ORCID Profile
0000-0001-9028-7751
Current Organisation
University of Western Australia
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Publisher: Wiley
Date: 05-07-2016
DOI: 10.1111/RESP.12841
Abstract: COPD is defined as airflow limitation that is not reversed by treatment. In asthma, airflow limitation is not only reversible, but also inducible. This is called 'airway hyperresponsiveness' (AHR) and is associated with thickening of the airway wall, predominantly the layer of airway smooth muscle, due to more cells, bigger cells and more extracellular matrix (ECM) in proportion to the increase in smooth muscle. AHR is also observed in COPD if the changes in airflow are expressed as a percent of the baseline lung function. However, the absolute change in baseline lung function that can be induced in COPD is actually less than that seen in normal subjects, suggesting that the airways in COPD are resistant not only to opening, but also to closing. This observation agrees with physiological measures showing increased airway wall stiffness in COPD. Like asthma, airway wall thickness is increased in COPD, including the layer of smooth muscle. Unlike asthma, however, fixed airflow obstruction appears to be characterized by a disproportionate increase in the ECM within the smooth muscle layer. In this review, we summarize the studies of airway matrix deposition in COPD and put forward the proposal that the airway remodelling in COPD is different from that in asthma and call for a systematic analysis of airway matrix deposition in COPD.
Publisher: Frontiers Media SA
Date: 23-08-2019
Publisher: European Respiratory Society (ERS)
Date: 09-03-2012
DOI: 10.1183/09031936.00204311
Abstract: In healthy in iduals, 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.
Publisher: Springer Science and Business Media LLC
Date: 04-10-2018
DOI: 10.1038/S41598-018-32407-0
Abstract: Miniaturised optical coherence tomography (OCT) fibre-optic probes have enabled high-resolution cross-sectional imaging deep within the body. However, existing OCT fibre-optic probe fabrication methods cannot generate miniaturised freeform optics, which limits our ability to fabricate probes with both complex optical function and dimensions comparable to the optical fibre diameter. Recently, major advances in two-photon direct laser writing have enabled 3D printing of arbitrary three-dimensional micro/nanostructures with a surface roughness acceptable for optical applications. Here, we demonstrate the feasibility of 3D printing of OCT probes. We evaluate the capability of this method based on a series of characterisation experiments. We report fabrication of a micro-optic containing an off-axis paraboloidal total internal reflecting surface, its integration as part of a common-path OCT probe, and demonstrate proof-of-principle imaging of biological s les.
Publisher: Wiley
Date: 17-01-2016
DOI: 10.1111/RESP.12727
Publisher: American Physiological Society
Date: 12-2022
DOI: 10.1152/JAPPLPHYSIOL.00493.2022
Abstract: Bronchial thermoplasty is a treatment for asthma that targets the airway smooth muscle directly. We demonstrate the feasibility and constraints of predicting patient-specific response to thermoplasty using a computational model informed by pretreatment CT scans at different lung volumes. Predictions are compared with functional outcomes and posttreatment CT scans. This has the potential to form the basis for improved clinical practice.
Publisher: American Physiological Society
Date: 09-2010
Publisher: Elsevier BV
Date: 09-2020
Publisher: Elsevier BV
Date: 08-2020
Publisher: American Physiological Society
Date: 04-2021
DOI: 10.1152/JAPPLPHYSIOL.00959.2020
Abstract: CT scanning was used to evaluate the response of in idual airways in patients undergoing bronchial thermoplasty. Airways dilated after treatment by 6.4% on average with substantial heterogeneity and a greater response in the most distal airways measured.
Publisher: American Physiological Society
Date: 06-2011
DOI: 10.1152/JAPPLPHYSIOL.01226.2010
Abstract: In healthy in iduals, 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 ( 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.
Publisher: IEEE
Date: 04-2013
Publisher: American Thoracic Society
Date: 07-2022
Publisher: American Physiological Society
Date: 15-09-2013
DOI: 10.1152/AJPLUNG.00162.2013
Abstract: Sustained lung inflations (SI) at birth may recruit functional residual capacity (FRC). Clinically, SI increase oxygenation and decrease need for intubation in preterm infants. We tested whether a SI to recruit FRC would decrease lung injury from subsequent ventilation of fetal, preterm lambs. The preterm fetus (128 ± 1 day gestation) was exteriorized from the uterus, a tracheostomy was performed, and fetal lung fluid was removed. While maintaining placental circulation, fetuses were randomized to one of four 15-min interventions: 1) positive end-expiratory pressure (PEEP) 8 cmH 2 O ( n = 4), 2) 20 s SI to 50 cmH 2 O then PEEP 8 cmH 2 O ( n = 10), 3) mechanical ventilation at tidal volume (V T ) 7 ml/kg ( n = 13), or 4) 20 s SI then ventilation at V T 7 ml/kg ( n = 13). Lambs were ventilated with 95% N 2 /5% CO 2 and PEEP 8 cmH 2 O. Volume recruitment was measured during SI, and fetal tissues were collected after an additional 30 min on placental support. SI achieved a mean FRC recruitment of 15 ml/kg (range 8–27). Fifty percent of final FRC was achieved by 2 s, 65% by 5 s, and 90% by 15 s, demonstrating prolonged SI times are needed to recruit FRC. SI alone released acute-phase proteins into the fetal lung fluid and increased mRNA expression of proinflammatory cytokines and acute-phase response genes in the lung. Mechanical ventilation further increased all markers of lung injury. SI before ventilation, regardless of the volume of FRC recruited, did not alter the acute-phase and proinflammatory responses to mechanical ventilation at birth.
Publisher: European Respiratory Society (ERS)
Date: 11-2005
DOI: 10.1183/09031936.05.00065405
Abstract: During bronchoconstriction elastic after-loads arise due to distortion of lung parenchyma by the narrowing airway. In the present study, the functional effect of parenchymal elastic after-load on airway narrowing was determined. Airway narrowing was measured in vivo over a range of transpulmonary pressures and compared with in vitro narrowing measured at corresponding transmural pressures. Bronchi were generation 10 with internal diameters of approximately 4 mm. In vivo luminal narrowing was measured by videobronchoscopy in anaesthetised and ventilated pigs. In vitro luminal narrowing was measured by videoendoscopy in isolated bronchial segments. Airways were activated by maximum vagal nerve stimulation and maximum electrical field stimulation in vivo and in vitro, respectively. At 5 cmH2O, stimulation produced a 35.9+/-3.2% (n = 6) and a 36.5+/-2.4% (n = 11) decrease in lumen diameter in vivo and in vitro, respectively. At 30 cmH2O, luminal narrowing fell to 23.7+/-2.0% in vivo and 23.4+/-2.5% in vitro. There was no difference between luminal narrowing in vivo and in vitro at any pressure. In conclusion, these findings suggest that in mid-sized, cartilaginous bronchi, parenchymal elastic after-loads do not restrict airway narrowing.
Publisher: Elsevier BV
Date: 09-2020
Publisher: Wiley
Date: 24-01-2023
DOI: 10.1111/RESP.14454
Publisher: European Respiratory Society (ERS)
Date: 17-03-2016
Publisher: American Physiological Society
Date: 12-2021
Publisher: American Physiological Society
Date: 02-2010
DOI: 10.1152/JAPPLPHYSIOL.00511.2009
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.
Publisher: American Physiological Society
Date: 09-2007
DOI: 10.1152/JAPPLPHYSIOL.00314.2007
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 ∼5–10 cmH 2 O for tidal maneuvers and ∼5–30 cmH 2 O for DIs. ACh dose-response curves (10 −7 –3 × 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 (∼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.
Publisher: Public Library of Science (PLoS)
Date: 10-04-2015
Publisher: Elsevier BV
Date: 10-2021
Publisher: SPIE
Date: 07-03-2019
DOI: 10.1117/12.2510838
Publisher: American Thoracic Society
Date: 11-2013
Publisher: Springer Science and Business Media LLC
Date: 22-01-2010
Publisher: Wiley
Date: 23-09-2014
DOI: 10.1111/BPH.12781
Publisher: Wiley
Date: 26-06-2018
DOI: 10.1111/RESP.13360
Abstract: The pathology of asthma is characterized by airway inflammation (granulocytic (GA) or paucigranulocytic (PGA)) and remodelling of airway structures. However, the relationship between inflammatory phenotypes and remodelling is unclear. We hypothesized that some features of airway remodelling are dependent on granulocytic airway inflammation while others are not. Post-mortem airway sections from control subjects (n = 48) and cases of asthma with (n = 51) or without (n = 29) granulocytic inflammation in the inner airway wall were studied. The thickness of the airway smooth muscle (ASM) layer, basement membrane and inner and outer airway walls, the size and number of ASM cells, the volume fraction of extracellular matrix within the ASM layer, ASM shortening and luminal mucus were estimated. Airway dimensions were compared between the three subject groups. In cases of PGA, only the thickness of the ASM layer and basement membrane was increased compared with control subjects. In cases of GA, not only the ASM and basement membrane were increased in thickness, but there was also increased inner and outer airway wall thickness and increased narrowing of the airway lumen due to ASM shortening and mucus obstruction, compared with control subjects. Granulocytic inflammation was observed more often in cases of fatal asthma. These findings suggest that inner and outer wall thickening coexists with inflammation, whereas thickening of the ASM layer and basement membrane may be present even in the absence of inflammation. Remodelling of the ASM layer and basement membrane may therefore be less susceptible to anti-inflammatory therapy.
Publisher: American Physiological Society
Date: 10-2018
DOI: 10.1152/JAPPLPHYSIOL.00342.2018
Abstract: In asthma, it is unclear if the airway smooth muscle cells proliferate more or are increased at the onset of asthma and remain stable. This study aimed to compare smooth muscle cell proliferation in in iduals with and without asthma and correlate proliferation rates with cell size and number and with granulocytic airway inflammation. Postmortem airway sections were labeled with proliferating cell nuclear antigen (PCNA) and percent positive muscle cells calculated. On the same sections, smooth muscle cell size and number and the number of eosinophils and neutrophils were estimated and compared in cases of nonfatal ( n = 15) and fatal ( n = 15) asthma and control subjects ( n = 15). The %PCNA + muscle cells was not significantly different in fatal (29.4 ± 7.7%, mean ± SD), nonfatal asthma (28.6 ± 8.3%), or control subjects (24.6 ± 6.7%) and not related to mean muscle cell size ( r = 0.09), number ( r = 0.36), thickness of the muscle layer ( r = 0.05), or eosinophil numbers ( r = 0.04) in the asthma cases. These data support the hypothesis that in asthma the increased thickness of the smooth muscle layer may be present before or at the onset of asthma and independent of concurrent granulocytic inflammation or exacerbation. NEW & NOTEWORTHY There is debate regarding the origins of the increased airway smooth muscle in asthma. It may be independent of inflammation or arise as a proliferative response to inflammation. The present study found no increase in the proportion of proliferating smooth muscle cells in asthma and no relation of proliferation to numbers of airway smooth muscle cells or inflammation. These results support a stable increase in smooth muscle in asthma that is independent of airway inflammation.
Publisher: American Physiological Society
Date: 09-2014
DOI: 10.1152/PHYSIOL.00002.2014
Abstract: Optical coherence tomography is a rapidly maturing optical imaging technology, enabling study of the in vivo structure of lung tissue at a scale of tens of micrometers. It has been used to assess the layered structure of airway walls, quantify both airway lumen caliber and compliance, and image in idual alveoli. This article provides an overview of the technology and reviews its capability to provide new insights into respiratory disease.
Publisher: Wiley
Date: 05-09-2022
DOI: 10.1002/AR.25059
Abstract: The extent of lung hypoplasia impacts the survival and severity of morbidities associated with congenital diaphragmatic hernia (CDH). The alveoli of CDH infants and in experimental models of CDH have thickened septa with fewer type II pneumocytes and capillaries. Fetal treatments of CDH‐risk preterm birth. Therefore, treatments must aim to balance the need for increased gas exchange surface area with the restoration of pulmonary epithelial type II cells and the long‐term respiratory and neurodevelopmental consequences of prematurity. Achievement of sufficient lung development in utero for successful postnatal transition requires adequate intra‐thoracic space for lung growth, maintenance of sufficient volume and appropriate composition of fetal lung fluid, regular fetal breathing movements, appropriate gas exchange area, and le surfactant production. The review aims to examine the rationale for current and future therapeutic strategies to improve postnatal outcomes of infants with CDH.
Publisher: American Physiological Society
Date: 07-2021
DOI: 10.1152/PHYSIOL.00042.2020
Abstract: Trajectories of airway remodeling and functional impairment in asthma are consistent with the notion that airway pathology precedes or coincides with the onset of asthma symptoms and may be present at birth. An association between intrauterine growth restriction (IUGR) and asthma development has also been established, and there is value in understanding the underlying mechanism. This review considers airway pathophysiology as a consequence of IUGR that increases susceptibility to asthma.
Publisher: Portland Press Ltd.
Date: 10-2023
DOI: 10.1042/CS20230792
Publisher: Wiley
Date: 09-2009
DOI: 10.1111/J.1440-1843.2009.01596.X
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 litude of the lumen pressure cycles and the volume of oscillation. Volume oscillation reduced contractions to acetylcholine and electrical field stimulation in an litude-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.
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.RESP.2022.103884
Abstract: Clinical visualization and quantification of the amount and distribution of airway smooth muscle (ASM) in the lungs of in iduals with asthma has major implications for our understanding of airway wall remodeling as well as treatments targeted at the ASM. This paper theoretically investigates the feasibility of quantifying airway wall thickness (focusing on the ASM) throughout the lung in vivo by means of bronchoscopic polarization-sensitive optical coherence tomography (PS-OCT). Using extensive human biobank data from subjects with and without asthma in conjunction with a mathematical model of airway compliance, we define constraints that airways of various sizes pose to any endoscopic imaging technique and how this is impacted by physiologically relevant processes such as constriction, inflation and deflation. We identify critical PS-OCT system parameters and pinpoint parts of the airway tree that are conducive to successful quantification of ASM. We further quantify the impact of breathing and ASM contraction on the measurement error and recommend strategies for standardization and normalization.
Publisher: European Respiratory Society
Date: 28-09-2019
Publisher: Springer Science and Business Media LLC
Date: 30-03-2020
DOI: 10.1186/S12931-020-1330-5
Abstract: The mechanism for symptomatic improvement after bronchial thermoplasty (BT) is unclear, since spirometry reveals little or no change. In this study, the effects of BT on airway resistance were examined using two independent techniques. Eighteen consecutive patients, with severe asthma (57.6 ± 14.2 years) were evaluated by spirometry and plethysmography at three time points: (i) baseline, (ii) left lung treated but right lung untreated and (iii) 6 weeks after both lungs were treated with BT. At each assessment, total and specific airway resistance (Raw, sRaw) were measured. High resolution CT scans were undertaken at the first two assessments, and measurements of lobar volume, airway volume and airway resistance were made. The Asthma Control Questionnaire (ACQ) was administered at each assessment. The baseline ACQ score was 3.5 ± 0.9, and improved progressively to 1.8 ± 1.2 ( p 0.01). At baseline, severe airflow obstruction was observed, FEV1 44.8 ± 13.7% predicted, together with gas trapping, and elevated Raw at 342 ± 173%predicted. Following BT, significant improvements in Raw and sRaw were observed, as well as a reduction in Residual Volume, increase in Vital Capacity and no change in FEV1. The change in Raw correlated with the change in ACQ ( r = 0.56, p 0.05). CT scans demonstrated reduced airway volume at baseline, which correlated with the increased Raw determined by plethysmography ( p = − 0.536, p = 0.05). Following BT, the airway volume increased in the treated lung, and this was accompanied by a significant reduction in CT-determined local airway resistance. Symptomatic improvement after BT is mediated by increased airway volume and reduced airway resistance.
Publisher: Wiley
Date: 20-02-2018
DOI: 10.1111/RESP.13271
Abstract: Lung hyperinflation and reduced bronchodilation to deep inspiration (DI) are features of chronic obstructive pulmonary disease (COPD). Hyperinflation might impair the ability of a DI to stretch airway smooth muscle (ASM), as the bronchi operate at a stiff region of the pressure-volume curve. Bronchial segments from pig lungs were mounted in an organ bath and equilibrated at either 5 cm H Oscillatory loads halved E Hyperinflated bronchi exhibit reduced bronchodilation to breathing and increased sensitivity to bronchoconstrictor stimuli. Findings suggest that hyperinflation may directly alter airway function by reducing the protective effects of DI and initiating contraction at low doses of contractile stimuli.
Publisher: Wiley
Date: 09-03-2022
DOI: 10.1111/RESP.14240
Abstract: The airway smooth muscle (ASM) layer thickens during development. Identifying the mechanism(s) for normal structural maturation of the ASM reveals pathways susceptible to disease processes. This study characterized thickening of the ASM layer from foetal life to childhood and elucidated the underlying mechanism in terms of hypertrophy, hyperplasia and extracellular matrix (ECM) deposition. Airways from post‐mortem cases were examined from seven different age groups: 22–24 weeks gestation, 25–31 weeks gestation, term (37–41 weeks gestation), .5 year, 0.5–1 year, 2–5 years and 6–10 years. The ASM layer area (thickness), the number and size of ASM cells and the volume fraction of ECM were assessed by planimetry and stereology. From late gestation to the first year of life, normalized ASM thickness more than doubled as a result of ASM hypertrophy. Thereafter, until childhood, the ASM layer grew in proportion to airway size, which was mediated by ASM hyperplasia. Hypertrophy and hyperplasia of ASM were accompanied by a proportional change in ECM such that the broad composition of the ASM layer was constant across age groups. These data suggest that the mechanisms of ASM growth from late gestation to childhood are temporally decoupled, with early hypertrophy and subsequent proliferation. We speculate that the developing airway is highly susceptible to ASM thickening in the first year of life and that the timing of an adverse event will determine structural phenotype.
Publisher: American Thoracic Society
Date: 05-2020
DOI: 10.1164/AJRCCM-CONFERENCE.2020.201.1_MEETINGABSTRACTS.A1240
Publisher: Frontiers Media SA
Date: 31-05-2021
Abstract: Introduction: Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected in iduals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness. Methods: Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O 2 ) from gestational day (GD) 11-GD 17.5 (IUGR group term = GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O 2 ). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). All offspring were sensitized to ovalbumin (OVA) and assigned to one of four treatment groups: Control – normoxic and saline challenge IUGR – hypoxic and saline challenge Allergy – normoxic and OVA challenge and IUGR + Allergy – hypoxic and OVA challenge. At 8 weeks of age, and 24 h post-aerosol challenge, mice were tracheostomised for methacholine challenge and assessment of lung mechanics by the forced oscillation technique, and lungs subsequently fixed for morphometry. Results: IUGR offspring were lighter than Control at birth and in adulthood. Both Allergy and IUGR independently increased airway resistance after methacholine challenge. The IUGR group also exhibited an exaggerated increase in tissue d ing and elastance after methacholine challenge compared with Control. However, there was no incremental effect on airway responsiveness in the combined IUGR + Allergy group. There was no impact of IUGR or Allergy on airway structure and no effect of sex on any outcome. Conclusion: IUGR and aeroallergen independently increased bronchoconstrictor response, but when combined the pathophysiology was not worsened. Findings suggest that an association between IUGR and asthma is mediated by baseline airway responsiveness rather than susceptibility to allergen.
Publisher: Wiley
Date: 30-01-2023
DOI: 10.1002/CPHY.C220011
Publisher: Springer Science and Business Media LLC
Date: 17-05-2017
DOI: 10.1038/PR.2017.99
Abstract: BackgroundPregnant women at a high risk of preterm delivery receive glucocorticoids to accelerate fetal lung maturation and surfactant synthesis. However, the effect of antenatal steroids on the developing diaphragm remains unclear. We hypothesized that maternal betamethasone impairs the fetal diaphragm, and the magnitude of the detrimental effect increases with longer duration of exposure. We aimed to determine how different durations of fetal exposure to maternal betamethasone treatment influence the fetal diaphragm at the functional and molecular levels.MethodsDate-mated merino ewes received intramuscular injections of saline (control) or two doses of betamethasone (5.7 mg) at an interval of 24 h commencing either 2 or 14 days before delivery. Preterm lambs were killed after cesarean delivery at 121-day gestational age. In vitro contractile measurements were performed on the right hemidiaphragm, whereas molecular/cellular analyses used the left costal diaphragm.ResultsDifferent durations of fetal exposure to maternal betamethasone had no consistent effect on the protein metabolic pathway, expression of glucocorticoid receptor and its target genes, cellular oxidative status, or contractile properties of the fetal lamb diaphragm.ConclusionThese data suggest that the potential benefits of betamethasone exposure on preterm respiratory function are not compromised by impaired diaphragm function after low-dose maternal intramuscular glucocorticoid exposure.
Publisher: American Thoracic Society
Date: 07-2023
Publisher: American Physiological Society
Date: 10-2002
DOI: 10.1152/JAPPLPHYSIOL.00150.2002
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.
Publisher: American Physiological Society
Date: 05-2022
DOI: 10.1152/AJPLUNG.00487.2021
Abstract: Excessive production, secretion, and retention of abnormal mucus is a pathological feature of many obstructive airways diseases including asthma. Azithromycin is an antibiotic that also possesses immunomodulatory and mucoregulatory activities, which may contribute to the clinical effectiveness of azithromycin in asthma. The current study investigated these nonantibiotic activities of azithromycin in mice exposed daily to intranasal house dust mite (HDM) extract for 10 days. HDM-exposed mice exhibited airways hyperresponsiveness to aerosolized methacholine, a pronounced mixed eosinophilic and neutrophilic inflammatory response, increased airway smooth muscle (ASM) thickness, and elevated levels of epithelial mucin staining. Azithromycin (50 mg/kg sc, 2 h before each HDM exposure) attenuated HDM-induced airways hyperresponsiveness to methacholine, airways inflammation (bronchoalveolar lavage eosinophil and neutrophils numbers, and IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, and RANTES levels), and epithelial mucin staining (mucous metaplasia) by at least 50% (compared with HDM-exposed mice, P 0.05). Isolated tracheal segments of HDM-exposed mice secreted Muc5ac and Muc5b (above baseline levels) in response to exogenous ATP. Moreover, ATP-induced secretion of mucins was attenuated in segments obtained from azithromycin-treated, HDM-exposed mice ( P 0.05). In additional ex vivo studies, ATP-induced secretion of Muc5ac (but not muc5b) from HDM-exposed tracheal segments was inhibited by in vitro exposure to azithromycin. In vitro azithromycin also inhibited ATP-induced secretion of Muc5ac and Muc5b in tracheal segments from IL-13-exposed mice. In summary, azithromycin inhibited ATP-induced mucin secretion and airways inflammation in HDM-exposed mice, both of which are likely to contribute to suppression of airways hyperresponsiveness.
Publisher: Wiley
Date: 26-08-2015
DOI: 10.1111/RESP.12615
Abstract: In utero infection may critically influence diaphragm development and predispose preterm infants to postnatal respiratory failure. We aimed to determine how frequency and gestational age (GA) at time of intra-amniotic (IA) lipopolysaccharide (LPS) exposure affects preterm diaphragm function. Pregnant ewes received IA injections of saline or 10-mg LPS at 7 days or 21 days or weekly injections 21, 14 and 7 days before delivery at 121-day GA. Foetal lambs were killed with pentobarbitone (150 mg/kg intravenous). Diaphragm contractile function was measured in vitro. Muscle fibre type, activation of protein synthesis and degradation pathways, pro-inflammatory signalling and oxidative stress were evaluated using immunofluorescence staining, RT-qPCR, ELISA, Western blotting and biochemical assay. In utero LPS exposure significantly impaired diaphragm contractile function. LPS exposure 7 days before delivery caused maximum specific twitch and tetanic forces 30% lower than controls. When the initial LPS exposure occurred 21 days before delivery maximum specific forces were 40% lower than controls. Earlier LPS exposure also prolonged twitch contraction time, increased fatigue resistance and elevated protein carbonyl content. Despite increased white blood cell counts and interleukin-6 mRNA expression following weekly LPS exposure, there were no significant differences in contractile properties between exposure 21 days before delivery and repeated LPS groups suggesting that frequency of inflammatory exposure does not influence the severity of contractile dysfunction. GA at time of initial LPS exposure, rather than frequency of exposure, determines the extent of inflammation-induced diaphragm dysfunction.
Publisher: The Optical Society
Date: 08-05-2014
DOI: 10.1364/OL.39.002888
Publisher: Institute of Mathematics, Polish Academy of Sciences
Date: 2019
DOI: 10.4064/DM786-7-2019
Publisher: American Physiological Society
Date: 15-05-2013
DOI: 10.1152/JAPPLPHYSIOL.01489.2012
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 maneuvers. Fixed airway segments were sectioned for measurement of airway wall dimensions, particularly the airway smooth muscle (ASM) layer. Airways from subjects with a history of asthma had increased 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 r = −0.64)), 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.
Publisher: European Respiratory Society (ERS)
Date: 04-2009
DOI: 10.1183/09031936.00116908
Abstract: Airway relaxation in response to isoprenaline, sodium nitroprusside (SNP) and electrical field stimulation (EFS) was compared under static and dynamic conditions. The capacity of relaxants to reduce airway stiffness and, thus, potentially contribute to bronchodilation was also investigated. Relaxation responses were recorded in fluid filled bronchial segments from pigs under static conditions and during volume oscillations simulating tidal and twice tidal manoeuvres. Bronchodilation was assessed from the reduction in carbachol-induced lumen pressure, at isovolume points in pressure cycles produced by volume oscillation, and stiffness was assessed from cycle litudes. Under static conditions, all three inhibitory stimuli produced partial relaxation of the carbachol-induced contraction. Volume oscillation alone also reduced the contraction in an litude-dependent manner. However, maximum relaxation was observed when isoprenaline or SNP were combined with volume oscillation, virtually abolishing contraction at the highest drug concentrations. The proportional effects of isoprenaline and EFS were not different under static or oscillating conditions, whereas relaxation to SNP was slightly greater in oscillating airways. All three inhibitory stimuli also strongly reduced carbachol-induced airway stiffening. The current authors conclude that bronchoconstriction is strongly suppressed by combining the inhibitory stimulation of airway smooth muscle with cyclical mechanical strains. The capacity of airway smooth muscle relaxants to also reduce stiffness may further contribute to bronchodilation.
Publisher: American Physiological Society
Date: 04-2020
DOI: 10.1152/JAPPLPHYSIOL.00439.2019
Abstract: The volume fraction of extracellular matrix (ECM) within the layer of airway smooth muscle (ASM) is increased in subjects with fixed airflow obstruction. We postulated that changes in ECM within the ASM layer will impact force transmission during induced contraction and/or in response to externally applied stresses like a deep inspiration (DI). Subjects were patients undergoing lung resection surgery who were categorized as unobstructed ( n = 12) or “fixed” obstructed ( n = 6) on the basis of preoperative spirometry. The response to a DI, assessed by the ratio of isovolumic flows from maximal and partial inspirations (M/P), was also measured preoperatively. M/P was reduced in the obstructed group ( P = 0.02). Postoperatively, bronchial segments were obtained from resected tissue, and luminal narrowing to acetylcholine and bronchodilation to simulated DI were assessed in vitro. Airway wall dimensions and the volume fraction of ECM within the ASM were quantified. Maximal airway narrowing to acetylcholine ( P = 0.01) and the volume fraction of ECM within the ASM layer ( P = 0.02) were increased in the obstructed group, without a change in ASM thickness. Whereas bronchodilation to simulated DI in vitro was not different between obstructed and unobstructed groups, it was correlated with increased M/P (bronchodilation/less bronchoconstriction) in vivo ( P = 0.03). The volume fraction of ECM was inversely related to forced expiratory volume in 1 s FEV 1 %predicted ( P = 0.04) and M/P ( P = 0.01). Results show that in subjects with fixed airflow obstruction the mechanical behavior of the airway wall is altered and there is a contemporaneous shift in the structural composition of the ASM layer. NEW & NOTEWORTHY Cartilaginous airways from subjects with fixed airflow obstruction have an increase in the volume fraction of extracellular matrix within the airway smooth muscle layer. These airways are also intrinsically more reactive to a contractile stimulus, which is expected to contribute to airway hyperresponsiveness in this population, often attributed to geometric mechanisms. In view of these results, we speculate on how changes in extracellular matrix may impact airway mechanics.
Publisher: Wiley
Date: 03-06-2020
DOI: 10.1111/RESP.13851
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1016/J.PUPT.2008.09.008
Abstract: Contraction of airway smooth muscle (ASM) is regulated by the physiological, structural and mechanical environment in the lung. We review two in vitro techniques, lung slices and airway segment preparations, that enable in situ ASM contraction and airway narrowing to be visualized. Lung slices and airway segment approaches bridge a gap between cell culture and isolated ASM, and whole animal studies. Imaging techniques enable key upstream events involved in airway narrowing, such as ASM cell signalling and structural and mechanical events impinging on ASM, to be investigated.
Publisher: Wiley
Date: 20-05-2016
DOI: 10.1111/RESP.12800
Abstract: While chronic inflammation of the airway wall and the failure of deep inspiration (DI) to produce bronchodilation are both common to asthma, whether pro-inflammatory cytokines modulate the airway smooth muscle response to strain during DI is unknown. The primary aim of the study was to determine how an inflammatory environment (simulated by the use of pro-inflammatory cytokines) alters the bronchodilatory response to DI. We used whole porcine bronchial segments in vitro that were cultured in medium containing tumour necrosis factor and interleukin-1β for 2 days. A custom-built servo-controlled syringe pump and pressure transducer was used to measure airway narrowing and to simulate tidal breathing with intermittent DI manoeuvres. Culture with tumour necrosis factor and interleukin-1β increased airway narrowing to acetylcholine but did not affect the bronchodilatory response to DI. The failure of DI to produce bronchodilation in patients with asthma may not necessarily involve a direct effect of pro-inflammatory cytokines on airway tissue. A relationship between inflammation and airway hyper-responsiveness is supported, however, regulated by separate disease processes than those which attenuate or abolish the bronchodilatory response to DI in patients with asthma.
Publisher: American Thoracic Society
Date: 15-02-2023
Publisher: European Respiratory Society (ERS)
Date: 26-01-2012
DOI: 10.1183/09031936.00187411
Abstract: In a healthy human, deep inspirations produce bronchodilation of contracted airways, which probably occurs due to the transient distension of the airway smooth muscle (ASM). We hypothesised that deep expiratory manoeuvres also produce bronchodilation due to transient airway wall and ASM compression. We used porcine bronchial segments to assess the effects of deep inspirations, and maximal and partial expiration (submaximal) on airway calibre. Respiratory manoeuvres were simulated by varying transmural pressure using a hydrostatic pressure column: deep inspiration 5 to 30 cmH(2)O, maximal expiration 30 to -15 cmH(2)O, partial expiration 10 to -15 cmH(2)O amidst a background of tidal oscillations, 5 to 10 cmH(2)O at 0.25 Hz. Changes in luminal cross-sectional area in carbachol-contracted airways were measured using video endoscopy. Deep inspirations produce an immediate bronchodilation (∼40-60%, p=0.0076) that lasts for up to 1 min (p=0.0479). In comparison, after maximal expiration there was no immediate change in airway calibre however, a delayed bronchodilatory response was observed from 4 s after the manoeuvre (p=0.0059) and persisted for up to 3 min (p=0.0182). Partial expiration had little or no effect or airway calibre. The results observed demonstrate that the airway wall dilates to deep inspiration manoeuvres but is unresponsive to deep expiratory manoeuvres.
Publisher: Springer Science and Business Media LLC
Date: 08-2017
DOI: 10.1038/S41467-017-00532-5
Abstract: Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans. In order to address this deficiency, ASL pH was measured in vivo in children using a novel luminescent technology integrated with fibre-optic probes. Here we show that ASL pH in children with CF is similar to that of children without CF. Findings were supported by highly controlled direct pH measurements in primary human airway epithelial cell culture models, which also suggest that the potential ASL pH gradient produced by defective apical ion transport is balanced out by paracellular shunting of acid/base. Thus, reduced baseline ASL pH is unlikely to be an important pathobiological factor in early CF lung disease.
Publisher: SPIE-Intl Soc Optical Eng
Date: 11-10-2017
Publisher: ASME International
Date: 02-2019
DOI: 10.1115/1.4042312
Abstract: Fetal airway smooth muscle (ASM) exhibits phasic contractile behavior, which transitions to a more sustained “tonic” contraction after birth. The timing and underlying mechanisms of ASM transition from a phasic to a tonic contractile phenotype are yet to be established. We characterized phasic ASM contraction in preterm (128 day gestation), term (∼150 day gestation), 1–4 month, 1 yr, and adult sheep (5yr). Spontaneous phasic activity was measured in bronchial segments as litude, frequency, and intensity. The mechanism of phasic ASM contraction was investigated further with a computational model of ASM force development and lumen narrowing. The computational model comprised a two-dimensional cylindrical geometry of a network of contractile units and the activation of neighboring cells was dependent on the strength of coupling between cells. As expected, phasic contractions were most prominent in fetal airways and decreased with advancing age, to a level similar to the level in the 1–4 month lambs. Computational predictions demonstrated phasic contraction through the generation of a wave of activation events, the magnitude of which is determined by the number of active cells and the strength of cell–cell interactions. Decreases in phasic contraction with advancing age were simulated by reducing cell–cell coupling. Results show that phasic activity is suppressed rapidly after birth, then sustained at a lower intensity from the preweaning phase until adulthood in an ovine developmental model. Cell–cell coupling is proposed as a key determinant of phasic ASM contraction and if reduced could explain the observed maturational changes.
Publisher: Portland Press Ltd.
Date: 25-01-2018
DOI: 10.1042/CS20171554
Abstract: Epidemiological studies demonstrate an association between intrauterine growth restriction (IUGR) and asthma however the underlying mechanism is unknown. We investigated the impact of maternal hypoxia-induced IUGR on airway responsiveness in male and female mice during juvenility and adulthood. Pregnant BALB/c mice were housed under hypoxic conditions for gestational days 11–17.5 and then returned to normoxic conditions for the remainder of pregnancy. A control group was housed under normoxic conditions throughout pregnancy. Offspring were studied at 2 weeks (juveniles) and 8 weeks (adults), where lung volume was assessed by plethysmography, airway responsiveness to methacholine determined by the forced oscillation technique and lungs fixed for morphometry. IUGR offspring were lighter at birth, exhibited “catch-up growth” by 2 weeks, but were again lighter in adulthood. IUGR males were “hyper-responsive” at 2 weeks and “hypo-responsive” as adults, in contrast with IUGR females who were hyper-responsive in adulthood. IUGR males had increased inner and total wall thickness at 2 weeks which resolved by adulthood, while airways in IUGR females were structurally normal throughout life. There were no differences in lung volume between Control and IUGR offspring at any age. Our data demonstrate changes in airway responsiveness as a result of IUGR that could influence susceptibility to asthma development and contribute to sexual dimorphism in asthma prevalence which switches from a male dominated disease in early life to a female dominated disease in adulthood.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.PUPT.2014.07.005
Abstract: Asthma is an obstructive airway disease, with a heterogeneous and multifactorial pathogenesis. Although generally considered to be a disease principally driven by chronic inflammation, it is becoming increasingly recognised that the immune component of the pathology poorly correlates with the clinical symptoms of asthma, thus highlighting a potentially central role for non-immune cells. In this context airway smooth muscle (ASM) may be a key player, as it comprises a significant proportion of the airway wall and is the ultimate effector of acute airway narrowing. Historically, the contribution of ASM to asthma pathogenesis has been contentious, yet emerging evidence suggests that ASM contractile activation imparts chronic effects that extend well beyond the temporary effects of bronchoconstriction. In this review article we describe the effects that ASM contraction, in combination with cellular mechanotransduction and novel contraction-inflammation synergies, contribute to asthma pathogenesis. Specific emphasis will be placed on the effects that ASM contraction exerts on the mechanical properties of the airway wall, as well as novel mechanisms by which ASM contraction may contribute to more established features of asthma such as airway wall remodelling.
Publisher: Wiley
Date: 16-03-2023
DOI: 10.1002/AR.25202
Abstract: Postnatal corticosteroids are used in the critical care of preterm infants for the prevention and treatment of bronchopulmonary dysplasia. We aimed to investigate the effects of early postnatal dexamethasone therapy and dose on cardiac maturation and morphology in preterm lambs. Lambs were delivered prematurely at ~128 days of gestational age and managed postnatally according to best clinical practice. Preterm lambs were administered dexamethasone daily at either a low‐dose ( n = 9) or a high‐dose ( n = 7), or were naïve to steroid treatment and administered saline ( n = 9), over a 7‐day time‐course. Hearts were studied at postnatal Day 7 for gene expression and assessment of myocardial structure. High‐dose dexamethasone treatment in the early postnatal period led to marked differences in cardiac gene expression, altered cardiomyocyte maturation and reduced cardiomyocyte endowment in the right ventricle, as well as increased inflammatory infiltrates into the left ventricle. Low‐dose exposure had minimal effects on the preterm heart. Neonatal dexamethasone treatment led to adverse effects in the preterm heart in a dose‐dependent manner within the first week of life. The observed cardiac changes associated with high‐dose postnatal dexamethasone treatment may influence postnatal growth and remodeling of the preterm heart and subsequent long‐term cardiac function.
Publisher: IEEE
Date: 12-2011
Publisher: SPIE-Intl Soc Optical Eng
Date: 03-06-2013
Publisher: Elsevier BV
Date: 04-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2015
DOI: 10.1097/ALN.0000000000000898
Abstract: Despite the theoretical benefits of high-frequency oscillatory ventilation (HFOV) in preterm infants, systematic reviews of randomized clinical trials do not confirm improved outcomes. The authors hypothesized that oscillating a premature lung with multiple frequencies simultaneously would improve gas exchange compared with traditional single-frequency oscillatory ventilation (SFOV). The goal of this study was to develop a novel method for HFOV, termed “multifrequency oscillatory ventilation” (MFOV), which relies on a broadband flow waveform more suitable for the heterogeneous mechanics of the immature lung. Thirteen intubated preterm lambs were randomly assigned to either SFOV or MFOV for 1 h, followed by crossover to the alternative regimen for 1 h. The SFOV waveform consisted of a pure sinusoidal flow at 5 Hz, whereas the customized MFOV waveform consisted of a 5-Hz fundamental with additional energy at 10 and 15 Hz. Per standardized protocol, mean pressure at airway opening () and inspired oxygen fraction were adjusted as needed, and root mean square of the delivered oscillatory volume waveform (Vrms) was adjusted at 15-min intervals. A ventilatory cost function for SFOV and MFOV was defined as , where Wt denotes body weight. Averaged over all time points, MFOV resulted in significantly lower VC (246.9 ± 6.0 vs. 363.5 ± 15.9 ml2 mmHg kg−1) and (12.8 ± 0.3 vs. 14.1 ± 0.5 cm H2O) compared with SFOV, suggesting more efficient gas exchange and enhanced lung recruitment at lower mean airway pressures. Oscillation with simultaneous multiple frequencies may be a more efficient ventilator modality in premature lungs compared with traditional single-frequency HFOV.
Publisher: American Thoracic Society
Date: 09-2018
Publisher: American Physiological Society
Date: 02-2023
DOI: 10.1152/AJPLUNG.00288.2022
Abstract: Patients with comorbid asthma-obesity experience greater disease severity and are less responsive to therapy. We have previously reported adipose tissue within the airway wall that positively correlated with body mass index. Accumulation of biologically active adipose tissue may result in the local release of adipokines and disrupt large and small airway function depending on its anatomical distribution. This study therefore characterized airway-associated adipose tissue distribution, lipid composition, and adipokine activity in a porcine model. Airway segments were systematically dissected from different locations of the bronchial tree in inflation-fixed lungs. Cryosections were stained with hematoxylin and eosin (H& E) for airway morphology, oil red O to distinguish adipose tissue, and Nile blue A for lipid subtype delineation. Excised airway-associated adipose tissue was cultured for 72 h to quantify adipokine release using immunoassays. Results showed that airway-associated adipose tissue extended throughout the bronchial tree and occupied an area proportionally similar to airway smooth muscle within the wall area. Lipid composition consisted of pure neutral lipids (61.7 ± 3.5%), a mixture of neutral and acidic lipids (36.3 ± 3.4%), or pure acidic lipids (2.0 ± 0.8%). Following tissue culture, there was rapid release of IFN-γ, IL-1β, and TNF-α at 12 h. Maximum IL-4 and IL-10 release was at 24 and 48 h, and peak leptin release occurred between 48 and 72 h. These data extend previous findings and demonstrate that airway-associated adipose tissue is prevalent and biologically active within the bronchial tree, providing a local source of adipokines that may be a contributing factor in airway disease.
Publisher: European Respiratory Society (ERS)
Date: 10-2020
DOI: 10.1183/23120541.00300-2020
Abstract: Bronchial thermoplasty induces atrophy of the airway smooth muscle layer, but the mechanism whereby this improves patient health is unclear. In this study, we use computed tomography (CT) to evaluate the effects of bronchial thermoplasty on airway volume 12 months post-procedure. 10 consecutive patients with severe asthma were evaluated at baseline by the Asthma Control Questionnaire (ACQ), and high-resolution CT at total lung capacity (TLC) and functional residual capacity (FRC). The CT protocol was repeated 4 weeks after the left lung had been treated by bronchial thermoplasty, but prior to right lung treatment, and then again 12 months after both lungs were treated. The CT data were also used to model the implications of including the right middle lobe (RML) in the treatment field. The mean patient age was 62.7±7.7 years and forced expiratory volume in 1 s (FEV 1 ) 42.9±11.5% predicted. 12 months post-bronchial-thermoplasty, the ACQ improved, from 3.4±1.0 to 1.5±0.9 (p=0.001), as did the frequency of oral steroid-requiring exacerbations (p=0.008). The total airway volume increased 12 months after bronchial thermoplasty in both the TLC (p=0.03) and the FRC scans (p=0.02). No change in airway volume was observed in the untreated central airways. In the bronchial thermoplasty-treated distal airways, increases in airway volume of 38.4±31.8% at TLC (p=0.03) and 30.0±24.8% at FRC (p=0.01) were observed. The change in distal airway volume was correlated with the improvement in ACQ (r=−0.71, p=0.02). Modelling outputs demonstrated that treating the RML conferred no additional benefit. Bronchial thermoplasty induces long-term increases in airway volume, which correlate with symptomatic improvement.
Publisher: Wiley
Date: 18-09-2019
DOI: 10.1002/PPUL.24519
Abstract: In utero diaphragm development is critically important for postnatal respiratory function and any disturbance to fetal development may lead to diaphragm dysfunction and respiratory complications in the postnatal period. Intrauterine growth restriction (IUGR) has been shown to affect respiratory function in a sex-dependent manner however, the effect of IUGR on diaphragm function is unknown. This study used a maternal hypoxia-induced mouse model of IUGR to investigate the impact of IUGR on diaphragm function and structure in male and female adult offspring. Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O IUGR offspring were lighter at birth and remained lighter at 8 weeks of age compared to Controls. While diaphragm force (maximal or twitch) was not affected by treatment or sex, the IUGR group exhibited a longer half-relaxation time after twitch contractions compared to Control. Female offspring had a lower maximum rate of force development and higher fatigue resistance compared to males, independent of IUGR. There was no difference in the diaphragm myofibre cross-sectional area between groups or sexes. Sex and IUGR independently affect diaphragm contraction in adult mice without changes in structure. This study demonstrates that IUGR affects diaphragm contractile function in later life and could impair respiratory function if exacerbated under conditions of increased respiratory load.
Publisher: European Respiratory Society (ERS)
Date: 12-10-2023
Publisher: American Thoracic Society
Date: 11-2019
Publisher: American Physiological Society
Date: 10-2022
DOI: 10.1152/JAPPLPHYSIOL.00097.2022
Abstract: Abnormalities of the airway smooth muscle (ASM) layer in asthma may develop before birth. Using an ovine model of antenatal inflammation, we demonstrate thickening and increased contraction of the premature ASM layer. If such physiological abnormalities persist throughout postnatal life, this represents a predisposition to an asthma diagnosis.
Publisher: American Physiological Society
Date: 12-2005
DOI: 10.1152/JAPPLPHYSIOL.00485.2005
Abstract: The bronchial mucosa contributes to elastic properties of the airway wall and may influence the degree of airway expansion during lung inflation. In the deflated lung, folds in the epithelium and associated basement membrane progressively unfold on inflation. Whether the epithelium and basement membrane also distend on lung inflation at physiological pressures is uncertain. We assessed mucosal distensibility from strain-stress curves in mucosal strips and related this to epithelial length and folding. Mucosal strips were prepared from pig bronchi and cycled stepwise from a strain of 0 (their in situ length at 0 transmural pressure) to a strain of 0.5 (50% increase in length). Mucosal stress and epithelial length in situ were calculated from morphometric data in bronchial segments fixed at 5 and 25 cmH(2)O luminal pressure. Mucosal strips showed nonlinear strain-stress properties, but regions at high and low stress were close to linear. Stresses calculated in bronchial segments at 5 and 25 cmH(2)O fell in the low-stress region of the strain-stress curve. The epithelium of mucosal strips was deeply folded at low strains (0-0.15), which in bronchial segments equated to < or =10 cmH(2)O transmural pressure. Morphometric measurements in mucosal strips at greater strains (0.3-0.4) indicated that epithelial length increased by approximately 10%. Measurements in bronchial segments indicated that epithelial length increased approximately 25% between 5 and 25 cmH(2)O. Our findings suggest that, at airway pressures <10 cmH(2)O, airway expansion is due primarily to epithelial unfolding but at higher pressures the epithelium also distends.
Publisher: Springer Science and Business Media LLC
Date: 23-11-2020
DOI: 10.1186/S12931-020-01575-X
Abstract: Despite demonstrated symptomatic benefit from bronchial thermoplasty (BT), the underlying pathophysiological benefits have been uncertain. The purpose of the present study was to relate clinical benefit after BT to changes in lung physiology, focusing on ventilation homogeneity assessed using multiple breath nitrogen washout (MBNW), and how this may be affected by changes in airway volume and resistance. Consecutive patients (n = 21) with severe asthma scheduled for BT, were evaluated at baseline, 6 weeks and 6 months after completion of treatment. Assessments included the Asthma Control Questionnaire (ACQ), medication usage, exacerbation frequency, spirometry, plethysmography and MBNW. Eighteen of these patients underwent detailed CT evaluation for the estimation of airway volume at baseline and then after the left lung had received BT treatment but prior to right lung treatment. Data are mean ± STDEV. Patients responded to BT with an improvement in ACQ from 3.4 ± 0.8 at baseline to 2.0 ± 1.1 at 6 months (p 0.001). Steroid requiring exacerbations fell from 3.1 ± 2.9 in the 6 months prior to BT to 1.4 ± 1.7 following BT (p 0.001). Significant reductions in maintenance oral steroid dosing and short acting beta agonist use were observed. Airway volume measured by CT scanning significantly increased after treatment. The FEV1 improved from 1.34 ± 0.65 l to 1.52 ± 0.76 l (p = 0.024). The Residual Volume fell from 2.87 ± 0.89 l to 2.71 ± 0.93 l (p = 0.008) and Total Airway Resistance (Raw) from 10.58 ± 6.56 to 7.64 ± 3.74 cmH 2 O.s.l −1 (p = 0.020). The Lung Clearance Index (LCI) was 187 ± 63% predicted at baseline and improved after treatment from 12.7 ± 3.3 to 11.8 ± 2.4 (p = 0.049). The improvement in LCI correlated with the improvement in Raw (r = 0.463, p = 0.035). Clinical benefit after BT is accompanied by improvements in lung physiology, including normalisation of lung homogeneity that seems to be driven by airway dilation and reduced resistance.
Publisher: Optica Publishing Group
Date: 24-01-2020
DOI: 10.1364/BOE.382755
Abstract: The organization of fibrillar tissue on the micrometer scale carries direct implications for health and disease but remains difficult to assess in vivo . Polarization-sensitive optical coherence tomography measures birefringence, which relates to the microscopic arrangement of fibrillar tissue components. Here, we demonstrate a critical improvement in leveraging this contrast mechanism by employing the improved spatial resolution of focus-extended optical coherence microscopy (1.4 µm axially in air and 1.6 µm laterally, over more than 70 µm depth of field). Vectorial birefringence imaging of sheep cornea ex vivo reveals its lamellar organization into thin sections with distinct local optic axis orientations, paving the way to resolving similar features in vivo .
Publisher: Elsevier BV
Date: 2016
DOI: 10.1016/J.RESP.2015.09.006
Abstract: Length adaptation is a phenomenon observed in airway smooth muscle (ASM) wherein over time there is a shift in the length-tension curve. There is potential for length adaptation to play an important role in airway constriction and airway hyper-responsiveness in asthma. Recent results by Ansell et al., 2015 (JAP 2014 10.1152/japplphysiol.00724.2014) have cast doubt on this role by testing for length adaptation using an intact airway preparation, rather than strips of ASM. Using this technique they found no evidence for length adaptation in intact airways. Here we attempt to resolve this apparent discrepancy by constructing a minimal mathematical model of the intact airway, including ASM which follows the classic length-tension curve and undergoes length adaptation. This allows us to show that (1) no evidence of length adaptation should be expected in large, cartilaginous, intact airways (2) even in highly compliant peripheral airways, or at more compliant regions of the pressure-volume curve of large airways, the effect of length adaptation would be modest and at best marginally detectable in intact airways (3) the key parameters which control the appearance of length adaptation in intact airways are airway compliance and the relaxation timescale. The results of this mathematical simulation suggest that length adaptation observed at the level of the isolated ASM may not clearly manifest in the normal intact airway.
Publisher: American Thoracic Society
Date: 12-2019
Publisher: European Respiratory Society (ERS)
Date: 10-2019
Publisher: American Physiological Society
Date: 15-09-2012
DOI: 10.1152/JAPPLPHYSIOL.00051.2012
Abstract: Imaging of alveoli in situ has for the most part been infeasible due to the high resolution required to discern in idual 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 in idual alveoli during simulated cyclical lung inflation and deflation.
Publisher: The Optical Society
Date: 15-10-2018
DOI: 10.1364/BOE.9.005437
Publisher: American Physiological Society
Date: 03-2004
DOI: 10.1152/JAPPLPHYSIOL.01082.2003
Abstract: A period of deep inspiration in humans has been shown to attenuate subsequent bronchoconstriction, a phenomenon termed bronchoprotection. The bronchoprotective effect of deep inspiration may be caused though a depression in the force production of airway smooth muscle (ASM). We determined the response of whole airway segments and isolated ASM to a period of cyclic stretches. Isovolumetric contraction to electrical field stimulation (EFS) was assessed in porcine bronchial segments before and after intraluminal pressure oscillation from 5 to 25 cmH 2 O for 10 min at 0.5 Hz. Morphometry showed that this pressure oscillation stretched ASM length by 21%. After pressure oscillation, the response to EFS was not reduced but instead was modestly enhanced ( P 0.01). Airway responses to EFS returned to preoscillation levels 10 min after the end of oscillation. The increase in EFS response after pressure oscillation was not altered by the addition of indomethacin. In a separate experiment, we assessed isometric force in isolated ASM strips before and after length oscillation. The litude, frequency, and duration of length oscillation were similar to those induced in bronchial segments. In contrast to bronchial segments, length oscillation of ASM produced a significant depression in isometric force induced by EFS ( P 0.01). These results suggest that the response of ASM to length oscillation is modified by the airway wall. They also suggest that the phenomenon of bronchoprotection reported in some in vivo studies may not be an intrinsic property of the airway.
Publisher: Wiley
Date: 17-05-2017
DOI: 10.1111/RESP.13071
Abstract: Intrauterine growth restriction (IUGR) is associated with asthma development. We hypothesized that IUGR disrupts airway development leading to postnatal structural abnormalities of the airway that predispose to disease. This study therefore examined structural changes to the airway and lung in a rat model of maternal hypoxia-induced IUGR. Pregnant rats were housed under hypoxic conditions (11.5% O IUGR offspring were lighter at birth compared with control, but not at 7 weeks. While there was no difference in mean airway dimensions or lung volume, there was greater anatomical variation in airway lumen area in the IUGR group. A mathematical model of the human lung was used to show that greater heterogeneity in lumen area in IUGR-affected in iduals increases bronchoconstriction during simulated bronchial challenge. More macrophages were identified in the BALF of IUGR offspring. The rat model demonstrates that IUGR leads to a more heterogeneous distribution of airway lumen calibre in adulthood with potential implications for bronchoconstriction in human subjects. Together with increased lung macrophages, these findings support a phenotypic shift after IUGR that may impact disease susceptibility.
Publisher: American Physiological Society
Date: 04-2018
DOI: 10.1152/AJPREGU.00150.2017
Abstract: The preterm diaphragm is functionally immature compared with its term counterpart. In utero inflammation further exacerbates preterm diaphragm dysfunction. We hypothesized that preterm lambs are more vulnerable to in utero inflammation-induced diaphragm dysfunction compared with term lambs. Pregnant ewes received intra-amniotic (IA) injections of saline or 10 mg lipopolysaccharide (LPS) 2 or 7 days before delivery at 121 days (preterm) or ∼145 days (term) of gestation. Diaphragm contractile function was assessed in vitro. Plasma cytokines, diaphragm myosin heavy chain (MHC) isoforms, and oxidative stress were evaluated. Maximum diaphragm force in preterm control lambs was significantly lower (22%) than in term control lambs ( P 0.001). Despite similar inflammatory cytokine responses to in utero LPS exposure, diaphragm function in preterm and term lambs was affected differentially. In term lambs, maximum force after a 2-day LPS exposure was significantly lower than in controls (by ~20%, P 0.05). In preterm lambs, maximum forces after 2-day and 7-day LPS exposures were significantly lower than in controls (by ~30%, P 0.05). Peak twitch force after LPS exposure was significantly lower in preterm than in controls, but not in term lambs. In term lambs, LPS exposure increased the proportion of MHC-I fibers, increased twitch contraction times, and increased fatigue resistance relative to controls. In preterm diaphragm, the cross-sectional area of embryonic MHC fibers was significantly lower after 7-day versus 2-day LPS exposures. We conclude that preterm lambs are more vulnerable to IA LPS-induced diaphragm dysfunction than term lambs. In utero inflammation exacerbates diaphragm dysfunction and may increase susceptibility to postnatal respiratory failure.
Publisher: Wiley
Date: 08-02-2013
DOI: 10.1002/PPUL.22762
Abstract: The preterm diaphragm is structurally and functionally immature, potentially contributing to an increased risk of respiratory distress and failure. We investigated developmental changes in contractile function and susceptibility to fatigue of the costal diaphragm in the fetal lamb to understand factors contributing to the risk of developing diaphragm dysfunction and respiratory disorders. We hypothesized that the functional capacity of the diaphragm will vary with maturational stage as will its susceptibility to fatigue. Lambs were studied at 75, 100, 125, 145, 154, 168, and 200 days postconceptional age (term = 147 days). Lambs were euthanized (sodium pentobarbitone, 100 mg/kg) either at delivery or immediately prior to post-mortem for postnatal lambs. Contractile function was assessed on longitudinal strips of intact muscle fibers and the remaining tissue frozen in liquid nitrogen for analysis of myosin heavy chain (MHC) mRNA expression and protein content. Fetal development of diaphragm function was characterized by a significant increase in maximum specific force, increased susceptibility to fatigue, reduced twitch contraction times, and a progressive increase in MHCI and MHCII protein content. Postnatally, there was a progressive decrease in the susceptibility to fatigue that coincided with an increase in the MHC I:II protein ratio. These data indicate that the functional capacity of the diaphragm varies with maturational age and may be an important determinant of the susceptibility to preterm respiratory failure.
Publisher: Public Library of Science (PLoS)
Date: 06-09-2013
Publisher: American Physiological Society
Date: 08-2008
DOI: 10.1152/JAPPLPHYSIOL.01220.2007
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 cmH 2 O at 0.25 Hz (tidal breathing) interspersed with single DIs of litude 5–20 cmH 2 O, 5–30 cmH 2 O, or 5–40 cmH 2 O (6-s duration) or DI of litude 5–30 cmH 2 O (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 litude dependent 5–20 cmH 2 O DIs produced less dilation than 5–30 cmH 2 O and 5–40 cmH 2 O 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.
Publisher: American Physiological Society
Date: 03-2019
DOI: 10.1152/JAPPLPHYSIOL.00951.2018
Abstract: Bronchial thermoplasty is a recent treatment for asthma in which ablative thermal energy is delivered to specific large airways according to clinical guidelines. Therefore, current practice is effectively “blind,” as it is not informed by patient-specific data. The present study seeks to establish whether a patient-specific approach based on structural or functional patient data can improve outcomes and/or reduce the number of procedures required for clinical efficacy. We employed a combination of extensive human lung specimens and novel computational methods to predict bronchial thermoplasty outcomes guided by structural or functional data compared with current clinical practice. Response to bronchial thermoplasty was determined from changes in airway responses to strong bronchoconstrictor simulations and flow heterogeneity after one or three simulated thermoplasty procedures. Structure-guided treatment showed significant improvement over current unguided clinical practice, with a single session of structure-guided treatment producing improvements comparable with three sessions of unguided treatment. In comparison, function-guided treatment did not produce a significant improvement over current practice. Structure-guided targeting of bronchial thermoplasty is a promising avenue for improving therapy and reinforces the need for advanced imaging technologies. The functional imaging-guided approach is predicted to be less effective presently, and we make recommendations on how this approach could be improved. NEW & NOTEWORTHY Bronchial thermoplasty is a recent treatment for asthma in which thermal energy is delivered via bronchoscope to specific airways in an effort to directly target airway smooth muscle. Current practice involves the treatment of a standard set of airways, unguided by patient-specific data. We consider the potential for guided treatments, either by functional or structural data from the lung, and show that treatment guided by structural data has the potential to improve clinical practice.
Publisher: Hindawi Limited
Date: 17-10-2012
DOI: 10.1155/2012/157047
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 in iduals 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.
Publisher: European Respiratory Society (ERS)
Date: 03-2023
Publisher: American Physiological Society
Date: 03-2015
DOI: 10.1152/JAPPLPHYSIOL.00724.2014
Abstract: In isolated airway smooth muscle (ASM) strips, an increase or decrease in ASM length away from its current optimum length causes an immediate reduction in force production followed by a gradual time-dependent recovery in force, a phenomenon termed length adaptation. In situ, length adaptation may be initiated by a change in transmural pressure (P tm ), which is a primary physiological determinant of ASM length. The present study sought to determine the effect of sustained changes in P tm and therefore, ASM perimeter, on airway function. We measured contractile responses in whole porcine bronchial segments in vitro before and after a sustained inflation from a baseline P tm of 5 cmH 2 O to 25 cmH 2 O, or deflation to −5 cmH 2 O, for ∼50 min in each case. In one group of airways, lumen narrowing and stiffening in response to electrical field stimulation (EFS) were assessed from volume and pressure signals using a servo-controlled syringe pump with pressure feedback. In a second group of airways, lumen narrowing and the perimeter of the ASM in situ were determined by anatomical optical coherence tomography. In a third group of airways, active tension was determined under isovolumic conditions. Both inflation and deflation reduced the contractile response to EFS. Sustained P tm change resulted in a further decrease in contractile response, which returned to baseline levels upon return to the baseline P tm . These findings reaffirm the importance of P tm in regulating airway narrowing. However, they do not support a role for ASM length adaptation in situ under physiological levels of ASM lengthening and shortening.
Publisher: European Respiratory Society (ERS)
Date: 17-10-2019
DOI: 10.1183/13993003.00857-2019
Abstract: Epidemiological studies report that overweight or obese asthmatic subjects have more severe disease than those of a healthy weight. We postulated that accumulation of adipose tissue within the airway wall may occur in overweight patients and contribute to airway pathology. Our aim was to determine the relationship between adipose tissue within the airway wall and body mass index (BMI) in in iduals with and without asthma. Transverse airway sections were s led in a stratified manner from post mortem lungs of control subjects (n=15) and cases of nonfatal (n=21) and fatal (n=16) asthma. The relationship between airway adipose tissue, remodelling and inflammation was assessed. The areas of the airway wall and adipose tissue were estimated by point count and expressed as area per mm of basement membrane perimeter (Pbm). The number of eosinophils and neutrophils were expressed as area densities. BMI ranged from 15 to 45 kg·m −2 and was greater in nonfatal asthma cases (p .05). Adipose tissue was identified in the outer wall of large airways (Pbm mm), but was rarely seen in small airways (Pbm mm). Adipose tissue area correlated positively with eosinophils and neutrophils in fatal asthma (Pbm mm, p .01), and with neutrophils in control subjects (Pbm mm, p=0.04). These data show that adipose tissue is present within the airway wall and is related to BMI, wall thickness and the number of inflammatory cells. Therefore, the accumulation of airway adipose tissue in overweight in iduals may contribute to airway pathophysiology.
Publisher: American Physiological Society
Date: 15-08-2013
DOI: 10.1152/JAPPLPHYSIOL.01286.2012
Abstract: During deep inspirations (DI), a distending force is applied to airway smooth muscle (ASM i.e., stress) and the muscle is lengthened (i.e., strain), which produces a transient reversal of bronchoconstriction (i.e., bronchodilation). The aim of the present study was to determine whether an increase in ASM stress or the accompanying increase in strain mediates the bronchodilatory response to DI. We used whole porcine bronchial segments in vitro and a servo-controlled syringe pump that applied fixed-transmural pressure (P tm ) or fixed-volume oscillations, simulating tidal breathing and DI. The relationship between ASM stress and strain during oscillation was altered by increasing doses of acetylcholine, which stiffened the airway wall, or by changing the rate of inflation during DI, which utilized the viscous properties of the intact airway. Bronchodilation to DI was positively correlated with ASM strain (range of r values from 0.81 to 0.95) and negatively correlated with stress (range of r values from −0.42 to −0.98). Fast fixed-P tm DI produced greater bronchodilation than slow DI, despite less ASM strain. Fast fixed-volume DI produced greater bronchodilation than slow DI, despite identical ASM strain. We show that ASM strain, rather than stress, is the critical determinant of bronchodilation and, unexpectedly, that the rate of inflation during DI also impacts on bronchodilation, independent of the magnitudes of either stress or strain.
Publisher: American Physiological Society
Date: 15-04-2014
Publisher: Frontiers Media SA
Date: 23-06-2017
Publisher: American Physiological Society
Date: 12-2021
Publisher: Elsevier BV
Date: 12-2013
Publisher: Wiley
Date: 06-2020
DOI: 10.14814/PHY2.14451
Publisher: American Physiological Society
Date: 09-2004
DOI: 10.1152/JAPPLPHYSIOL.00262.2004
Abstract: Bronchoconstrictor responses are quantitatively different when they are evoked under static conditions and during or after periods of deep inspiration. In vivo, deep inspirations produce bronchodilation and protect the lung from subsequent bronchoconstriction (termed bronchoprotection). These effects may be due in part to dynamic stretch on airways produced by cyclical expansion of airway diameter. However, airways also lengthen cyclically during breathing. The effects of cyclical airway elongation on evoked bronchoconstriction have not been examined. This study recorded evoked contractions of pig bronchial segments 1) at different airway lengths, 2) after a period of cyclical lengthening in relaxed airways, and 3) during cyclical lengthening in pretoned airways. Airway segments were mounted in organ baths and bathed in Krebs solution luminally and on the adventitia. Airways were cyclically lengthened by 5–30% of their deflated length at 0.5–2 Hz for 5 min. Contractions were evoked by electrical field stimulation or carbachol and were recorded under isovolumic conditions. Under static conditions, there was a blunt relationship between length and response to electrical field stimulation. After a period of airway length cycling, electrical field stimulation-induced contractions were increased. In airways pretoned with carbachol, cyclical lengthening produced a transient bronchodilation and a sustained increase in contraction. Contractile responses were not blocked by indomethacin. The results show that isolated airways respond actively to dynamic changes in length. Our results indicate that cyclical lengthening of airways could contribute to lung function in vivo but does not appear to account for the phenomenon of bronchoprotection.
Publisher: Cambridge University Press (CUP)
Date: 17-08-2021
DOI: 10.1017/S2040174420000744
Abstract: Evidence from animal models demonstrate that intrauterine growth restriction (IUGR) alters airway structure and function which may affect susceptibility to disease. Airway inflammation and dysregulated epithelial barrier properties are features of asthma which have not been examined in the context of IUGR. This study used a maternal hypoxia-induced IUGR mouse model to assess lung-specific and systemic inflammation and airway epithelial tight junctions (TJs) protein expression. Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O 2 ) from gestational day (GD) 11 to 17.5 (IUGR group term, GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O 2 ). A Control group was housed under normoxic conditions throughout pregnancy. Offspring weights were recorded at 2 and 8 weeks of age and euthanized for bronchoalveolar lavage (BAL) and peritoneal cavity fluid collection for inflammatory cells counts. From a separate group of mice, right lungs were collected for Western blotting of TJs proteins. IUGR offspring had greater inflammatory cells in the BAL fluid but not in peritoneal fluid compared with Controls. At 8 weeks of age, interleukin (IL)-2, IL-13, and eotaxin concentrations were higher in male IUGR compared with male Control offspring but not in females. IUGR had no effect on TJs protein expression. Maternal hypoxia-induced IUGR increases inflammatory cells in the BAL fluid of IUGR offspring with no difference in TJs protein expression. Increased cytokine release, specific to the lungs of IUGR male offspring, indicates that both IUGR and sex can influence susceptibility to airway disease.
Publisher: The Optical Society
Date: 20-10-2017
DOI: 10.1364/BOE.8.005127
Publisher: American Physiological Society
Date: 03-2002
DOI: 10.1152/JAPPLPHYSIOL.00662.2001
Abstract: Structural components of the airway wall may act to load airway smooth muscle and restrict airway narrowing. In this study, the effect of load on airway narrowing was investigated in pig isolated bronchial segments. In some bronchi, pieces of cartilage were removed by careful dissection. Airway narrowing was produced by maximum electrical field stimulation. An endoscope was used to record lumen narrowing. The compliance of the bronchial segments was determined from the cross-sectional area of the lumen and the transmural pressure. Airway narrowing and the velocity of airway narrowing were increased in cartilage-removed airways compared with intact control bronchi. Morphometric assessment of smooth muscle length showed greater muscle shortening to acetylcholine in cartilage-removed airways than in controls. Airway narrowing was positively correlated with airway compliance. Compliance and area of cartilage were negatively correlated. These results show that airway narrowing is increased in compliant airways and that cartilage significantly loads airway smooth muscle in whole bronchi.
No related grants have been discovered for Peter Noble.