were the most enriched. Targeted metabolomics analysis showed that Cd treatment also increased metabolites in pathways of glutamatergic (glutamate), serotonergic (tryptophan), cholinergic (choline), and catecholaminergic (tyrosine) receptors in the lung tissue. Protein abundance measurements showed that the glutamate receptor GRIN2A was increased in mouse lung tissue. Together, these results show that in mice, oral low-dose Cd increased lung Cd to levels comparable to humans, increased airway hyperresponsiveness and disrupted neuronal pathways regulating bronchial tone. Therefore, dietary Cd may promote or worsen airway hyperresponsiveness in multiple lung diseases including asthma.

[Bronchoscopic treatments for COPD].

Several non-surgical and minimally invasive bronchoscopic interventions, such as bronchoscopic lung volume reduction (BLVR) techniques, have been developed to treat patients with severe chronic obstructive pulmonary disease (COPD). BLVR has been studied for treatment in severe COPD patients with emphysema. BLVR with one-way endobronchial valves is reported to be effective for patients with a heterogeneous emphysema distribution and without inter-lobar collateral ventilation. For the patients with collateral ventilation, and for the patients with homogeneous emphysema, BLVR with lung volume reduction coil has shown promising results. Targeted lung denervation(TLD) is a novel bronchoscopic intervention based on ablation of parasympathetic nerves surrounding the main bronchi. TLD seems to be effective for COPD with chronic bronchitis phenotype. This review gives a general overview of BLVR with one-way valve and lung volume reduction coil, and TLD.

Preserving the pulmonary vagus nerve branches during thoracoscopic esophagectomy.

BACKGROUND: Pulmonary vagus branches are transected as part of a transthoracic esophagectomy and lymphadenectomy for cancer. This may contribute to the development of postoperative pulmonary complications. Studies in which sparing of the pulmonary vagus nerve branches during thoracoscopic esophagectomy is investigated are lacking. Therefore, this study aimed to determine the feasibility and pitfalls of sparing pulmonary vagus nerve branches during thoracoscopic esophagectomy. METHODS: In 10 human cadavers, a thoracoscopic esophagectomy was performed while sparing the pulmonary vagus nerve branches. The number of intact nerve branches, their distribution over the lung lobes and the number and location of the remaining lymph nodes in the relevant esophageal lymph node stations (7, 10R and 10L) were recorded during microscopic dissection. RESULTS: A median of 9 (range 5-16) right pulmonary vagus nerve branches were spared, of which 4 (0-12) coursed to the right middle/inferior lung lobe. On the left side, 10 (3-12) vagus nerve branches were spared, of which 4 (2-10) coursed to the inferior lobe. In 8 cases, lymph nodes were left behind, at stations 10R and 10L while sparing the vagus nerve branches. Lymph nodes at station 7 were always removed. CONCLUSIONS: Sparing of pulmonary vagus nerve branches during thoracoscopic esophagectomy is feasible. Extra care should be given to the dissection of peribronchial lymph nodes, station 10R and 10L.