Nicotinic Acetylcholine Receptors in the Respiratory Tract

Nicotinic acetylcholine receptors (nAChR) are widely distributed in neuronal and nonneuronal tissues, where they play diverse physiological roles. In this review, we highlight the recent findings regarding the role of nAChR in the respiratory tract with a special focus on the involvement of nAChR in the regulation of multiple processes in health and disease. We discuss the role of nAChR in mucociliary clearance, inflammation, and infection and in airway diseases such as asthma, chronic obstructive pulmonary disease, and cancer. The subtype diversity of nAChR enables differential regulation, making them a suitable pharmaceutical target in many diseases. The stimulation of the α3β4 nAChR could be beneficial in diseases accompanied by impaired mucociliary clearance, and the anti-inflammatory effect due to an α7 nAChR stimulation could alleviate symptoms in diseases with chronic inflammation such as chronic obstructive pulmonary disease and asthma, while the inhibition of the α5 nAChR could potentially be applied in non-small cell lung cancer treatment. However, while clinical studies targeting nAChR in the airways are still lacking, we suggest that more detailed research into this topic and possible pharmaceutical applications could represent a valuable tool to alleviate the symptoms of diverse airway diseases

Large-scale cross-sectional online survey on patient-neurologist communication, burden of disease assessment and disease monitoring in people with multiple sclerosis

Background Management of multiple sclerosis (MS) requires a high level of communication between health care professionals (HCPs) and people with MS (pwMS) including profound investigation and discussion of symptoms to identify therapeutic needs. For treatment decisions, monitoring of disease activity is important, in this respect self-monitoring devices and apps, as well as magnetic resonance imaging are important tools. Methods MS Perspectives is a cross-sectional online survey conducted in Germany which was designed to collect data, among others, on the communication between pwMS and HCPs regarding treatment goals, symptom assessment, usage of devices and apps to self-monitor health functions, as well as to identify patients' attitude toward the role of magnetic resonance imaging (MRI). Between December 2021 and February 2022, 4,555 pwMS completed the survey. Results In total, 63.7% of participants reported that treatment goals have been discussed with their HCPs. Symptoms worsening in the past 12 months independent of relapses was more often reported by pwMS than inquired by HCPs, according to patients' report. Devices or apps for health monitoring were used by less than half of participants. Frequency of MRI controls was much lower in participants with longer compared to shorter disease duration (47.5 vs. 86.3%). The proportion of patients with annual or semiannual scans was highest among pwMS receiving infusion therapy (93.5%), followed by oral medication (82.5%) and injectables (73.4%), and lowest for pwMS without immunotherapy (58.2%). Conclusion MS Perspectives identified a rather low patient involvement regarding treatment goals and symptom assessment in clinical practice. Regarding this and our findings for health self-monitoring and MRI usage, strategies for improving patient-HCP communication and disease monitoring may be considered

Chemosensory cells in the respiratory tract as crucial regulators of innate immune responses

During recent years chemosensory cells in extraoral tissues have been established as mediators for the detection and regulation of innate immune processes in response to pathogens. Under physiological conditions, chemosensory cells are present throughout the respiratory epithelium of the upper and lower airways as well as in the main olfactory epithelium. Additionally, they emerge in the alveolar region of the lung upon viral infections. Chemosensory cells in the upper and the lower airways detect signalling molecules from gram-positive and gram-negative bacteria as well as aeroallergens and fungi. Upon stimulation they release multiple molecules, such as the transmitter acetylcholine, the cysteinyl leukotriene E4 and the cytokine interleukin-25, which act as autocrine and paracrine signals and thereby orchestrate the innate immune responses in the respiratory system. Activation of chemosensory cells stimulates various immune cells, e.g. type 2 innate lymphoid cells, modulates mucociliary clearance and induces a protective neurogenic inflammation. This review compiles and discusses recent findings regarding chemosensory cell function in the respiratory tract

Prolonged-release fampridine for the treatment of myoclonus after cervical myelitis: a case report

Prolonged-release fampridine (PR-FAM), a potassium channel blocker, is approved for improving walking ability in patients with multiple sclerosis (MS). Beyond this, positive effects on other MS symptoms like fatigue, cognition, and tremor have been described. To our knowledge, a positive effect of PR-FAM on spinal myoclonus has not been described so far. Here, we report a 32-year-old female with myoclonus after cervical myelitis affecting both hands which markedly improved after administration of PR-FAM. Treatments used before such as carbamazepine or levetiracetam had to be withdrawn because of intolerable side effects or lack of efficacy. The positive effect of PR-FAM could be confirmed by transient suspension. PR-FAM may be considered as a treatment option in refractory spinal myoclonus after myelitis in selected cases

Nicotine stimulates ion transport via metabotropic β4 subunit containing nicotinic ACh receptors

Background and Purpose Mucociliary clearance is an innate immune process of the airways, essential for removal of respiratory pathogens. It depends on ciliary beat and ion and fluid homeostasis of the epithelium. We have shown that nicotinic ACh receptors (nAChRs) activate ion transport in mouse tracheal epithelium. Yet the receptor subtypes and signalling pathways involved remained unknown. Experimental Approach Transepithelial short circuit currents (ISC) of freshly isolated mouse tracheae were recorded using the Ussing chamber technique. Changes in [Ca2+]i were studied on freshly dissociated mouse tracheal epithelial cells. Key Results Apical application of the nAChR agonist nicotine transiently increased ISC. The nicotine effect was abolished by the nAChR antagonist mecamylamine. α‐Bungarotoxin (α7 antagonist) had no effect. The agonists epibatidine (α3β2, α4β2, α4β4 and α3β4) and A‐85380 (α4β2 and α3β4) increased ISC. The antagonists dihydro‐β‐erythroidine (α4β2, α3β2, α4β4 and α3β4), α‐conotoxin MII (α3β2) and α‐conotoxin PnIA (α3β2) reduced the nicotine effect. Nicotine‐ and epibatidine‐induced currents were unaltered in β2−/−mice, but in β4−/− mice no increase was observed. In the presence of thapsigargin (endoplasmatic reticulum Ca2+‐ATPase inhibitor) or the ryanodine receptor antagonists JTV‐519 and dantrolene there was a reduction in the nicotine‐effect, indicating involvement of Ca2+ release from intracellular stores. Additionally, the PKA inhibitor H‐89 and the TMEM16A (Ca2+‐activated chloride channel) inhibitor T16Ainh‐A01 significantly reduced the nicotine‐effect. Conclusion and Implications α3β4 nAChRs are responsible for the nicotine‐induced current changes via Ca2+ release from intracellular stores, PKA and ryanodine receptor activation. These nAChRs might be possible targets to stimulate chloride transport via TMEM16A

Correlation of room acoustic parameters and noise level in eating establishments

This article addresses the impact of the occupancy level, the average acoustic absorption and the so-called acoustic capacity of a space, which is proportional with the volume and inversely proportional with the reverberation time, on the behavior of talking people in an eating establishments. Four different settings were compared: two casual dining restaurants, a self-service student canteen and a small faculty club. The Lombard effect was observed in all cases. In a restaurant with an average amount of absorbing surface of 2.4 m2 or more per person, the sound pressure level increased with more than 3 dB per doubling of the number of people. Results for the student canteen show that people started to communicate less when the number of people present was so high that the absorbing surface dropped under 1.5 m2/person (80 people). The level even stopped to increase with increasing occupancy from 150 people present and beyond, corresponding with 0.8 m2 of absorbing surface per person. This is roughly consistent with an estimated value for the acoustic capacity of that space, which was 189 people (corresponding with a table occupancy of about 72%). In the latter circumstances, the background noise level, as expressed by LA,95 was as high as 69 dB. Overcoming this level for oral communication would require a not sustainable vocal effort. In the tests performed in other restaurants, the observed occupancy was below 60%, which, thanks to the higher number of absorbing surfaces in those restaurants, was well below the acoustic capacity

Human airway tuft cells influence the mucociliary clearance through cholinergic signalling

Background Airway tuft cells, formerly called brush cells have long been described only morphologically in human airways. More recent RNAseq studies described a chemosensory cell population, which includes tuft cells, by a distinct gene transcription signature. Yet, until which level in the tracheobronchial tree in native human airway epithelium tuft cells occur and if they function as regulators of innate immunity, e.g., by regulating mucociliary clearance, remained largely elusive. Methods We performed immunohistochemistry, RT-PCR and immunoblotting analyses for various tuft cell markers to confirm the presence of this cell type in human tracheal samples. Immunohistochemistry was conducted to study the distribution of tuft cells along the intrapulmonary airways in humans. We assessed the influence of bitter substances and the taste transduction pathway on mucociliary clearance in mouse and human tracheal samples by measuring particle transport speed. Results Tuft cells identified by the expression of their well-established marker POU class 2 homeobox 3 (POU2F3) were present from the trachea to the bronchioles. We identified choline acetyltransferase in POU2F3 expressing cells as well as the transient receptor potential melastatin 5 (TRPM5) channel in a small population of tracheal epithelial cells with morphological appearance of tuft cells. Application of bitter substances, such as denatonium, led to an increase in mucociliary clearance in human tracheal preparations. This was dependent on activation of the TRPM5 channel and involved cholinergic and nitric oxide signalling, indicating a functional role for human tuft cells in the regulation of mucociliary clearance. Conclusions We were able to detect tuft cells in the tracheobronchial tree down to the level of the bronchioles. Moreover, taste transduction and cholinergic signalling occur in the same cells and regulate mucociliary clearance. Thus, tuft cells are potentially involved in the regulation of innate immunity in human airways

Giant cell arteritis with vertebral artery involvement—baseline characteristics and follow-up of a monocentric patient cohort

Vertebral artery (VA) involvement in giant cell arteritis (GCA) has rarely been reported. We aimed to evaluate the prevalence, patients’ characteristics, and immunotherapies used in patients with GCA and VA involvement at diagnosis and 1 year follow-up, retrospectively including patients being diagnosed between January 2011 and March 2021 in our department. Clinical features, laboratory data, VA imaging, immunotherapy, and 1 year follow-up data were analyzed. Baseline characteristics were compared to GCA patients without VA involvement. Among all 77 cases with GCA, 29 patients (37.7%) had VA involvement, as diagnosed by imaging and/or clinical signs and symptoms. Gender distribution and erythrocyte sedimentation rate (ESR) were significantly different in the groups with and without VA involvement, with more women being affected (38/48 patients, 79.2%) and a significantly higher median ESR in patients without VA involvement (62 vs. 46 mm/h; p = 0.012). MRI and/or CT showed vertebrobasilar stroke at GCA diagnosis in 11 cases. 67/77 patients (87.0%) received high-dose intravenous glucocorticosteroids (GCs) at diagnosis, followed by oral tapering. Six patients were treated with methotrexate (MTX), one with rituximab, and five with tocilizumab (TCZ). 2/5 TCZ patients achieved clinical remission after 1 year, vertebrobasilar stroke within the first year occurred in 2/5 patients. Diagnosis of VA involvement might be underrecognized in GCA patients. VA imaging should be performed in elderly patients with vertebrobasilar stroke presenting with GCA symptoms, not to miss GCA as the etiology of stroke. Efficacy of immunotherapies in GCA with VA affection and long-term outcomes need to be investigated further