Metachrony drives effective mucociliary transport via a calcium-dependent mechanism.

The mucociliary transport apparatus is critical for maintaining lung health via the coordinated movement of cilia to clear mucus and particulates. A metachronal wave propagates across the epithelium when cilia on adjacent multiciliated cells beat slightly out of phase along the proximal-distal axis of the airways in alignment with anatomically directed mucociliary clearance. We hypothesized that metachrony optimizes mucociliary transport (MCT) and that disruptions of calcium signaling would abolish metachrony and decrease MCT. We imaged bronchi from human explants and ferret tracheae using micro-optical coherence tomography (µOCT) to evaluate airway surface liquid depth (ASL), periciliary liquid depth (PCL), cilia beat frequency (CBF), MCT, and metachrony in situ. We developed statistical models that included covariates of MCT. Ferret tracheae were treated with BAPTA-AM (chelator of intracellular Ca2+), lanthanum chloride (nonpermeable Ca2+ channel competitive antagonist), and repaglinide (inhibitor of calaxin) to test calcium dependence of metachrony. We demonstrated that metachrony contributes to mucociliary transport of human and ferret airways. MCT was augmented in regions of metachrony compared with nonmetachronous regions by 48.1%, P = 0.0009 or 47.5%, P < 0.0020 in humans and ferrets, respectively. PCL and metachrony were independent contributors to MCT rate in humans; ASL, CBF, and metachrony contribute to ferret MCT rates. Metachrony can be disrupted by interference with calcium signaling including intracellular, mechanosensitive channels, and calaxin. Our results support that the presence of metachrony augments MCT in a calcium-dependent mechanism.NEW & NOTEWORTHY We developed a novel imaging-based analysis to detect coordination of ciliary motion and optimal coordination, a process called metachrony. We found that metachrony is key to the optimization of ciliary-mediated mucus transport in both ferret and human tracheal tissue. This process appears to be regulated through calcium-dependent mechanisms. This study demonstrates the capacity to measure a key feature of ciliary coordination that may be important in genetic and acquired disorders of ciliary function.

A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Editorial for special issue-human precision cut lung slices: an Ex vivo platform for therapeutic target discovery and drug testing in lung disease.

Publications utilizing precision cut lung slices (PCLS) steadily increased from the 1970's, with a significant increase in 2010, to tripling by 2023. PCLS have been used to study a vast array of pulmonary diseases and exposures to pathogens and toxicants to understand pathogenesis of disease but also to examine basic cellular mechanisms that underly lung biology. This Special Issue will highlight new, exciting, and novel research using PCLS, while acknowledging the substantial fund of knowledge that has been gained using this platform.

Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery.

Precision Cut Lung Slices (PCLS) have emerged as a sophisticated and physiologically relevant ex vivo model for studying the intricacies of lung diseases, including fibrosis, injury, repair, and host defense mechanisms. This innovative methodology presents a unique opportunity to bridge the gap between traditional in vitro cell cultures and in vivo animal models, offering researchers a more accurate representation of the intricate microenvironment of the lung. PCLS require the precise sectioning of lung tissue to maintain its structural and functional integrity. These thin slices serve as invaluable tools for various research endeavors, particularly in the realm of airway diseases. By providing a controlled microenvironment, precision-cut lung slices empower researchers to dissect and comprehend the multifaceted interactions and responses within lung tissue, thereby advancing our understanding of pulmonary pathophysiology.

Yawning and airway physiology: a scoping review and novel hypothesis.

BACKGROUND AND PURPOSE: Yawning is a stereotypical complex muscular movement and is commonly executed by most vertebrates. In seconds, the entire airway is fully dilated and surrounding muscles are powerfully stretched, most prominently around the pharynx. To date, yawning has been rarely studied, and as of yet there is no consensus on its main function. MATERIAL AND METHODS: To investigate a mechanical airway function for yawning, a literature search was conducted to relate the frequency of yawning and obstructive airway conditions. RESULTS: The results show that changes in obstructive airway conditions and alteration of the frequency of yawning are temporally related. INTERPRETATION: These relationships, however, cannot be interpreted as causal, nor can they be extrapolated to explain the function of yawning. Yet airway management and yawning share many physiological characteristics. We therefore propose a novel hypotheses: yawning plays a significant role in airway physiology by muscle repositioning and widening the airway lumen, thereby securing long-term oxygenation.

Advances in asthma: New understandings of asthma's natural history, risk factors, underlying mechanisms, and clinical management.

The last 2 years yielded a proliferation of high-quality asthma research. These include new understandings of the incidence and natural history of asthma, findings on the effects of exposure to air pollution, allergens, and intake of acetaminophen, soy isoflavones, and polyunsaturated fatty acids, and exposure to microbial products. The past 2 years have benefited from great strides in determining potential mechanisms of asthma development and asthma exacerbations. These novel understandings led to identification and development of exciting new avenues for potential therapeutic intervention. Finally, there has been significant progress made in the development of tools to facilitate the diagnosis of asthma and measurement of airway physiology and in precision diagnostic approaches. Asthma guidelines were updated and new insights into the pharmacologic management of patients, including biologics, were reported. We review the most notable advances in the natural history of asthma, risk factors for the development of asthma, underlying mechanisms, diagnostic approaches, and treatments. Although greater knowledge of the mechanisms underlying responses and nonresponses to novel therapeutics and across asthma phenotypes would be beneficial, the progress over just the past 2 years has been immense and impactful.

The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial.

KEY POINTS: Recent animal and human physiology studies indicate that noradrenergic and muscarinic processes are key mechanisms that mediate pharyngeal muscle control during sleep. The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, whether these findings translate to the clinically relevant patient population of people with obstructive sleep apnoea (OSA), and the effects of the agents on OSA severity, are unknown. We found that reboxetine plus hyoscine butylbromide reduced OSA severity, including overnight hypoxaemia, via increases in pharyngeal muscle responsiveness, improvements in respiratory control and airway collapsibility without changing the respiratory arousal threshold. These findings provide mechanistic insight into the role of noradrenergic and anti-muscarinic agents on upper airway stability and breathing during sleep and are important for pharmacotherapy development for OSA. ABSTRACT: The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, the effects of this drug combination on obstructive sleep apnoea (OSA) severity are unknown. Accordingly, this study aimed to determine if reboxetine plus hyoscine butylbromide reduces OSA severity. Secondary aims were to investigate the effects on key upper airway physiology and endotypic traits. Twelve people with OSA aged 52 ± 13 years, BMI = 30 ± 5 kg/m2 , completed a double-blind, randomised, placebo-controlled, crossover trial (ACTRN12617001326381). Two in-laboratory sleep studies with nasal mask, pneumotachograph, epiglottic pressure sensor and bipolar fine-wire electrodes into genioglossus and tensor palatini muscles were performed separated by approximately 1 week. Each participant received either reboxetine (4 mg) plus hyoscine butylbromide (20 mg), or placebo immediately prior to sleep. Polysomnography, upper airway physiology and endotypic estimates of OSA were compared between conditions. Reboxetine plus hyoscine butylbromide reduced the apnoea/hypopnoea index by (mean ± SD) 17 ± 17 events/h from 51 ± 30 to 33 ± 22 events/h (P = 0.005) and nadir oxygen saturation increased by 6 ± 5% from 82 ± 5 to 88 ± 2% (P = 0.002). The drug combination increased tonic genioglossus muscle responsiveness during non-REM sleep (median [25th, 75th centiles]: -0.007 [-0.0004, -0.07] vs. -0.12 [-0.02, -0.40] %maxEMG/cmH2 O, P = 0.02), lowered loop gain (0.43 ± 0.06 vs. 0.39 ± 0.07, P = 0.01), and improved airway collapsibility (90 [69, 95] vs. 93 [88, 96] %eupnoea, P = 0.02), without changing the arousal threshold (P = 0.39). These findings highlight the important role that noradrenergic and muscarinic processes have on upper airway function during sleep and the potential for pharmacotherapy to target these mechanisms to treat OSA.

Computational Fluid Dynamic Modeling Reveals Nonlinear Airway Stress during Trachea Development.

Normative trachea dimensions and aerodynamic information during development was collected to establish clinical benchmarks and showed that airway development seems to outpace respiratory demands. Infants and toddlers' trachea exhibit higher aerodynamic stress that significantly decreases by teenage years. This implies large airway pathology in younger children may have a more substantial clinical impact.

Influence of head flexion and rotation on obstructive sleep apnea severity during supine sleep.

Head posture influences the collapsibility of the passive upper airway during anaesthesia. However, little is known about the impact of head posture during sleep. The objective of this study was to develop and validate an instrument to measure head posture during supine sleep and to apply this instrument to investigate the influence of head posture on obstructive sleep apnea (OSA) severity. A customized instrument to quantify head flexion and rotation during supine sleep was developed and validated in a benchtop experiment. Twenty-eight participants with suspected OSA were successfully studied using diagnostic polysomnography with the addition of the customized instrument. Head posture in supine sleep was discretized into four categories by two variables: head flexed or not (flexion >15°); and head rotated or not (rotation >45°). Sleep time in each posture and the posture-specific apnea-hypopnea index (AHI) were quantified. Linear mixed-effect modelling was applied to determine the influence of flexion and rotation on supine OSA severity. Twenty-four participants had ≥15 min of supine sleep in at least one head-posture category. Only one participant had ≥15 min of supine sleep time with the head extended. Head flexion was associated with a 12.9 events/h increase in the AHI (95% CI: 3.7-22.1, p = .007). Head rotation was associated with an 11.0 events/h decrease in the AHI (95% CI: 0.3-21.6, p = .04). Despite substantial interparticipant variability, head flexion worsened OSA severity, and head rotation improved OSA severity. Interventions to promote rotation and restrict flexion may have therapeutic benefit in selected patients.

Measurement of airway pressure during high-flow nasal therapy in apnoeic oxygenation: a randomised controlled crossover trial.

It is recognised that high-flow nasal therapy can prevent desaturation during airway management. Studies in spontaneously breathing patients show an almost linear relationship between flow rate and positive airway pressure in the nasopharynx. Positive airway pressure has been suggested as one of the possible mechanisms explaining how high-flow nasal therapy works. However, data on pressures generated by high-flow nasal therapy in apnoeic adults under general anaesthesia are absent. This randomised controlled crossover trial investigated airway pressures generated by different flow rates during high-flow nasal therapy in anaesthetised and paralysed apnoeic patients, comparing pressures with closed and open mouths. Following induction of anaesthesia and neuromuscular blockade, a continuous jaw thrust was used to enable airway patency. Airway pressure was measured in the right main bronchus, the middle of the trachea and the pharynx, using a fibreoptically-placed catheter connected to a pressure transducer. Each measurement was randomised with respect to closed or open mouth and different flow rates. Twenty patients undergoing elective surgery were included (mean (SD) age 38 (18) years, BMI 25.0 (3.3) kg.m-2 , nine women, ASA physical status 1 (35%), 2 (55%), 3 (10%). While closed mouths and increasing flow rates demonstrated non-linear increases in pressure, the pressure increase was negligible with an open mouth. Airway pressures remained below 10 cmH2 O even with closed mouths and flow rates up to 80 l.min-1 ; they were not influenced by catheter position. This study shows an increase in airway pressures with closed mouths that depends on flow rate. The generated pressure is negligible with an open mouth. These data question positive airway pressure as an important mechanism for maintenance of oxygenation during apnoea.

Evaluating the ventilatory effect of transnasal humidified rapid insufflation ventilatory exchange in apnoeic small children with two different oxygen flow rates: a randomised controlled trial.

Transnasal humidified rapid insufflation ventilatory exchange prolongs safe apnoeic oxygenation time in children. In adults, transnasal humidified rapid insufflation ventilatory exchange is reported to have a ventilatory effect with PaCO2 levels increasing less rapidly than without it. This ventilatory effect has yet to be reproduced in children. In this non-inferiority study, we tested the hypothesis that children weighing 10-15 kg exhibit no difference in carbon dioxide clearance when comparing two different high-flow nasal therapy flow rates during a 10-min apnoea period. Following standardised induction of anaesthesia including neuromuscular blockade, patients were randomly allocated to high-flow nasal therapy of 100% oxygen at 2 or 4 l.kg-1 .min-1 . Airway patency was ensured by continuous jaw thrust. The study intervention was terminated for safety reasons when SpO2 values dropped < 95%, or transcutaneous carbon dioxide levels rose > 9.3 kPa, or near-infrared spectroscopy values dropped > 20% from their baseline values, or after an apnoeic period of 10 min. Fifteen patients were included in each group. In the 2 l.kg-1 .min-1 group, mean (SD) transcutaneous carbon dioxide increase was 0.46 (0.11) kPa.min-1 , while in the 4 l.kg-1 .min-1 group it was 0.46 (0.12) kPa.min-1 . The upper limit of a one-sided 95%CI for the difference between groups was 0.07 kPa.min-1 , lower than the predefined non-inferiority margin of 0.147 kPa.min-1 (p = 0.001). The lower flow rate of 2 l.kg-1 .min-1 was non-inferior to 4 l.kg-1 .min-1 relative to the transcutaneous carbon dioxide increase. In conclusion, an additional ventilatory effect of either 2 or 4 l.kg-1 .min-1 high-flow nasal therapy in apnoeic children weighing 10-15 kg appears to be absent.

Roles of mucus adhesion and cohesion in cough clearance.

Clearance of intrapulmonary mucus by the high-velocity airflow generated by cough is the major rescue clearance mechanism in subjects with mucoobstructive diseases and failed cilial-dependent mucus clearance, e.g., subjects with cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD). Previous studies have investigated the mechanical forces generated at airway surfaces by cough but have not considered the effects of mucus biophysical properties on cough efficacy. Theoretically, mucus can be cleared by cough from the lung by an adhesive failure, i.e., breaking mucus-cell surface adhesive bonds and/or by cohesive failure, i.e., directly fracturing mucus. Utilizing peel-testing technologies, mucus-epithelial surface adhesive and mucus cohesive strengths were measured. Because both mucus concentration and pH have been reported to alter mucus biophysical properties in disease, the effects of mucus concentration and pH on adhesion and cohesion were compared. Both adhesive and cohesive strengths depended on mucus concentration, but neither on physiologically relevant changes in pH nor bicarbonate concentration. Mucus from bronchial epithelial cultures and patient sputum samples exhibited similar adhesive and cohesive properties. Notably, the magnitudes of both adhesive and cohesive strength exhibited similar velocity and concentration dependencies, suggesting that viscous dissipation of energy within mucus during cough determines the efficiency of cough clearance of diseased, hyperconcentrated, mucus. Calculations of airflow-induced shear forces on airway mucus related to mucus concentration predicted substantially reduced cough clearance in small versus large airways. Studies designed to improve cough clearance in subjects with mucoobstructive diseases identified reductions of mucus concentration and viscous dissipation as key therapeutic strategies.

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity.

KEY POINTS: A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia. ABSTRACT: A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10 mg zolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6 ± 12.3 vs. 40.3 ± 16.4 events/h (means ± SD), p = 0.938) or nadir oxyhaemoglobin saturation (79.6 ± 6.6 vs. 79.7 ± 7.4%, p = 0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9 ± 14% (83 ± 11 vs. 73 ± 17%, p = 0.010). Arousal threshold increased by 15 ± 5% with zolpidem throughout all sleep stages (p = 0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10 mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by ∼10%, which may be beneficial in people with OSA and insomnia.

Changes in pharyngeal collapsibility and genioglossus reflex responses to negative pressure during the respiratory cycle in obstructive sleep apnoea.

KEY POINTS: Impaired pharyngeal anatomy and increased airway collapsibility is a major cause of obstructive sleep apnoea (OSA) and a mediator of its severity. Upper airway reflexes to changes in airway pressure provide important protection against airway closure. This study shows increased pharyngeal collapsibility and attenuated genioglossus reflex responses during expiration in people with OSA. ABSTRACT: Upper airway collapse contributes to obstructive sleep apnoea (OSA) pathogenesis. Pharyngeal dilator muscle activity varies throughout the respiratory cycle and may contribute to dynamic changes in pharyngeal collapsibility. However, whether upper airway collapsibility and reflex responses to changes in airway pressure vary throughout the respiratory cycle in OSA is unclear. Thus, this study quantified differences in upper airway collapsibility and genioglossus electromyographic (EMG) activity and reflex responses during different phases of the respiratory cycle. Twelve middle-aged people with OSA (2 female) were fitted with standard polysomnography equipment: a nasal mask, pneumotachograph, two fine-wire intramuscular electrodes into the genioglossus, and a pressure catheter positioned at the epiglottis and a second at the choanae (the collapsible portion of the upper airway). At least 20 brief (∼250 ms) pressure pulses (∼-11 cmH2 O at the mask) were delivered every 2-10 breaths during four conditions: (1) early inspiration, (2) mid-inspiration, (3) early expiration, and (4) mid-expiration. Mean baseline genioglossus EMG activity 100 ms prior to pulse delivery and genioglossus reflex responses were quantified for each condition. The upper airway collapsibility index (UACI), quantified as 100 × (nadir choanal - epiglottic pressure)/nadir choanal pressure during negative pressure pulses, varied throughout the respiratory cycle (early inspiration = 43 ± 25%, mid-inspiration = 29 ± 19%, early expiration = 83 ± 19% and mid-expiration = 95 ± 11% (mean ± SD) P < 0.01). Genioglossus EMG activity was lower during expiration (e.g. mid-expiration vs. mid-inspiration = 76 ± 23 vs. 127 ± 41% of early-inspiration, P < 0.001). Similarly, genioglossus reflex excitation was delayed (39 ± 11 vs. 23 ± 7 ms, P < 0.001) and reflex excitation amplitude attenuated during mid-expiration versus early inspiration (209 ± 36 vs. 286 ± 80%, P = 0.009). These findings may provide insight into the physiological mechanisms of pharyngeal collapse in OSA.

Polysomnography with an epiglottic pressure catheter does not alter obstructive sleep apnea severity or sleep efficiency.

Pharyngeal and oesophageal manometry is used clinically and in research to quantify respiratory effort, upper-airway mechanics and the pathophysiological contributors to obstructive sleep apnea. However, the effects of this equipment on respiratory events and sleep in obstructive sleep apnea are unclear. As part of a clinical trial (ANZCTRN12613001106729), data from 28 participants who successfully completed a physiology night with an epiglottic catheter and nasal mask followed by a standard in-laboratory polysomnography were compared. The apnea-hypopnea index was not different during the physiology night versus standard polysomnography (22 ±â€…14 versus 23 ±â€…13 events per hr, p = 0.71). Key sleep parameters were also not different compared between conditions, including sleep efficiency (79 ±â€…13 versus 81 ±â€…11%, p = 0.31) and the arousal index (26 ±â€…11 versus 27 ±â€…11 arousals per hr, p = 0.83). There were, however, sleep stage distribution changes between nights with less N3 and rapid eye movement sleep and more N1 on the physiology night, with no difference in N2 (53 ±â€…15 versus 48 ±â€…9, p = 0.08). However, these changes did not increase next-day sleepiness. These findings indicate that while minor sleep stage distribution changes do occur towards lighter sleep, epiglottic manometry does not alter obstructive sleep apnea severity or sleep efficiency. Thus, epiglottic manometry can be used clinically and to collect detailed physiological information for research without major sleep disruption.

Genioglossus reflex responses to negative upper airway pressure are altered in people with tetraplegia and obstructive sleep apnoea.

KEY POINTS: Protective reflexes in the throat area (upper airway) are crucial for breathing. Impairment of these reflexes can cause breathing problems during sleep such as obstructive sleep apnoea (OSA). OSA is very common in people with spinal cord injury for unknown reasons. This study shows major changes in protective reflexes that serve to keep the upper airway open in response to suction pressures in people with tetraplegia and OSA. These results help us understand why OSA is so common in people with tetraplegia and provide new insight into how protective upper airway reflexes work more broadly. ABSTRACT: More than 60% of people with tetraplegia have obstructive sleep apnoea (OSA). However, the specific causes are unknown. Genioglossus, the largest upper-airway dilator muscle, is important in maintaining upper-airway patency. Impaired genioglossus muscle function following spinal cord injury may contribute to OSA. This study aimed to determine if genioglossus reflex responses to negative upper-airway pressure are altered in people with OSA and tetraplegia compared to non-neurologically impaired able-bodied individuals with OSA. Genioglossus reflex responses measured via intramuscular electrodes to ∼60 brief (250 ms) pulses of negative upper-airway pressure (∼-15 cmH2 O at the mask) were compared between 13 participants (2 females) with tetraplegia plus OSA and 9 able-bodied controls (2 females) matched for age and OSA severity. The initial short-latency excitatory reflex response was absent in 6/13 people with tetraplegia and 1/9 controls. Genioglossus reflex inhibition in the absence of excitation was observed in three people with tetraplegia and none of the controls. When the excitatory response was present, it was significantly delayed in the tetraplegia group compared to able-bodied controls: excitation onset latency (mean ± SD) was 32 ± 16 vs. 18 ± 9 ms, P = 0.045; peak excitation latency was 48 ± 17 vs. 33 ± 8 ms, P = 0.038. However, when present, amplitude of the excitation response was not different between groups, 195 ± 26 vs. 219 ± 98% at baseline, P = 0.55. There are major differences in genioglossus reflex morphology and timing in response to rapid changes in airway pressure in people with tetraplegia and OSA. Altered genioglossus function may contribute to the increased risk of OSA in people with tetraplegia. The precise mechanisms mediating these differences are unknown.

Discrepancy between in vivo and in vitro comparisons of forced oscillation devices.

The forced oscillation technique (FOT) is an emerging clinical lung function test, with commercial devices becoming increasingly available. However comparability across existing devices has not been established. We evaluated in vivo and in vitro measurements made using three commercial devices against a custom-built device (WIMR): Resmon Pro Diary (Restech srl, Italy), tremoFlo C-100 (Thorasys Medical Systems, Canada), Jaeger Masterscope CT IOS (CareFusion, Hoechberg, Germany). Respiratory system resistance Rrs and reactance Xrs at 5 Hz were examined in twelve healthy subjects (mean age 33 ± 11 years, 7 males), and in two test standards of known resistance and reactance. Subjects performed three measurements during tidal breathing on the four devices in random order. Total, inspiratory and expiratory Rrs and Xrs were calculated and compared using one-way repeated measures ANOVA and Bonferroni post-hoc tests. Rrs did not differ between devices, with <10% deviation from predicted, except for the IOS device. With Xrs, similar values were seen between the WIMR and Resmon devices and between the tremoFlo and IOS devices. No differences were observed using test standards; deviation from theoretical value was <2% for resistance and <5% for reactance. The WIMR, tremoFlo and Resmon Pro but not IOS devices measure similar Rrs, whereas there was more disparity across devices in the estimation of Xrs parameters. The discrepancy between in vivo and in vitro measurements suggest that FOT validation procedures need to take into account the breathing pattern, either using biological controls or a breathing model.

Small airway involvement in the late allergic response in asthma.

BACKGROUND: Allergy and asthma are closely linked. Inhalation of allergen induces an early allergic response (EAR) within the airways of allergic asthmatic subjects, which is followed by a late allergic response (LAR) in approximately 50% of the subjects. The LAR is defined as a drop in forced expiratory volume in 1 second (FEV1 ) from baseline usually occurring 4-8 hours after exposure and is believed to affect small airways. However, FEV1 is insensitive to changes in small airway physiology. OBJECTIVE: Our aim was to investigate and compare the pathophysiological processes in large and small airways during the EAR and the LAR and to characterize subjects with both an EAR and a LAR (dual responders) versus those with an EAR only (single responders). METHODS: Thirty-four subjects with allergic asthma underwent an inhaled allergen challenge. Lung physiology was assessed by spirometry, impulse oscillometry (IOS), body plethysmography, inert gas washout, single breath methane dilution carbon monoxide diffusion and exhaled breath temperature (EBT), at baseline and repeatedly for 23 hours post-allergen challenge. RESULTS: Peripheral airway resistance, air trapping and ventilation heterogeneity were significantly increased in dual responders (n = 15) compared to single responders (n = 19) 6-8 hours post-challenge. Parameters of peripheral airway resistance and ventilation heterogeneity, measured with IOS and inert gas washout, respectively, correlated at baseline and during the allergic airway response in all subjects. CONCLUSION: The LAR involves increased resistance and ventilation defects within the peripheral airways. Alternative definitions of the LAR including small airways pathophysiology could be considered. CLINICAL RELEVANCE: Small airway dysfunction during the LAR suggests that dual responders may have more extensive airway pathology and underscores the relevance of small airways assessment in asthma.

Dynamic loop gain increases upon adopting the supine body position during sleep in patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: Obstructive sleep apnoea (OSA) is typically worse in the supine versus lateral sleeping position. One potential factor driving this observation is a decrease in lung volume in the supine position which is expected by theory to increase a key OSA pathogenic factor: dynamic ventilatory control instability (i.e. loop gain). We aimed to quantify dynamic loop gain in OSA patients in the lateral and supine positions, and to explore the relationship between change in dynamic loop gain and change in lung volume with position. METHODS: Data from 20 patients enrolled in previous studies on the effect of body position on OSA pathogenesis were retrospectively analysed. Dynamic loop gain was calculated from routinely collected polysomnographic signals using a previously validated mathematical model. Lung volumes were measured in the awake state with a nitrogen washout technique. RESULTS: Dynamic loop gain was significantly higher in the supine than in the lateral position (0.77 ± 0.15 vs 0.68 ± 0.14, P = 0.012). Supine functional residual capacity (FRC) was significantly lower than lateral FRC (81.0 ± 15.4% vs 87.3 ± 18.4% of the seated FRC, P = 0.021). The reduced FRC we observed on moving to the supine position was predicted by theory to increase loop gain by 10.2 (0.6, 17.1)%, a value similar to the observed increase of 8.4 (-1.5, 31.0)%. CONCLUSION: Dynamic loop gain increased by a small but statistically significant amount when moving from the lateral to supine position and this may, in part, contribute to the worsening of OSA in the supine sleeping position.

Taste Receptors Mediate Sinonasal Immunity and Respiratory Disease.

The bitter taste receptor T2R38 has been shown to play a role in the pathogenesis of chronic rhinosinusitis (CRS), where the receptor functions to enhance upper respiratory innate immunity through a triad of beneficial immune responses. Individuals with a functional version of T2R38 are tasters for the bitter compound phenylthiocarbamide (PTC) and exhibit an anti-microbial response in the upper airway to certain invading pathogens, while those individuals with a non-functional version of the receptor are PTC non-tasters and lack this beneficial response. The clinical ramifications are significant, with the non-taster genotype being an independent risk factor for CRS requiring surgery, poor quality-of-life (QOL) improvements post-operatively, and decreased rhinologic QOL in patients with cystic fibrosis. Furthermore, indirect evidence suggests that non-tasters also have a larger burden of biofilm formation. This new data may influence the clinical management of patients with infectious conditions affecting the upper respiratory tract and possibly at other mucosal sites throughout the body.