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ABSTRACT: The present study presents preliminary findings on how structural/functional abnormalities of the airway wall relate to excessive airway narrowing and reduced bronchodilatory response to deep inspiration (DI) in subjects with a history of asthma. Bronchial segments were acquired from subjects undergoing surgery, mostly to remove pulmonary neoplasms. Subjects reported prior doctor-diagnosed asthma (n=5) or had no history of asthma (n=8). In vitro airway narrowing in response to acetylcholine was assessed to determine maximal bronchoconstriction and sensitivity, under static conditions and during simulated tidal and DI manoeuvres. Fixed airway segments were sectioned for measurement of airway wall dimensions, particularly the ASM layer. Airways from subjects with a history of asthma had increased airway smooth muscle (ASM, P=0.014), greater maximal airway narrowing under static conditions (P=0.003) but no change in sensitivity. Maximal airway narrowing was positively correlated with the area of the ASM layer (r=0.58, P=0.039). In tidally oscillating airways, DI produced bronchodilation in airways from the control group (P=0.0001) and the group with a history of asthma (P=0.001). While bronchodilation to DI was reduced with increased airway narrowing (P=0.02), when the level of airway narrowing was matched, there was no difference in magnitude of bronchodilation to DI between groups. Results suggest that greater ASM mass in asthma contributes to exaggerated airway narrowing in vivo. In comparison, the airway wall in asthma may have a normal response to mechanical stretch during DI. We propose that increased maximal airway narrowing and the reduced bronchodilatory response to DI in asthma are independent.
Journal of Applied Physiology 03/2013; · 3.75 Impact Factor
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ABSTRACT: Imaging of alveoli in situ has for the most part been infeasible due to the high resolution required to discern individual alveoli and limited access to alveoli beneath the lung surface. In this study, we present a novel technique to image alveoli using optical coherence tomography (OCT). We propose the use of OCT needle probes, where the distal imaging probe has been miniaturized and encased within a hypodermic needle (as small as 30-gauge, outer diameter 310 μm), allowing insertion deep within the lung tissue with minimal tissue distortion. Such probes enable imaging at a resolution of ∼12 μm within a three-dimensional cylindrical field of view with diameter ∼1.5 mm centered on the needle tip. The imaging technique is demonstrated on excised lungs from three different species: adult rats, fetal sheep, and adult pigs. OCT needle probes were used to image alveoli, small bronchioles, and blood vessels, and results were matched to histological sections. We also present the first dynamic OCT images acquired with an OCT needle probe, allowing tracking of individual alveoli during simulated cyclical lung inflation and deflation.
Journal of Applied Physiology 07/2012; 113(6):967-74. · 3.75 Impact Factor
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ABSTRACT: In healthy individuals, deep inspirations (DIs) taken prior to a bronchial challenge reduce the bronchoconstrictor response, which is termed "bronchoprotection". The mechanism(s) of DI-induced bronchoprotection is unclear. The forced oscillation technique was used to assess the effect of prior DI on subsequent bronchoconstriction to methacholine (MCh) in BALB/c mice. We assessed likely mechanisms for the bronchoprotective effects of DI including reduced airway narrowing (from changes in airway resistance) and/or closure (changes in tissue elastance) and enhanced bronchodilation to a subsequent DI (% reversal in airway narrowing). DI prior to MCh challenge: 1) did not reduce but instead enhanced airway narrowing (p<0.05); 2) increased ventilation heterogeneity (p<0.05); 3) enhanced the subsequent bronchodilatory response to DI (p<0.05); and 4) reduced tissue elastance (p<0.05), suggesting opening of closed airways or alveoli units. Our findings suggest that DI prior to MCh challenge may elicit a series of changes, some of which are beneficial to respiratory function (enhanced bronchodilation), while others place greater load on the system (enhanced bronchoconstriction and ventilation heterogeneity). It is proposed that the relative magnitudes of these opposing physiological and mechanical effects will determine the net effect on respiratory function in health and disease.
European Respiratory Journal 03/2012; 40(4):982-9. · 5.89 Impact Factor
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ABSTRACT: The primary functional abnormality in asthma is airway hyperresponsiveness (AHR)-excessive airway narrowing to bronchoconstrictor stimuli. Our understanding of the underlying mechanism(s) producing AHR is incomplete. While structure-function relationships have been evoked to explain AHR (e.g., increased airway smooth muscle (ASM) mass in asthma) more recently there has been a focus on how the dynamic mechanical environment of the lung impacts airway responsiveness in health and disease. The effects of breathing movements such as deep inspiration reveal innate protective mechanisms in healthy individuals that are likely mediated by dynamic ASM stretch but which may be impaired in asthmatic patients and thereby facilitate AHR. This perspective considers the evidence for and against a role of dynamic ASM stretch in limiting the capacity of airways to narrow excessively. We propose that lung function measured after bronchial provocation in the laboratory and changes in lung function perceived by the patient in everyday life may be quite different in their dependence on dynamic ASM stretch.
Journal of Allergy 01/2012; 2012:157047.
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ABSTRACT: In situ imaging of alveoli and the smaller airways with optical coherence tomography (OCT) has significant potential in the assessment of lung disease. We present a minimally invasive imaging technique utilizing an OCT needle probe. The side-facing needle probe comprises miniaturized focusing optics consisting of no-core and GRIN fiber encased within a 23-gauge needle. 3D-OCT volumetric data sets were acquired by rotating and retracting the probe during imaging. The probe was used to image an intact, fresh (not fixed) sheep lung filled with normal saline, and the results validated against a histological gold standard. We present the first published images of alveoli acquired with an OCT needle probe and demonstrate the potential of this technique to visualize other anatomical features such as bifurcations of the bronchioles.
Journal of Biomedical Optics 03/2011; 16(3):036009. · 3.16 Impact Factor
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ABSTRACT: In healthy individuals, deep inspiration produces bronchodilation and reduced airway responsiveness, which may be a response of the airway wall to mechanical stretch. The aim of this study was to examine the in vitro response of isolated human airways to the dynamic mechanical stretch associated with normal breathing. Human bronchial segments (n = 6) were acquired from patients without airflow obstruction undergoing lung resection for pulmonary neoplasms. The side branches were ligated and the airways were mounted in an organ bath chamber. Airway narrowing to cumulative concentrations of acetylcholine (3 × 10(-6) M to 3 × 10(-3) M) was measured under static conditions and in the presence of "tidal" oscillations with intermittent "deep inspiration." Respiratory maneuvers were simulated by varying transmural pressure using a motor-controlled syringe pump (tidal 5 to 10 cmH(2)O at 0.25 Hz, deep inspiration 5 to 30 cmH(2)O). Airway narrowing was determined from decreases in lumen volume. Tidal oscillation had no effect on airway responses to acetylcholine which was similar to those under static conditions. Deep inspiration in tidally oscillating, acetylcholine-contracted airways produced potent, transient (<1 min) bronchodilation, ranging from full reversal in airway narrowing at low acetylcholine concentrations to ∼50% reversal at the highest concentration. This resulted in a temporary reduction in maximal airway response (P < 0.001), without a change in sensitivity to acetylcholine. Our findings are that the mechanical stretch of human airways produced by physiological transmural pressures generated during deep inspiration produces bronchodilation and a transient reduction in airway responsiveness, which can explain the beneficial effects of deep inspiration in bronchial provocation testing in vivo.
Journal of Applied Physiology 02/2011; 110(6):1510-8. · 3.75 Impact Factor
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Journal of Applied Physiology 09/2010; 109(3):938-9; author reply 940-1. · 3.75 Impact Factor
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ABSTRACT: Previous histological and imaging studies have shown the presence of variability in the degree of bronchoconstriction of airways sampled at different locations in the lung (i.e., heterogeneity). Heterogeneity can occur at different airway generations and at branching points in the bronchial tree. Whilst heterogeneity has been detected by previous experimental approaches, its spatial relationship either within or between airways is unknown.
In this study, distribution of airway narrowing responses across a portion of the porcine bronchial tree was determined in vitro. The portion comprised contiguous airways spanning bronchial generations (#3-11), including the associated side branches. We used a recent optical imaging technique, anatomical optical coherence tomography, to image the bronchial tree in three dimensions. Bronchoconstriction was produced by carbachol administered to either the adventitial or luminal surface of the airway. Luminal cross sectional area was measured before and at different time points after constriction to carbachol and airway narrowing calculated from the percent decrease in luminal cross sectional area.
When administered to the adventitial surface, the degree of airway narrowing was progressively increased from proximal to distal generations (r = 0.80 to 0.98, P < 0.05 to 0.001). This 'serial heterogeneity' was also apparent when carbachol was administered via the lumen, though it was less pronounced. In contrast, airway narrowing was not different at side branches, and was uniform both in the parent and daughter airways.
Our findings demonstrate that the bronchial tree expresses intrinsic serial heterogeneity, such that narrowing increases from proximal to distal airways, a relationship that is influenced by the route of drug administration but not by structural variations accompanying branching sites.
Respiratory research 01/2010; 11:9. · 3.36 Impact Factor
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Peter B Noble,
Adrian R West,
Robert A McLaughlin,
Julian J Armstrong,
Sven Becker,
Peter K McFawn,
Jonathan P Williamson,
Peter R Eastwood,
David R Hillman,
David D Sampson,
Howard W Mitchell
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ABSTRACT: Regulation of airway caliber by lung volume or bronchoconstrictor stimulation is dependent on physiological, structural, and mechanical events within the airway wall, including airway smooth muscle (ASM) contraction, deformation of the mucosa and cartilage, and tensioning of elastic matrices linking wall components. Despite close association between events in the airway wall and the resulting airway caliber, these have typically been studied separately: the former primarily using histological approaches, the latter with a range of imaging modalities. We describe a new optical technique, anatomical optical coherence tomography (aOCT), which allows changes at the luminal surface (airway caliber) to be temporally related to corresponding dynamic movements within the airway wall. A fiber-optic aOCT probe was inserted into the lumen of isolated, liquid-filled porcine airways. It was used to image the response to ASM contraction induced by neural stimulation and to airway inflation and deflation. Comparisons with histology indicated that aOCT provided high-resolution images of the airway lumen including mucosal folds, the entire inner wall (mucosa and ASM), and partially the cartilaginous outer wall. Airway responses assessed by aOCT revealed several phenomena in "live" airways (i.e., not fixed) previously identified by histological investigations of fixed tissue, including a geometric relationship between ASM shortening and luminal narrowing, and sliding and bending of cartilage plates. It also provided direct evidence for distensibility of the epithelial membrane and anisotropic behavior of the airway wall. Findings suggest that aOCT can be used to relate changes in airway caliber to dynamic events in the wall of airways.
Journal of Applied Physiology 11/2009; 108(2):401-11. · 3.75 Impact Factor
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ABSTRACT: In adults, respiratory movements, such as tidal and deep breaths, reduce airway smooth muscle force and cause bronchodilation. Evidence suggests that these beneficial effects of oscillatory strain do not occur in children, possibly because of reduced coupling of the airways to lung tissue or maturational differences in the intrinsic response of the airways to oscillatory strain.
The bronchodilator effects of oscillatory strain were compared in isolated airway segments from immature (3-4 weeks and 8-10 weeks old) and mature (18-20 weeks old) pigs. The lumen of fluid-filled bronchi was volume-oscillated to simulate tidal breaths and 0.5x, 2x and 4x tidal volumes. Contractions to acetylcholine and electrical field stimulation were recorded from the lumen pressure and were compared under oscillating and static conditions. Airway stiffness was determined from the amplitude of the lumen pressure cycles and the volume of oscillation.
Volume oscillation reduced contractions to acetylcholine and electrical field stimulation in an amplitude-dependent manner and the percentage reduction was the same for the different stimuli across all age groups. There was no difference in the relaxed dynamic stiffness of airways from the different age groups.
The intrinsic response of the airway wall to equivalent dynamic strain did not differ in airways from pigs of different ages. These findings suggest that mechanisms external to the airway wall may produce age-related differences in the response to lung inflation during development.
Respirology 08/2009; 14(7):991-8. · 2.42 Impact Factor
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ABSTRACT: Deep inspirations (DIs) are large periodic breathing maneuvers that regulate airway caliber and prevent airway obstruction in vivo. This study characterized the intrinsic response of the intact airway to DI, isolated from parenchymal attachments and other in vivo interactions. Porcine isolated bronchial segments were constricted with carbachol and subjected to transmural pressures of 5-10 cmH2O at 0.25 Hz (tidal breathing) interspersed with single DIs of amplitude 5-20 cmH2O, 5-30 cmH2O, or 5-40 cmH2O (6-s duration) or DI of amplitude 5-30 cmH2O (30-s duration). Tidal breathing was ceased after DI in a subset of airways and in control airways in which no DI was performed. Luminal cross-sectional area was measured using a fiber-optic endoscope. Bronchodilation by DI was amplitude dependent; 5-20 cmH2O DIs produced less dilation than 5-30 cmH2O and 5-40 cmH2O DIs (P=0.003 and 0.012, respectively). Effects of DI duration were not significant (P=0.182). Renarrowing after DI followed a monoexponential decay function to pre-DI airway caliber with time constants between 27.4+/-4.3 and 36.3+/-6.9 s. However, when tidal breathing was ceased after DI, further bronchoconstriction occurred within 30s. This response was identical in both the presence and absence of DI (P=0.919). We conclude that the normal bronchodilatory response to DI occurs as a result of the direct mechanical effects of DI on activated ASM in the airway wall. Further bronchoconstriction occurs by altering the airway wall stress following DI, demonstrating the importance of continual transient strains in maintaining airway caliber.
Journal of Applied Physiology 07/2008; 105(2):479-85. · 3.75 Impact Factor
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ABSTRACT: In vivo, breathing movements, including tidal and deep inspirations (DIs), exert a number of beneficial effects on respiratory system responsiveness in healthy humans that are diminished or lost in asthma, possibly as a result of reduced distension (strain) of airway smooth muscle (ASM). We used bronchial segments from pigs to assess airway responsiveness under static conditions and during simulated tidal volume oscillations with and without DI and to determine the roles of airway stiffness and ASM strain on responsiveness. To simulate airway dilations during breathing, we cycled the luminal volume of liquid-filled segments. Volume oscillations (15 cycles/min) were set so that, in relaxed airways, they produced a transmural pressure increase of approximately 5-10 cmH(2)O for tidal maneuvers and approximately 5-30 cmH(2)O for DIs. ACh dose-response curves (10(-7)-3 x 10(-3) M) were constructed under static and dynamic conditions, and maximal response and sensitivity were determined. Airway stiffness was measured from tidal trough-to-peak pressure and volume cycles. ASM strain produced by DI was estimated from luminal volume, airway length, and inner wall area. DIs produced substantial ( approximately 40-50%) dilation, reflected by a decrease in maximal response (P < 0.001) and sensitivity (P < 0.05). However, the magnitude of bronchodilation decreased significantly in proportion to airway stiffening caused by contractile activation and an associated reduction in ASM strain. Tidal oscillations, in comparison, had little effect on responsiveness. We conclude that DI regulates airway responsiveness at the airway level, but this is limited by airway stiffness due to reduced ASM strain.
Journal of Applied Physiology 09/2007; 103(3):787-95. · 3.75 Impact Factor
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ABSTRACT: Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0-20 cmH(2)O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls (P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi (P < 0.01) and smooth muscle strips (P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.
Journal of Applied Physiology 10/2002; 93(4):1296-300. · 3.75 Impact Factor
