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.

Effects of dietary nitrate supplementation on peak power output: Influence of supplementation strategy and population.

Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability and its potential ergogenic effects across various population groups. This review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular peak power output in healthy adults, athletes, older adults and some clinical populations. Effect sizes were calculated for peak power output and absolute and/or relative nitrate doses were considered where applicable. There was no relationship between the effect sizes of peak power output change following nitrate supplementation and when nitrate dosage when considered in absolute or relative terms. Areas for further research are also recommended including a focus on nitrate dosing regimens that optimize nitric oxide bioavailability for enhancing peak power at times of increased muscular work in a variety of healthy and disease populations.

Effects of dietary nitrate supplementation on muscular power output: Influence of supplementation strategy and population.

Increasing evidence indicates that dietary nitrate supplementation has the potential to increase muscular power output during skeletal muscle contractions. However, there is still a paucity of data characterizing the impact of different nitrate dosing regimens on nitric oxide bioavailability its potential ergogenic effects across various population groups. This narrative review discusses the potential influence of different dietary nitrate supplementation strategies on nitric oxide bioavailability and muscular power output in healthy adults, athletes, older adults and some clinical populations. Areas for further research are also recommended including a focus individualized nitrate dosing regimens to optimize nitric oxide bioavailability and to promote muscular power enhancements in different populations.

Preclinical evaluation of the epithelial sodium channel inhibitor AZD5634 and implications on human translation.

Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis (CF), resulting in recurrent respiratory infections and exacerbations. Strategies to rehydrate airway mucus including inhibition of the epithelial sodium channel (ENaC) have the potential to improve mucosal defense by enhancing mucociliary clearance (MCC) and reducing the risk of progressive decline in lung function. In the current work, we evaluated the effects of AZD5634, an ENaC inhibitor that shows extended lung retention and safety profile as compared with previously evaluated candidate drugs, in healthy and CF preclinical model systems. We found that AZD5634 elicited a potent inhibition of amiloride-sensitive current in non-CF airway cells and airway cells derived from F508del-homozygous individuals with CF that effectively increased airway surface liquid volume and improved mucociliary transport (MCT) rate. AZD5634 also demonstrated efficacious inhibition of ENaC in sheep bronchial epithelial cells, translating to dose-dependent improvement of mucus clearance in healthy sheep in vivo. Conversely, nebulization of AZD5634 did not notably improve airway hydration or MCT in CF rats that exhibit an MCC defect, consistent with findings from a first single-dose evaluation of AZD5634 on MCC in people with CF. Overall, these findings suggest that CF animal models demonstrating impaired mucus clearance translatable to the human situation may help to successfully predict and promote the successful translation of ENaC-directed therapies to the clinic.

More questions than answers for the use of inhaled nitric oxide in COVID-19.

Inhaled nitric oxide (iNO) is a potent vasodilator approved for use in term and near-term neonates, but with broad off-label use in settings including acute respiratory distress syndrome (ARDS). As an inhaled therapy, iNO reaches well ventilated portions of the lung and selectively vasodilates the pulmonary vascular bed, with little systemic effect due to its rapid inactivation in the bloodstream. iNO is well documented to improve oxygenation in a variety of pathological conditions, but in ARDS, these transient improvements in oxygenation have not translated into meaningful clinical outcomes. In coronavirus disease 2019 (COVID-19) related ARDS, iNO has been proposed as a potential treatment due to a variety of mechanisms, including its vasodilatory effect, antiviral properties, as well as anti-thrombotic and anti-inflammatory actions. Presently however, no randomized controlled data are available evaluating iNO in COVID-19, and published data are largely derived from retrospective and cohort studies. It is therefore important to interpret these limited findings with caution, as many questions remain around factors such as patient selection, optimal dosing, timing of administration, duration of administration, and delivery method. Each of these factors may influence whether iNO is indeed an efficacious therapy - or not - in this context. As such, until randomized controlled trial data are available, use of iNO in the treatment of patients with COVID-19 related ARDS should be considered on an individual basis with sound clinical judgement from the attending physician.

Wearable activity trackers-advanced technology or advanced marketing?

Wearable devices represent one of the most popular trends in health and fitness. Rapid advances in wearable technology present a dizzying display of possible functions: from thermometers and barometers, magnetometers and accelerometers, to oximeters and calorimeters. Consumers and practitioners utilize wearable devices to track outcomes, such as energy expenditure, training load, step count, and heart rate. While some rely on these devices in tandem with more established tools, others lean on wearable technology for health-related outcomes, such as heart rhythm analysis, peripheral oxygen saturation, sleep quality, and caloric expenditure. Given the increasing popularity of wearable devices for both recreation and health initiatives, understanding the strengths and limitations of these technologies is increasingly relevant. Need exists for continued evaluation of the efficacy of wearable devices to accurately and reliably measure purported outcomes. The purposes of this review are (1) to assess the current state of wearable devices using recent research on validity and reliability, (2) to describe existing gaps between physiology and technology, and (3) to offer expert interpretation for the lay and professional audience on how best to approach wearable technology and employ it in the pursuit of health and fitness. Current literature demonstrates inconsistent validity and reliability for various metrics, with algorithms not publicly available or lacking high-quality validation studies. Advancements in wearable technology should consider standardizing validation metrics, providing transparency in used algorithms, and improving how technology can be tailored to individuals. Until then, it is prudent to exercise caution when interpreting metrics reported from consumer-wearable devices.

Permissive Modulation of Sphingosine-1-Phosphate-Enhanced Intracellular Calcium on BKCa Channel of Chromaffin Cells.

Sphingosine-1-phosphate (S1P), is a signaling sphingolipid which acts as a bioactive lipid mediator. We assessed whether S1P had multiplex effects in regulating the large-conductance Ca2+-activated K+ channel (BKCa) in catecholamine-secreting chromaffin cells. Using multiple patch-clamp modes, Ca2+ imaging, and computational modeling, we evaluated the effects of S1P on the Ca2+-activated K+ currents (IK(Ca)) in bovine adrenal chromaffin cells and in a pheochromocytoma cell line (PC12). In outside-out patches, the open probability of BKCa channel was reduced with a mean-closed time increment, but without a conductance change in response to a low-concentration S1P (1 µM). The intracellular Ca2+ concentration (Cai) was elevated in response to a high-dose (10 µM) but not low-dose of S1P. The single-channel activity of BKCa was also enhanced by S1P (10 µM) in the cell-attached recording of chromaffin cells. In the whole-cell voltage-clamp, a low-dose S1P (1 µM) suppressed IK(Ca), whereas a high-dose S1P (10 µM) produced a biphasic response in the amplitude of IK(Ca), i.e., an initial decrease followed by a sustained increase. The S1P-induced IK(Ca) enhancement was abolished by BAPTA. Current-clamp studies showed that S1P (1 µM) increased the action potential (AP) firing. Simulation data revealed that the decreased BKCa conductance leads to increased AP firings in a modeling chromaffin cell. Over a similar dosage range, S1P (1 µM) inhibited IK(Ca) and the permissive role of S1P on the BKCa activity was also effectively observed in the PC12 cell system. The S1P-mediated IK(Ca) stimulation may result from the elevated Cai, whereas the inhibition of BKCa activity by S1P appears to be direct. By the differentiated tailoring BKCa channel function, S1P can modulate stimulus-secretion coupling in chromaffin cells.

Seeing cilia: imaging modalities for ciliary motion and clinical connections.

The respiratory tract is lined with multiciliated epithelial cells that function to move mucus and trapped particles via the mucociliary transport apparatus. Genetic and acquired ciliopathies result in diminished mucociliary clearance, contributing to disease pathogenesis. Recent innovations in imaging technology have advanced our understanding of ciliary motion in health and disease states. Application of imaging modalities including transmission electron microscopy, high-speed video microscopy, and micron-optical coherence tomography could improve diagnostics and be applied for precision medicine. In this review, we provide an overview of ciliary motion, imaging modalities, and ciliopathic diseases of the respiratory system including primary ciliary dyskinesia, cystic fibrosis, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis.

Recent Advancements in Our Understanding of the Ergogenic Effect of Respiratory Muscle Training in Healthy Humans: A Systematic Review.

Shei, R-J. Recent advancements in our understanding of the ergogenic effect of respiratory muscle training in healthy humans: a systematic review. J Strength Cond Res 32(9): 2674-2685, 2018-Respiratory muscle training (RMT) has been shown to be an effective ergogenic aid for sport performance. Respiratory muscle training has been documented to improve performance in a wide range of exercise modalities including running, cycling, swimming, and rowing. The physiological effects of RMT that may explain the improvements in performance have been proposed to include diaphragm hypertrophy, muscle fiber-type switching, improved neural control of the respiratory muscles, increased respiratory muscle economy, attenuation of the respiratory muscle metaboreflex, and decreases in perceived breathlessness and exertion. This review summarizes recent studies on the ergogenicity and mechanisms of RMT since 2013 when the topic was last systematically reviewed. Recent evidence confirms the ergogenic effects of RMT and explores different loading protocols, such as concurrent exercise and RMT (i.e., "functional" RMT). These studies suggest that adapting new training protocols may have an additive improvement effect, but evidence of the efficacy of such an approach is conflicting thus far. Other recent investigations have furthered our understanding of the mechanisms underpinning RMT-associated improvements in performance. Importantly, changes in ventilatory efficiency, oxygen delivery, cytokine release, motor recruitment patterns, and respiratory muscle fatigue resistance are highlighted as potential mechanistic factors linking RMT with performance improvements. It is suggested that future investigations focus on development of sport-specific RMT loading protocols, and that further work be undertaken to better understand the mechanistic basis of RMT-induced performance improvements.

Repeated High-Intensity Cycling Performance Is Unaffected by Timing of Carbohydrate Ingestion.

Shei, R-J, Paris, HL, Beck, CP, Chapman, RF, and Mickleborough, TD. Repeated high-intensity cycling performance is unaffected by timing of carbohydrate ingestion. J Strength Cond Res 32(8): 2243-2249, 2018-To determine whether carbohydrate (CHO) feeding taken immediately before, early, or late in a series of high-intensity cycling exercises affected cycling performance. A total of 16 trained, male cyclists (>6 hours postprandial) performed 3-, 4-km cycling time trials (TT1, TT2, and TT3) separated by 15 minutes of active recovery on 4 separate occasions. Carbohydrate feeding (80 g) was given either before TT1 (PRE1), before TT2 (PRE2), before TT3 (PRE3), or not at all (control, CTL). Treatment order was randomized. Sweet placebo was given before the other TTs. Blood glucose (BG) concentration was measured before each trial. Mean power output (Pmean) and time to completion (TTC) were recorded. Pmean was higher in TT1 compared with TT2 (p = 0.001) and TT3 (p = 0.004) in all conditions, but no differences were observed between treatments. Time to completion was lower in TT1 compared with TT2 (p = 0.01), but no other differences in TTC (within or between treatments) were observed. Within CTL and PRE1, BG did not differ between TT1, TT2, and TT3. In PRE2, BG was significantly higher in TT2 compared with TT1 (p = 0.006), in TT3 compared with TT1 (p = 0.001), and in TT3 compared with TT2 (p = 0.01). In PRE3, BG was significantly higher in TT3 compared with TT1 and TT2 (p = 0.001 for both). Given that performance was not influenced by the timing of CHO ingestion, athletes engaging in repeated, high-intensity cycling exercise do not need to ingest CHO before- or between-exercise bouts; furthermore, athletes should refrain from ingesting CHO between bouts if they wish to avoid a rise in BG.

Physiological impact of load carriage exercise: Current understanding and future research directions.

Load carriage (LC) refers to the use of personal protective equipment (PPE) and/or load-bearing apparatus that is mostly worn over the thoracic cavity. A commonplace task across various physically demanding occupational groups, the mass being carried during LC duties can approach the wearer's body mass. When compared to unloaded exercise, LC imposes additional physiological stress that negatively impacts the respiratory system by restricting chest wall movement and altering ventilatory mechanics as well as circulatory responses. Consequently, LC activities accelerate the development of fatigue in the respiratory muscles and reduce exercise performance in occupational tasks. Therefore, understanding the implications of LC and the effects specific factors have on physiological capacities during LC activity are important to the implementation of effective mitigation strategies to ameliorate the detrimental effects of thoracic LC. Accordingly, this review highlights the current physiological understanding of LC activities and outlines the knowledge and efficacy of current interventions and research that have attempted to improve LC performance, whilst also highlighting pertinent knowledge gaps that must be explored via future research activities.

Real-world use of inhaled nitric oxide therapy in patients with COVID-19 and mild-to-moderate acute respiratory distress syndrome.

Background: Inhaled nitric oxide (iNO) has been studied in patients with severe acute respiratory distress syndrome (ARDS) due to COVID-19 when it may be too late to impact disease course. This article aims to describe real-world iNO use and outcomes in patients with COVID-19 with mild-to-moderate ARDS in the United States. Methods: This was a retrospective medical chart review study that included patients who were ≥18 years old, hospitalized for COVID-19, met the Berlin ARDS definition, received iNO for ≥24 hours continuously during hospitalization, and had a partial pressure of oxygen (PaO2)/fraction of inspired oxygen (FiO2) ratio (P/F ratio) of >100 to ≤300 mmHg at iNO initiation. Outcomes included oxygenation parameters, physician-rated Clinical Global Impression-Improvement (CGI-I) scale scores, and adverse events. Response to iNO was defined as >20% improvement in P/F ratio. Results: Thirty-seven patients at six sites were included. A P/F ratio of ≤100 was the most common reason for exclusion (n=146; 83% of excluded patients). The mean P/F ratio (SD) increased from 136.7 (34.4) at baseline to 140.3 (53.2) at 48 hours and 151.8 (50.0) at 72 hours after iNO initiation. The response rate was 62% (n=23). During hospitalization, no patient experienced adverse events, including methemoglobinaemia, airway injury, or worsening pulmonary oedema associated with iNO. At discharge, 54.0% (n=20) of patients improved or remained stable according to the CGI-I. Conclusion: In patients hospitalized with COVID-19 and mild-to-moderate ARDS, iNO was associated with improvement in the P/F ratio with no reported toxicity. This study provides additional evidence supporting a favourable benefit-risk profile for iNO in the treatment of mild-to-moderate ARDS in patients with COVID-19 infection.

Time to Move Beyond a "One-Size Fits All" Approach to Inspiratory Muscle Training.

Inspiratory muscle training (IMT) has been studied as a rehabilitation tool and ergogenic aid in clinical, athletic, and healthy populations. This technique aims to improve respiratory muscle strength and endurance, which has been seen to enhance respiratory pressure generation, respiratory muscle weakness, exercise capacity, and quality of life. However, the effects of IMT have been discrepant between populations, with some studies showing improvements with IMT and others not. This may be due to the use of standardized IMT protocols which are uniformly applied to all study participants without considering individual characteristics and training needs. As such, we suggest that research on IMT veer away from a standardized, one-size-fits-all intervention, and instead utilize specific IMT training protocols. In particular, a more personalized approach to an individual's training prescription based upon goals, needs, and desired outcomes of the patient or athlete. In order for the coach or practitioner to adjust and personalize a given IMT prescription for an individual, factors, such as frequency, duration, and modality will be influenced, thus inevitably affecting overall training load and adaptations for a projected outcome. Therefore, by integrating specific methods based on optimization, periodization, and personalization, further studies may overcome previous discrepancies within IMT research.

The influence of carbohydrate ingestion on peripheral and central fatigue during exercise in hypoxia: A narrative review.

Hypoxia impairs aerobic performance by accelerating fatiguing processes. These processes may originate from sites either distal (peripheral) or proximal (central) to the neuromuscular junction, though these are not mutually exclusive. Peripheral mechanisms include decrements in muscle glycogen or fluctuations in intramuscular metabolites, whereas central responses commonly refer to reductions in central motor drive elicited by alterations in blood glucose and neurotransmitter concentrations as well as arterial hypoxemia. Hypoxia may accelerate both peripheral and central pathways of fatigue, with the level of hypoxia strongly dictating the degree and primary locus of impairment. As more people journey to hypoxic settings for work and recreation, developing strategies to improve work capacity in these environments becomes increasingly relevant. Given that sea level performance improves with nutritional interventions such as carbohydrate (CHO) ingestion, a similar strategy may prove effective in delaying fatigue in hypoxia, particularly considering how the metabolic pathways enhanced with CHO supplementation overlap the fatiguing pathways upregulated in hypoxia. Many questions regarding the relationship between CHO, hypoxia, and fatigue remain unanswered, including specifics on when to ingest, what to ingest, and how varying altitudes influence supplementation effectiveness. Therefore, the purpose of this narrative review is to examine the peripheral and central mechanisms contributing to fatigue during aerobic exercise at varying degrees of hypoxia and to assess the role of CHO ingestion in attenuating fatigue onset.

Fibroblast Growth Factor Receptor 4 Deficiency Mediates Airway Inflammation in the Adult Healthy Lung?

Fibroblast growth factor receptor (FGFR) 4 has been shown to mediate pro-inflammatory signaling in the liver and airway epithelium in chronic obstructive pulmonary disease. In past reports, FGFR4 knockout (Fgfr4 -/- ) mice did not show any lung phenotype developmentally or at birth, unless FGFR3 deficiency was present simultaneously. Therefore, we wanted to know whether the loss of FGFR4 had any effect on the adult murine lung. Our results indicate that adult Fgfr4 -/- mice demonstrate a lung phenotype consisting of widened airway spaces, increased airway inflammation, bronchial obstruction, and right ventricular hypertrophy consistent with emphysema. Despite downregulation of FGF23 serum levels, interleukin (IL) 1ß and IL-6 in the Fgfr4 -/- lung, and abrogation of p38 signaling, primary murine Fgfr4 -/- airway cells showed increased expression of IL-1ß and augmented secretion of IL-6, which correlated with decreased airway surface liquid depth as assessed by micro-optical coherence tomography. These findings were paralleled by increased ERK phosphorylation in Fgfr4 -/- airway cells when compared with their control wild-type cells. Analysis of a murine model with constitutive activation of FGFR4 showed attenuation of pro-inflammatory mediators in the lung and airway epithelium. In conclusion, we are the first to show an inflammatory and obstructive airway phenotype in the adult healthy murine Fgfr4 -/- lung, which might be due to the upregulation of ERK phosphorylation in the Fgfr4 -/- airway epithelium.

Inspiration for the Future: The Role of Inspiratory Muscle Training in Cystic Fibrosis.

Cystic fibrosis (CF) is an inherited, multi-system, life-limiting disease characterized by a progressive decline in lung function, which accounts for the majority of CF-related morbidity and mortality. Inspiratory muscle training (IMT) has been proposed as a rehabilitative strategy to treat respiratory impairments associated with CF. However, despite evidence of therapeutic benefits in healthy and other clinical populations, the routine application of IMT in CF can neither be supported nor refuted due to the paucity of methodologically rigorous research. Specifically, the interpretation of available studies regarding the efficacy of IMT in CF is hampered by methodological threats to internal and external validity. As such, it is important to highlight the inherent risk of bias that differences in patient characteristics, IMT protocols, and outcome measurements present when synthesizing this literature prior to making final clinical judgments. Future studies are required to identify the characteristics of individuals who may respond to IMT and determine whether the controlled application of IMT can elicit meaningful improvements in physiological and patient-centered clinical outcomes. Given the equivocal evidence regarding its efficacy, IMT should be utilized on a case-by-case basis with sound clinical reasoning, rather than simply dismissed, until a rigorous evidence-based consensus has been reached.

Exercise Physiology Across the Lifespan in Cystic Fibrosis.

Cystic fibrosis (CF), a severe life-limiting disease, is associated with multi-organ pathologies that contribute to a reduced exercise capacity. At present, the impact of, and interaction between, disease progression and other age-related physiological changes in CF on exercise capacity from child- to adult-hood is poorly understood. Indeed, the influences of disease progression and aging are inherently linked, leading to increasingly complex interactions. Thus, when interpreting age-related differences in exercise tolerance and devising exercise-based therapies for those with CF, it is critical to consider age-specific factors. Specifically, changes in lung function, chronic airway colonization by increasingly pathogenic and drug-resistant bacteria, the frequency and severity of pulmonary exacerbations, endocrine comorbidities, nutrition-related factors, and CFTR (cystic fibrosis transmembrane conductance regulator protein) modulator therapy, duration, and age of onset are important to consider. Accounting for how these factors ultimately influence the ability to exercise is central to understanding exercise impairments in individuals with CF, especially as the expected lifespan with CF continues to increase with advancements in therapies. Further studies are required that account for these factors and the changing landscape of CF in order to better understand how the evolution of CF disease impacts exercise (in)tolerance across the lifespan and thereby identify appropriate intervention targets and strategies.