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Excessive dynamic airway collapse (EDAC) is a recognized cause of exertional dyspnea arising due to invagination of the trachea and/or main bronchi. EDAC is typically assessed by evaluating large airway movement with forced expiratory maneuvers. This differs from the respiratory response to exercise hyperpnea. We aimed to evaluate large airway movement during physical activity, with continuous bronchoscopy during exercise (CBE), in healthy subjects and compare findings with resting bronchoscopic maneuvers and imaging techniques. Twenty-eight individuals were recruited to complete two visits including treadmill-based CBE, to voluntary exhaustion, and cine magnetic resonance imaging (MRI) with forced expiratory maneuvers at rest. Twenty-five subjects [aged 29 (26–33) yr, 52% female] completed the study (n = 2 withdrew before bronchoscopy, and one was unable to tolerate insertion of bronchoscope). The majority (76%) achieved a peak heart rate of >90% predicted during CBE. The procedure was prematurely terminated in five subjects (n = 3; elevated blood pressure and n = 2; minor oxygen desaturation). The CBE assessment enabled adequate tracheal visualization in all cases. Excessive dynamic airway collapse (tracheal collapse ≥50%) was identified in 16 subjects (64%) on MRI, and in six (24%) individuals during resting bronchoscopy, but in no cases with CBE. No serious adverse events were reported, but minor adverse events were evident. The CBE procedure permits visualization of large airway movement during physical activity. In healthy subjects, there was no evidence of EDAC during strenuous exercise, despite evidence during forced maneuvers on imaging, thus challenging conventional approaches to diagnosis. NEW & NOTEWORTHY: This study demonstrates that large airway movement can be visualized with bronchoscopy undertaken during vigorous exercise. This approach does not require sedation and permits characterization of the behavior of the large airways and the tendency toward collapse during upright, ambulatory exercise. In healthy individuals, the response pattern of the large airways during exercise appears to differ markedly from the pattern of airway closure witnessed during forced expiratory maneuvers, assessed via imaging. [ABSTRACT FROM AUTHOR]

Tracheal displacement is thought to be the primary mechanismby which changes in lung volume influence upper airwaypatency. Caudal tracheal displacement during inspiration may helppreserve the integrity of the upper airway in response to increasingnegative airway pressure by stretching and stiffening pharyngealtissues. However, tracheal displacement has not been previouslyquantified in obstructive sleep apnea (OSA). Accordingly, we aimedto measure tracheal displacements in awake individuals with andwithout OSA. The upper head and neck of 34 participants [apneahypopneaindex (AHI) = 2-74 events/h] were imaged in the midsagittalplane using dynamic magnetic resonance imaging (MRI) duringsupine awake quiet breathing. MRI data were analyzed to identifypeak tracheal displacement and its timing relative to inspiration. Epiglottic pressure was measured separately for a subset of participants(n = 30) during similar experimental conditions. Nadir epiglotticpressure and its timing relative to inspiration were quantified. Peaktracheal displacement ranged from 1.0 -9.6 mm, with a median (25th-75th percentile) of 2.3 (1.7-3.5) mm, and occurred at 89 (78-99)% of inspiratory time. Peak tracheal displacement increased with increasingOSA severity (AHI) (R² = 0.28, P = 0.013) and increasing negativenadir epiglottic pressure (R² = 0.47, P = 0.023). Relative inspiratorytiming of peak tracheal displacement also correlated with OSA severity, with peak displacement occurring earlier in inspiration withincreasing AHI (R² = 0.36, P = 0.002). Tracheal displacements duringquiet breathing are larger in individuals with more severe OSAand tend to reach peak displacement earlier in the inspiratory cycle. Increased tracheal displacement may contribute to maintenance of upper airway patency during wakefulness in OSA, particularly inthose with severe disease. [ABSTRACT FROM AUTHOR]

The relationship between the pressure losses within the nasal airways and nasal geometry were studied in a 3:1 scale model. The geometry of the model was based on magnetic resonance images of the skull of a healthy male subject. Pressure measurements, flow visualization, and hot-wire anemometry studies were performed at flow rates that, in vivo, corresponded to flows of between 0.05 and 1.50 l/s. The influence of nasal congestion and the collapse of the external nares were examined by using modeling clay to simulate local constrictions in the cross section. A dimensionless analysis of the pressure losses within three sections of the airway revealed the influence of various anatomic dimensions on nasal resistance. The region of the exterior nose behaves as a contraction-expansion nozzle in which the pressure losses are a function of the smallest cross-sectional area. Losses in the interior nose resemble those associated with channel flow. The nasopharynx is modeled as a sharp bend in a circular duct. Good correspondence was found between the predicted and actual pressure losses in the model under conditions that stimulated local obstructions and congestion.

Recording of breathing frequency is a basic requirement for respiratory physiology. Usual techniques are invasive and constraining. Respiratory sinus arrhythmia (RSA) has recently been demonstrated to be a simple way to obtain respiration frequency at rest. In this study, we investigated whether this correlation is also observed during activity. We first compared RSA to the respiration frequency obtained in anesthetized rats using a pneumotachograph connected to the trachea (TRF). Data analyses using Passing and Bablok regression confirmed the absence of bias and proportional differences. Accordingly, the Bland-Altman plot did not show any significant differences in data sets. In a second experiment, we compared RSA to the respiration frequency obtained in freely moving rats using a subpleurally inserted telemetric catheter (PRF). Comparisons between RSA and PRF revealed no significant difference in determination of respiratory rate with the two methods, although the bias and confidence interval were greater when activity increased. This was, however, not the case during short episodes of sniffing-like tachypnea, during which no matching RSA peaks were observed. In conclusion, RSA frequency reflected regular respiration frequency independently of the level of activity and appears to be a good surrogate to usual techniques. [ABSTRACT FROM AUTHOR]

Deep inspirations (DIs) taken before an inhaled challenge with a spasmogen limit airway responsiveness in nonasthmatic subjects. This phenomenon is called bronchoprotection and is severely impaired in asthmatic subjects. The ability of DIs to prevent a decrease in forced expiratory volume in 1 s (FEV1) was initially attributed to inhibition of airway narrowing. However, DIs taken before methacholine challenge limit airway responsiveness only when a test of lung function requiring a DI is used (FEV1). Therefore, it has been suggested that prior DIs enhance the compliance of the airways or airway smooth muscle (ASM). This would increase the strain the airway wall undergoes during the subsequent DI, which is part of the FEV1 maneuver. To investigate this phenomenon, we used ovine tracheal smooth muscle strips that were subjected to shortening elicited by acetylcholine with or without prior strain mimicking two DIs. The compliance of the shortened strip was then measured in response to a stress mimicking one DI. Our results show that the presence of "DIs" before acetyl-choline-induced shortening resulted in 11% greater relengthening in response to the third DI, compared with the prior DIs. This effect, although small, is shown to be potentially important for the reopening of closed airways. The effect of prior DIs was abolished by the adaptation of ASM to either shorter or longer lengths or to a low baseline tone. These results suggest that DIs confer bronchoprotection because they increase the compliance of ASM, which, consequently, promotes greater strain from subsequent DI and fosters the reopening of closed airways. [ABSTRACT FROM AUTHOR]

Lung air trapping is estimated via quantitative computed tomography (CT) using density threshold-based measures on an expiration scan. However, the effects of scanner differences and imaging protocol adherence on quantitative assessment are known to be problematic. This study investigates the effects of protocol differences, such as using different CT scanners and breath-hold coaches in a multicenter asthmatic study, and proposes new methods that can adjust intersite and intersubject variations. CT images of 50 healthy subjects and 42 nonsevere and 52 severe asthmatics at total lung capacity (TLC) and functional residual capacity (FRC) were acquired using three different scanners and two different coaching methods at three institutions. A fraction threshold-based approach based on the corrected Hounsfield unit of air with tracheal density was applied to quantify air trapping at FRC. The new air-trapping method was enhanced by adding a lung-shaped metric at TLC and the lobar ratio of air-volume change between TLC and FRC. The fraction-based air-trapping method is able to collapse air-trapping data of respective populations into distinct regression lines. Relative to a constant value-based clustering scheme, the slope-based clustering scheme shows the improved performance and reduced misclassification rate of healthy subjects. Furthermore, both lung shape and air-volume change are found to be discriminant variables for differentiating among three populations of healthy subjects and nonsevere and severe asthmatics. In conjunction with the lung shape and air-volume change, the fraction-based measure of air trapping enables differentiation of severe asthmatics from nonsevere asthmatics and nonsevere asthmatics from healthy subjects, critical for the development and evaluation of new therapeutic interventions. [ABSTRACT FROM AUTHOR]

Caudal tracheal displacement (TD) leads to improvements in upper airway (UA) function and decreased collapsibility. To better understand the mechanisms underlying these changes, we examined effects of TD on peripharyngeal tissue stress distributions [i.e., extraluminal tissue pressure (ETP)], deformation of its topographical surface (UA lumen geometry), and hyoid bone position. We studied 13 supine, anesthetized, tracheostomized, spontaneously breathing, adult male New Zealand white rabbits. Graded TD was applied to the cranial tracheal segment from 0 to ~ 10 mm. ETP was measured at six locations distributed around/along the length of the UA, covering three regions: tongue, hyoid, and epiglottis. Axial images of the UA (nasal choanae to glottis) were acquired with computed tomography and used to measure lumen geometry (UA length; regional cross-sectional area) and hyoid bone displacement. TD resulted in nonuniform decreases in ETP (generally greatest at tongue region), ranging from -0.07 (-0.11 to -0.03) [linear mixed-effects model slope (95% confidence interval)] to -0.27 (-0.31 to -0.23) cmH2O/mm TD, across all sites. UA length increased by 1.6 (1.5-1.8)%/mm, accompanied by nonuniform increases in cross-sectional area (greatest at hyoid region) ranging from 2.8 (1.7-3.9) to 4.9 (3.8-6.0)%/mm. The hyoid bone was displaced caudally by 0.22 (0.18-0.25) mm/mm TD. In summary, TD imposes a load on the UA that results in heterogeneous changes in peripharyngeal tissue stress distributions and resultant lumen geometry. The hyoid bone may play a pivotal role in redistributing applied caudal tracheal loads, thus modifying tissue deformation distributions and determining resultant UA geometry outcomes. [ABSTRACT FROM AUTHOR]

Most previous computational studies on aerosol transport in models of the central airways of the human lung have focused on deposition, rather than transport of particles through these airways to the subtended lung regions. Using a model of the bronchial tree extending from the trachea to the segmental bronchi (J Appl Physiol 98: 970-980, 2005), we predicted aerosol delivery to the lung segments. Transport of 0.5-to 10-µm-diameter particles was computed at various gravity levels (0-1.6 G) during steady inspiration (100-500 ml/s). For each condition, the normalized aerosol distribution among the lung segments was compared with the normalized flow distribution by calculating the ratio (Ri) of the number of particles exiting each segmental bronchus i to the flow. When Ri = 1, particle transport was directly proportional to segmental flow. Flow and particle characteristics were represented by the Stokes number (Stk) in the trachea. For Stk < 0.01, Ri values were close to 1 and were unaffected by gravity. For Stk > 0.01, R1-varied greatly among the different outlets (Ri = 0.30-1.93 in normal gravity for 10-µm particles at 500 ml/s) and was affected by gravity and inertia. These data suggest that, for Stk < 0.01, ventilation defines the delivery of aerosol to lung segments and that the use of aerosol tracers is a valid technique to visualize ventilation in different parts of the lung. At higher Stokes numbers, inertia, but not gravitational sedimentation, is the second major factor affecting the transport of large particles in the lung. [ABSTRACT FROM AUTHOR]

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 cmH2O) 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 cmH2O for S < 25%, 6-8 cmH2O at S = 25% and 37.5%, and 5-7 cmH2O at S = 50% and 62.5%. Pc associated with fully developed airflow limitation was 4-6 cmH2O for S < 25%, >20 cmH2O at S = 25% (i.e., no flow limitation), 18 cmH2O at S = 37.5%, and 8-12 cmH2O 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. [ABSTRACT FROM AUTHOR]

Studies on isolated tracheal airway smooth muscle (ASM) strips have shown that length/force fluctuations, similar to those likely occurring during breathing, will mitigate ASM contractility. These studies conjecture that, solely by reducing length oscillations on a healthy, intact airway, one can create airway hyperresponsiveness, but this has never been explicitly tested. The intact airway has additional complexities of geometry and structure that may impact its relevance to isolated ASM strips. We examined the role of transmural pressure (Ptm) fluctuations of physiological amplitudes on the responsiveness of an intact airway. We developed an integrated system utilizing ultrasound imaging to provide real-time measurements of luminal radius and wall thickness over the full length of an intact airway (generation 10 and below) during Ptm oscillations. First, airway constriction dynamics to cumulative acetylcholine (ACh) doses (10-7 to 10-3 M) were measured during static and dynamic Ptm protocols. Regardless of the breathing pattern, the Ptm oscillation protocols were ineffective in reducing the net level of constriction for any ACh dose, compared with the static control (P = 0.225-0.793). Next, Ptm oscillations of increasing peak-to-peak amplitude were applied subsequent to constricting intact airways under static conditions (5.0-cmH2O Ptm) with a moderate ACh dose (10-5 M). Peak-to-peak Ptm oscillations ≤5.0 cmH2O resulted in no statistically significant bronchodilatory response (P = 0.429 and 0.490). Larger oscillations (10 cmH2O, peak to peak) produced modest dilation of 4.3% (P = 0.009). The lack of modulation of airway responsiveness by Ptm oscillations in intact, healthy airways suggests that ASM level mechanisms alone may not be the sole determinant of airway responsiveness. [ABSTRACT FROM AUTHOR]

Airways that collapse during deflation generate a crackle sound when they reopen during subsequent reinflation. Since each crackle is associated with the reopening of a collapsed airway, the likelihood of an airway to be a crackle source is identical to its vulnerability to collapse. To investigate this vulnerability of airways to collapse, crackles were recorded during the first inflation of six excised rabbit lungs from the collapsed state, and subsequent reinflations from 5, 2, 1, and 0 cmH2O end-expiratory pressure levels. We derived a relationship between the amplitude of a crackle sound at the trachea and the generation number (n) of the source airway where the crackle was generated. Using an asymmetrical tree model of the rabbit airways with elastic walls, airway vulnerability to collapse was also determined in terms of airway diameter D. During the reinflation from end-expiratory pressure = 0 cmH2O, the most vulnerable airways were estimated to be centered at n = 12 with a peak. Vulnerability in terms of D ranged between 0.1 and 1.3 mm, with a peak at 0.3 mm. During the inflation from the collapsed state, however, vulnerability was much less localized to a particular n or D, with maximum values of n = 8 and D = 0.75 mm. Numerical simulations using a tree model that incorporates airway opening and closing support these conclusions. Thus our results indicate that there are airways of a given range of diameters that can become unstable during deflation and vulnerable to collapse and subsequent injury. [ABSTRACT FROM AUTHOR]

Given the ubiquitous use of mice to study lung disease, it is curious that more investigators do not use repeated intubation to study mechanical and cellular changes in individual mice. One of the reasons for this limited use of intubation is that it is relatively difficult, despite there being several published studies that describe ways to achieve it. In this paper, we describe a complete procedure, including novel approaches that simplify this intubation, so that it can be routinely accomplished with relatively little training. The technique can also be set up with relatively little expense and expertise. This should make it possible for any laboratory to routinely carry out this intubation, thereby allowing longitudinal studies in individual mice and potentially increasing the statistical power by using each mouse as its own control. [ABSTRACT FROM AUTHOR]

The continuous changes in lung mechanics were related to those in pulmonary vascular resistance (Rv) during lung inflations to clarify the mechanical changes in the bronchoalveolar system and the pulmonary vasculature. Rv and low-frequency lung impedance data (ZL) were measured continuously in isolated, perfused rat lungs during 2-min inflation-deflation maneuvers between transpulmonary pressures of 2.5 and 22 cmH2O, both by applying positive pressure at the trachea and by generating negative pressure around the lungs in a closed box. ZL was averaged and evaluated for 2-s time windows; airway resistance (Raw), parenchymal damping and elastance (H) were determined in each window. Lung inflation with positive and negative pressures led to very similar changes in lung mechanics, with maximum decreases in Raw [-68 ± 4 (SE) vs. -64 ± 18%] and maximum increases in H (379 ± 36 vs. 348 ± 37%). Rv, however, increased with positive inflation pressure (15 ± 1%), whereas it exhibited mild decreases during negative-pressure expansions (-3 ± 0.3%). These results demonstrate that pulmonary mechanical changes are not affected by the opposing modes of lung inflations and confirm the importance of relating the pulmonary vascular pressures in interpreting changes in Rv. [ABSTRACT FROM AUTHOR]

Access to interstitial fluid from trachea is important for understanding tracheal microcirculation and pathophysiology. We tested whether a centrifugation method could be applied to isolate this fluid in rats by exposing excised trachea to 0 forces up to 609 g. The ratio between the concentration of the equilibrated extracellular tracer 51Cr-labeled EDTA in fluid isolated at 239 g and plasma averaged 0.94 ± 0.03 (n = 14), suggesting that contamination from the intracellular fluid phase was negligible. The protein pattern of the isolated fluid resembled plasma closely and had a protein concentration 83% of that in plasma. The colloid osmotic pressure in the centrifugate in controls (n = 5) was 18.8 ± 0.6 mmHg with a corresponding pressure in plasma of 22 ± 1.5 mmHg, whereas after overhydration (n = 5) these pressures fell to 9.8 ± 0.4 and 11.9 ± 0.4 mmHg, respectively. We measured inflammatory cytokine concentration in serum, interstitial fluid, and bronchoalveolar lavage fluid in LPS-induced inflammation. In control animals, low levels of IL-1β, IL-α, and TNF-a in serum, trachea interstitial fluid, and bronchoalveolar lavage fluid were detected. LPS resulted in a significantly higher concentration in IL-1β and IL-6 in interstitial fluid than in serum, showing a local production. To conclude, we have shown that interstitial fluid can be isolated from trachea by centrifugation and that trachea interstitial fluid has a high protein concentration and colloid osmotic pressure relative to plasma. Trachea interstitial fluid may also reflect lower airways and thus be of importance for understanding, e.g., inflammatory-induced airway obstruction. [ABSTRACT FROM AUTHOR]

Neutrophil elastase is a mediator common to asthma, chronic obstructive pulmonary disease, and cystic fibrosis and thought to contribute to the pathophysiology of these diseases. Previously, we found that inhaled hyaluronan blocked elastase-induced bronchoconstriction in allergic sheep through its control of tissue kallikrein. Here, we extend those studies by deter- mining if inhaled hyaluronan can protect against the elastase-induced depression in tracheal mucus velocity, a surrogate marker of whole lung mucociliary clearance. We measured tracheal mucus velocity in allergic sheep before, and sequentially for 6 h after, aerosol challenge with porcine pancreatic elastase alone and after pretreatment with 1.5 or 6 mg aerosolized hyaluronan. Elastase (2.55 U) decreased tracheal mucus velocity. Pretreatment with 6 mg, but not 1.5 mg, hyaluronan inhibited the elastase-induced decrease in tracheal mucus velocity. Hyaluronan (6 mg) given 1 h after elastase challenge was ineffective, suggesting the involvement of secondary mediators. The elastase- induced depression in mucus transport appeared to be mediated, in part, by reactive oxygen species and bradykinin because pretreatment with either aerosolized catalase (38 mg/3 ml) or the bradykinin B2-receptor antagonist HOE140 (400 nM/kg) was also effective in blocking the response. These latter two findings are consistent with oxygen radical-induced degradation of hyaluronan with concomitant loss of its regulatory effect on tissue kallikrein, resulting in kinin generation. This hypothesis is supported by the demonstration that hyaluronan failed to block the oxygen radical-induced fall in tracheal mucus velocity resulting from xanthine-xanthine oxidase challenge and that inhaled bradykinin itself can slow mucociliary transport. [ABSTRACT FROM AUTHOR]

We have shown previously that excessive distention of the rat trachea during mechanical ventilation results in enhanced leukocyte recruitment to the airway (Lim LH and Wagner EM. Am J Respir Crit Care Med 168:1068-1074, 2003). The objectives of this study were to develop a mouse model of positive end-expiratory pressure (PEEP)-induced leukocyte recruitment to the airway and begin to pursue molecular mechanisms that may contribute to the in vivo observation of increased leukocyte adhesion after PEEP exposure. We studied C57BL/6 wild-type mice and mice deficient in P-selectin or intercellular adhesion molecule-1 (ICAM-1) exposed to intermittent PEEP (8 cmH2O) applied five times for a 1-min duration, at 10-min intervals. After the imposed ventilatory stress, during normal ventilation (0.2 mI/breath, no PEEP), leukocyte adhesion in tracheal postcapillary venules was determined using intravital microscopy. PEEP induced a time-dependent increase in leukocyte adhesion that was significantly increased between 0 and 60 min (P < 0.01). Furthermore, PEEP-induced leukocyte adhesion at 60 min was ablated in P-selectin- and ICAM-1-deficient mice. These findings demonstrate the essential nature of both P-selectin and ICAM-1 within airway postcapillary venular endothelium for leukocyte recruitment after airway distension. [ABSTRACT FROM AUTHOR]

Patients referred for treatment of tracheal stenosis typically are asymptomatic until critical narrowing of the airway occurs, which then requires immediate intervention. To understand how tracheal stenosis affects local pressure drops and explore how a dramatic increase in pressure drop could possibly be detected at an early stage, a computational fluid dynamics (CFD) study was undertaken. We assessed flow patterns and pressure drops over tracheal stenoses artificially inserted into a realistic three-dimensional upper airway model derived from multislice computed tomography images obtained in healthy men. Solving the Navier-Stokes equations (with a Yang-shih k-ϵ turbulence model) for different degrees of tracheal constriction located approximately one tracheal diameter below the glottis, the simulated pressure drop over the stenosis (ΔP) was seen to dramatically increase only when well over 70% of the tracheal lumen was obliterated. At 30 1/mm, ΔP increased from 7 Pa for a 50% stenosis to, respectively, 46 and 235 Pa for 80% and 90% stenosis. The pressure-flow relationship in the entire upper airway model (between mouth and end of trachea) in the flow range 0-60 l/min showed a power law relationship with best-fit flow exponent of 1.77 in the absence of stenosis. The exponent became 1.92 and 2.00 in the case of 60% and 85% constriction, respectively. The present simulations confirm that the overall pressure drop at rest is only affected in case of severe constriction, and the simulated flow dependence of pressure drop suggests a means of detecting stenosis at a precritical stage. [ABSTRACT FROM AUTHOR]

Vasoactive intestinal peptide (VIP) and nitric oxide (NO) are neurotransmitters involved in the regulation of bronchial and pulmonary vascular tone. Published studies of the effects of VIP on airway mucus secretion have yielded conflicting results. The purpose of this study was to determine the effect of VIP on mucus secretion in the ferret trachea and if this effect was influenced by NO. We used a sandwich enzyme-linked lectin assay to measure mucin secretion and a turbidimetric assay to measure lysozyme (serous cell) secretion from ferret tracheal segments. VIP (10-7 M) increased mucin secretion over 2 h. VIP (10-9 to 10-5 M) stimulated mucin secretion in a dose-dependent fashion. VIP-induced mucin secretion was partially blocked by a VIP receptor antagonist (a chimeric VIP-pituitary adenylate cyclase-activating peptide analog, VIP receptor antagonist) at a 10-fold excess concentration. At all concentrations tested, neither NG-nitro-L-arginine methyl ester, an inhibitor of NO synthase, nor S-nitroso-N-acetyl-penicillamine, an NO donor, had any significant effect on constitutive or VIP-induced mucus secretion. We conclude that VIP-stimulated mucin and lysozyme secretion was both time dependent and dose dependent and that NO neither stimulates nor inhibits mucus secretion in the ferret trachea. [ABSTRACT FROM AUTHOR]

To test the hypothesis that peak expiratory flow is determined by the wave-speed-limiting mechanism, we studied the time dependency of the trachea and its effects on flow limitation. For this purpose, we assessed the relationship between transmural pressure and cross-sectional area [the tube law (TL)] of six excised human tracheae under controlled conditions of static (no flow) and forced expiratory flow. We found that TLs of isolated human tracheae followed quite well the mathematical representation proposed by Shapiro (Shapiro AH. J Biomech Eng 99: 126–147, 1977) for elastic tubes. Furthermore, we found that the TL measured at the onset of forced expiratory flow was significantly stiffer than the static TL. As a result, the stiffer TL measured at the onset of forced expiratory flow predicted theoretical maximal expiratory flows far greater than those predicted by the more compliant static TL, which in all cases studied failed to explain peak expiratory flows measured at the onset of forced expiration. We conclude that the observed viscoelasticity of the tracheal walls can account for the measured differences between maximal and ‘supramaximal’ expiratory flows seen at the onset of forced expiration. [ABSTRACT FROM AUTHOR]

The pharyngeal airway can be considered as an airway luminal shape formed by surrounding tissues, contained within a bony enclosure formed by the mandible, skull base, and cervical vertebrae. Mandibular advancement (MA), a therapy for obstructive sleep apnea, is thought to increase the size of this bony enclosure and to decrease the pressure in the upper airway extraluminal tissue space (ETP). We examined the effect of MA on upper airway airflow resistance (Rua) and ETP in a rabbit model. We studied 11 male, supine, anesthetized, spontaneously breathing New Zealand White rabbits in which ETP was measured via pressure transducer-tipped catheters inserted into the tissues surrounding the lateral (ETPlat) and anterior (ETPant) pharyngeal wall. Airflow, measured via surgically inserted pneumotachograph in series with the trachea, and tracheal pressure were recorded while graded MA at 75° and 100° to the horizontal was performed using an external traction device. Data were analyzed using a linear mixed-effects statistical model. We found that MA at 100° increased mouth opening from 4.7 ± 0.4 to 6.6 ± 0.4 (SE) mm (n = 7; P < 0.004), whereas mouth opening did not change from baseline (4.0 ± 0.2 mm) with MA at 75°. MA at both 75° and 100° decreased mean ETPlat and ETPant by ∼0.1 cmH2O/mm MA (n = 7–11; all P – 0.0005). However, the fall in Rua (measured at 20 ml/s) with MA was greater for MA at 75° (∼0.03 mmH2O·ml-1·s·mm-1) than at 100° (∼0.01 mmH2O·ml-1·s·mm-1; P < 0.02). From these findings, we conclude that MA decreases ETP and is more effective in reducing Rua without mouth opening. [ABSTRACT FROM AUTHOR]

Spontaneous or agonist-induced contraction of airway smooth muscle can be observed very early in fetal life, thus explaining the possible occurrence of bronchospasm in very low birth weight infants within the first days of life. In an attempt to better manage such bronchospasms, the aim of the present study was to investigate the age-specific modifications in airway smooth muscle relaxation to β2-agonists and muscarinic antagonists using a combination of functional and molecular techniques. In the rat, isometric relaxation to the β2-agonist salbutamol was examined in tracheae; we also examined muscarinic receptor expression (M2R and M3R mRNA levels) in airway smooth muscle by immunochemistry, Western blotting, and real-time PCR. Compared with adults, salbutamol-induced relaxation was twofold greater in immature rat isolated tracheae preconstricted by carbachol. This effect was associated with a lower expression of M2R in the smooth muscle of immature animals (sixfold and almost twofold as assessed by immunochemistry and Western blotting, re- spectively). Real-time PCR data indicate that changes in M2R expression according to age occurred at a posttranscriptional level. In adult airways, there was a significantly greater functional efficacy of M2R blockade by methoctramine compared with that shown in immature rats. Because of the limited availability of human neonate lung tissue, only the molecular part of the study was performed, and we observed a qualitatively similar effect, i.e., a lower M2R expression in the neonatal airway smooth muscle, although this was quantitatively smaller. We conclude that β2-agonist-induced relaxation is enhanced in immature compared with adult airways as a result of greater postjunctional M2R expression in adult airway smooth muscle. This finding may be of importance in the clinical management of broncho- constriction in neonates. [ABSTRACT FROM AUTHOR]

We have studied gas flow and particle deposition in a realistic three-dimensional (3D) model of the bronchial tree, extending from the trachea to the segmental bronchi (7th airway generation for the most distal ones) using computational fluid dynamics. The model is based on the morphometrical data of Horsfield et al. (Horsfield K, Dart G. Olson DE, Filley GF, and Cumming G. J Appl Physiol 31:207–217, 1971) and on bronchoscopic and computerized tomography images, which give the spatial 3D orientation of the crowed ducts. It incorporates realistic angles of successive branching planes. Steady inspiratory flow varying between 50 and 500 cm3/s was simulated, as well as deposition of spherical aerosol particles (l–7 μm diameter, 1 g/cm3 density). Flow simulations indicated nonfully developed flows in the branches due to their relative short lengths. Velocity flow profiles in the segmental bronchi, taken one diameter downstream of the bifurcation, were distorted compared with the flow in a simple curved tube, and wide patterns of secondary flow fields were observed. Both were due to the asymmetrical 3D configuration of the bifurcating network. Viscous pressure drop in the model was compared with results obtained by Pedley et al. (Pedley TJ, Schroter RC, and Sudlow MF. Respir Physiol 9:387–405, 1970), which are shown to be a good first approximation. Particle deposition increased with particle size and was minimal for ∼200 cm3/s inspiratory flow, but it was highly heterogeneous fur branches of the same generation. [ABSTRACT FROM AUTHOR]

We hypothesized that differences in actin filament length could influence force fluctuation-induced relengthening (FFIR) of contracted airway smooth muscle and tested this hypothesis as follows. One-hundred micromolar ACh-stimulated canine tracheal smooth muscle (TSM) strips set at optimal reference length (Lref) were allowed to shorten against 32% maximal isometric force (Fmax) steady preload, after which force oscillations of ± 16% Fmax were superimposed. Strips relengthened during force oscillations. We measured hysteresivity and calculated FFIR as the difference between muscle length before and after 20-min imposed force oscillations. Strips were relaxed by ACh removal and treated for 1 h with 30 nM latrunculin B (sequesters G-actin and promotes depolymerization) or 500 nM jasplakinolide (stabilizes actin filaments and opposes depolymerization). A second isotonic contraction protocol was then performed; FFIR and hysteresivity were again measured. Latrunculin B increased FFIR by 92.2 ± 27.6% Lref and hysteresivity by 31.8 ± 13.5% vs. pretreatment values. In contrast, jasplakinolide had little influence on relengthening by itself; neither FFIR nor hysteresivity was significantly affected. However, when jasplakinolide-treated tissues were then incubated with latrunculin B in the continued presence of jasplakinolide for 1 more h and a third contraction protocol performed, latrunculin B no longer substantially enhanced TSM relengthening. In TSM treated with latrunculin B + jasplakinolide, FFIR increased by only 3.03 ± 5.2% Lref and hysteresivity by 4.14 ± 4.9% compared with its first (pre-jasplakinolide or latrunculin B) value. These results suggest that actin filament length, in part, determines the relengthening of contracted airway smooth muscle. [ABSTRACT FROM AUTHOR]

Contraction of smooth muscle tissue involves interactions between active and passive structures within the cells and in the extracellular matrix. This study focused on a defined mechanical behavior (shortening-dependent stiffness) of canine tracheal smooth muscle tissues to evaluate active and passive contributions to tissue behavior. Two approaches were used. In one, mechanical measurements were made over a range of temperatures to identify those functions whose temperature sensitivity (Q10) identified them as either active or passive. Isotonic shortening velocity and rate of isometric force development had high Q10 values (2.54 and 2.13, respectively); isometric stiffness showed Q10 values near unity. The shape of the curve relating stiffness to isotonic shortening lengths was unchanged by temperature. In the other approach, muscle contractility was reduced by applying a sudden shortening step during the rise of isometric tension. Control contractions began with the muscle at the stepped length so that properties were measured over comparable length ranges. Under isometric conditions, redeveloped isometric force was reduced, but the ratio between force and stiffness did not change. Under isotonic conditions beginning during force redevelopment at the stepped length, initial shortening velocity and the extent of shortening were reduced, whereas the rate of relaxation was increased. The shape of the curve relating stiffness to isotonic shortening lengths was unchanged, despite the step-induced changes in muscle contractility. Both sets of findings were analyzed in the context of a quasistructural model describing the shortening-dependent stiffness of lightly loaded tracheal muscle strips. [ABSTRACT FROM AUTHOR]

Lung development is both a pre- and postnatal process. Although many lung diseases have their origins in early childhood, few quantitative data are available on the normal growth and differentiation of both the conducting airways and the airway epithelium during the postnatal period. We examined rhesus monkey lungs from five postnatal ages: 4–6 days and 1, 2, 3, and 6 mo. Airways increase significantly in both length and circumference as monkeys increase significantly in body weight from 5 days to 6 mo. In this study we asked; as basement membrane surface area increases, does the epithelial cell organization change? To answer this question, we quantified total epithelial cell mass using high-resolution light micrographs and morphometric techniques on sections from defined airway regions; trachea, proximal intrapulmonary bronchus (generations 1 or 2), and distal intrapulmonary bronchus (generations 6–8). Epithelial thickness decreased in the smaller, more distal, airways compared with trachea but did not change with age in the trachea and proximal bronchus. The volume fraction of all cell types measured did not change significantly. Ciliated cells in the distal bronchus and goblet cells in the trachea both decreased in abundance with increasing age. Overall, the epithelial cell populations changed little in terms of mass or relative abundance to each other during this period of active postnatal lung growth. Regarding the proximal conducting airway epithelium, we conclude that 1) the steady-state abundance is tightly regulated to keep the proportion of cell types constant, and 2) establishment of these cell types occurs before 4–6 days postnatal age. We conclude that growth of the proximal airways occurs primarily in length and lags behind that of the lung parenchyma. [ABSTRACT FROM AUTHOR]

Examines the possibility that an elastic load applied by the tracheal cartilage contributes to the in vivo limitation of shortening by the insertion of single pairs of sonomicrometry crystals into the trachealis muscle at the level of the fifth cartilage ring in dogs; Capability of airway smooth muscles from the canine trachea and major bronchii.

Studies the effects of tumor necrosis factor alpha on murine tracheal rings responsiveness of G-protein-coupled receptor agonists and KCl. Tissue preparation and organ culture; Carbachol-induced isometric force.

Studies modulation of cholinergic responsiveness through the beta-adrenoceptor signal transmission pathway in bovine trachealis. Capacity of airway smooth muscle to generate force and magnitude of stimuli.

Studies the effect of substance P released from intrinsic airway neurons to ozone-enhanced airway hyperresponsiveness in ferret trachea. Confirmation of sensory nerve depletion; Innervation to superficial muscular plexus.

Describes the immunolocalization of a Na-K-2Cl (NKCC) cotransporter in human tracheobronchial smooth muscle. Hypothesis that a NKCC cotransporter is present and functional in airway smooth muscle; Use of monoclonal and polyclonal antibodies to demonstrate the presence of NKCC cotransporter protein in isolated human fetal trachea and normal human bronchial smooth muscle cells by Western blotting.