Human Airway Function Research Articles

Human bone marrow-derived mesenchymal stem cells rescue neonatal CPAP-induced airway hyperreactivity

Continuous positive airway pressure (CPAP) is a primary non-invasive mode of respiratory support for preterm infants. However, emerging evidence suggests CPAP could be an underlying contributor to the unintended pathophysiology of wheezing and associated airway hyperreactivity (AHR) in former preterm infants. The therapeutic benefits of mesenchymal stem cells (MSCs) have been demonstrated in a variety of animal models and several clinical trials are currently underway to assess their safety profiles in the setting of prematurity and bronchopulmonary dysplasia (BPD). In the present study, using a mouse model of neonatal CPAP, we investigated whether conditioned medium harvested from cultures of human bone-marrow derived mesenchymal stem cells (hMSC) could rescue the CPAP-induced AHR, based upon previous observations of their anti-AHR properties. Newborn mice (male and female) were fitted with a custom-made mask for delivery of daily CPAP 3 h/day for the first 7 postnatal days. At postnatal day 21 (two weeks after CPAP ended), lungs were removed, precision-cut lung slices were sectioned and incubated for 48 h in vitro in conditioned medium collected from cultures of three different hMSC donors. As expected, CPAP resulted in AHR to methacholine compared to untreated control mice. hMSC conditioned medium from the cultures of all three donors completely reversed AHR. These data reveal potential therapeutic benefits of hMSC therapy, which may be capable of rescuing the long-term adverse effects of neonatal CPAP on human airway function.

Reboxetine and hyoscine butylbromide improve upper airway function during nonrapid eye movement and suppress rapid eye movement sleep in healthy individuals.

Recent findings indicate that noradrenergic and antimuscarinic processes are crucial for sleep-related reductions in pharyngeal muscle activity. However, there are few human studies. Accordingly, this study aimed to determine if a combined noradrenergic and antimuscarinic intervention increases pharyngeal dilator muscle activity and improves airway function in sleeping humans. Genioglossus (GG) and tensor palatini electromyography (EMG), pharyngeal pressure, upper airway resistance, and breathing parameters were acquired in 10 healthy adults (5 female) during two overnight sleep studies after 4 mg of reboxetine (REB) plus 20 mg of hyoscine butylbromide (HBB) or placebo using a double-blind, placebo-controlled, randomized, cross-over design. Compared with placebo, peak and tonic GG EMG were lower (Mean ± SD: 83 ± 73 vs. 130 ± 75, p = 0.021 and 102 ± 102 vs. 147 ± 123 % wakefulness, p = 0.021, respectively) but the sleep-related reduction in tensor palatini was less (Median [25th, 75th centiles]: 53[45, 62] vs. 34[28, 38] % wakefulness, p = 0.008) with the drug combination during nonrapid eye movement (non-REM) sleep. These changes were accompanied by improved upper airway function including reduced pharyngeal pressure swings, airway resistance, respiratory load compensation, and increased breathing frequency during N2. REB and HBB significantly reduced rapid eye movement sleep compared with placebo (0.6 ± 1.1 vs. 14.5 ± 6.8 % total sleep time, p < 0.001). Contrary to our hypothesis, GG muscle activity (% wakefulness) during non-REM sleep was lower with REB and HBB. However, sleep-related reductions in tensor palatini activity were less and upper airway function improved. These findings provide mechanistic insight into the role of noradrenergic and antimuscarinic processes on upper airway function in humans and have therapeutic potential for obstructive sleep apnea. Australian New Zealand Clinical Trials Registry, https://www.anzctr.org.au, trial ID: ACTRN12616000469415.

Onset of airflow limitation in a collapsible tube model: impact of surrounding pressure, longitudinal strain, and wall folding geometry

We studied the impact of wall strain and surrounding pressure on the onset of airflow limitation in a thin-walled "floppy" tube model. A vacuum source-generated steady-state (baseline) airflow (0-350 ml/s) through a thin-walled latex tube (length 80 mm, wall thickness 0.23 mm) enclosed within a rigid, sealed, air-filled, cylindrical chamber while upstream minus downstream pressure, chamber pressure (Pc), and lumen geometry [in-line digital camera; segmentation (Amira 5.2.2) and analysis (Rhinoceros 4) software] were monitored. Longitudinal strain (S; 0-62.5%) and Pc (0-20 cmH(2)O) combinations were imposed, and Pc associated with onset of 1) reduced airflow and 2) fully developed airflow limitation recorded. At any strain, increasing Pc resulted in a decrease in airflow. Across all baseline airflow, threshold pressure was 1-7 cmH(2)O for S < 25%, 6-8 cmH(2)O at S = 25% and 37.5%, and 5-7 cmH(2)O at S = 50% and 62.5%. Pc associated with fully developed airflow limitation was 4-6 cmH(2)O for S < 25%, >20 cmH(2)O at S = 25% (i.e., no flow limitation), 18 cmH(2)O at S = 37.5%, and 8-12 cmH(2)O at S = 50% and 62.5%. Lumen area decreased with increasing Pc but was 1) larger at S = 25% and 2) characterized by bifold narrowing at S < 25% and trifold narrowing at S ≥ 25%. In conclusion, tube function was modulated by Pc vs. S interactions, with S = 25% producing trifold lumen narrowing, maximal patency, and no airflow limitation. Findings may have implications for understanding peripharyngeal tissue pressure and pharyngeal wall strain effects on passive pharyngeal airway function in humans.

Virus-Induced Airway Dysfunction

Viral respiratory tract infections cause significant morbidity and mortality. Respiratory viruses are suspected to play a role in the inception of asthma early in life. Respiratory syncytial virus (RSV) is the most common cause of infant bronchiolitis, which is associated with the development of childhood wheezing and asthma. However, it is not clear whether this association is "causal" or "circumstantial." Animal models have been pivotal in studying the pathophysiology of viral respiratory infections. Various approaches to assessing airway inflammation and function have been used to define the mechanisms of virus-induced airway dysfunction and to address clinically relevant questions regarding the role of RSV in wheezing and asthma after bronchiolitis. Viral lower respiratory tract infections alter airway function in humans and animals. The extent and duration of the alterations may depend on the virus itself, host factors and environmental factors. Animal studies demonstrated that viral infection induces airway hyperresponsiveness and enhances this alteration in the allergen-sensitized and exposed host. This altered airway function is mediated by immune and neurogenic inflammatory mechanisms. Recent studies in mice show that neonatal RSV infection sensitizes the newborn to develop an asthma-like phenotype on reinfection, providing further opportunities to investigate the role of RSV in postbronchiolitis wheezing and asthma in this animal model. Further studies are needed to fully establish the mechanisms underlying the pathophysiology of viral respiratory tract infections and to clarify their role in the inception and/or progression of chronic airway diseases such as asthma. The results of ongoing therapeutic studies promise to minimize the impact of such viral infections.

Inflammatory cells as source of tachykinin-induced mucus secretion in chronic bronchitis

Substance P and neurokinin A are regulatory peptides of the tachykinin family that influence many aspects of human airway function in health and diseases such as bronchial asthma or chronic obstructive pulmonary disease (COPD). Tachykinin-induced mucus secretion has been regarded as sensory nerve-dependent so far. We studied the distribution of tachykinin-mRNA and -peptide and its relation to NK-1 subtype-positive cells in human airway glands to assess if tachykinins may also be expressed in inflammatory cells. RT-PCR demonstrated the expression of tachykinin- and NK-1-mRNA in human airway tissues. In situ hybridisation resulted in preprotachykinin (PPT)-A mRNA-signal detection in inflammatory cells which were in close contact to myoepithelial cells of airway glands. NK-1 immunoreactivity was found in myoepithelial cells which were in direct contact to the PPT-A mRNA and tachykinin-positive cells. The present data directly demonstrate the presence of both PPT-A mRNA and tachykinin immunoreactivity in inflammatory airway cells which are in direct contact to NK-1 receptor positive glandular myoepithelium. Our findings indicate that besides neurally released tachykinins, also inflammatory cell-derived tachykinins may lead to glandular secretion via NK-1 receptor stimulation. This points to a major second source of these proinflammatory mediators in chronic inflammatory airway diseases such as COPD or asthma.

Receptors in Asthmatic Airways

Airway tissue obtained postmortem from nondiseased and severely asthmatic human lung was used in functional, radioligand binding and autoradiographic studies to investigate aspects of various receptor systems for putative mediators of asthma. Results indicate that asthma does not involve an intrinsic abnormality of smooth muscle contractility to spasmogens. Nor was there any evidence for up-regulation of histamine H1-receptor, muscarinic cholinoceptor, or alpha 1-adrenoceptor function. Conversely, severe asthma involving intense airway inflammation resulted in significant beta-adrenoceptor dysfunction, probably caused by receptor uncoupling from adenylate cyclase. Evidence was also obtained for histamine and methacholine-induced release of a nonprostanoid, airway epithelium-derived inhibitory factor (EpDIF), which may have a significant dilator effect in the adjacent bronchial circulation. The activity of this potentially protective inhibitory autacoid system would be expected to be reduced in asthma, which commonly involves epithelium damage. The autoradiographic distribution of specific binding sites for 125I-labeled substance P (I-SP) was also determined in bronchi from healthy humans and asthmatics. In sharp contrast to guinea pig airways where high levels of binding were detected over smooth muscle, specific I-SP binding was sparse over human airway smooth muscle from both sources, while dense binding was associated with structures immediately beneath the epithelium and with deep submucosal glands. These data suggest a more significant role for SP in secretory processes than in spasmogenic processes in human bronchi and highlight the potential for drawing invalid conclusions concerning human airway function from studies using animal models.

Absence of effects of hypoxia on small airway function in humans.

We measured the effects of sustained isocapnic hypoxia (PAO2 = 40--50 Torr; PACO2 = 38--42 Torr) on tests sensitive to small airway function in healthy human subjects. Maximum expiratory flow-volume curves on air, nitrogen-hypoxic, helium-normoxic, and helium-hypoxic mixtures as well as closing volumes while subjects breathed air and a hypoxic mixture were obtained. We then measured total lung capacity (TLC), both plethysmographically and by inert gas dilution, and used the nonplethysmographic method to measure the effects of hypoxia on TLC. In none of these tests were there any statistically significant changes when values obtained during hypoxia were compared with those during normoxia. It is suggested that previous reports that indicated that TLC was increased by hypoxia might have arisen from a plethysmographic artifact.