Bronchoprotective effect of simulated deep inspirations in tracheal smooth muscle

2014 ◽  
Vol 117 (12) ◽  
pp. 1502-1513 ◽  
Author(s):  
Christopher D. Pascoe ◽  
Graham M. Donovan ◽  
Ynuk Bossé ◽  
Chun Y. Seow ◽  
Peter D. Paré
Keyword(s):  
Smooth Muscle ◽  
Lung Function ◽  
Airway Smooth Muscle ◽  
Forced Expiratory Volume ◽  
Airway Responsiveness ◽  
Tracheal Smooth Muscle ◽  
Airway Wall ◽  
Methacholine Challenge ◽  
Airway Narrowing ◽  
The Third

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

scholarly journals Airway responsiveness depends on the diffusion rate of methacholine across the airway wall

2012 ◽  
Vol 112 (10) ◽  
pp. 1670-1677 ◽  
Author(s):  
Jason H. T. Bates ◽  
Chelsea A. Stevenson ◽  
Minara Aliyeva ◽  
Lennart K. A. Lundblad
Keyword(s):  
Smooth Muscle ◽  
Time Course ◽  
Airway Resistance ◽  
Diffusion Rate ◽  
Airway Responsiveness ◽  
Airway Wall ◽  
Methacholine Challenge ◽  
Airway Narrowing ◽  
Challenge Tests ◽  
Important Possibility

During methacholine challenge tests of airway responsiveness, it is invariably assumed that the administered dose of agonist is accurately reflected in the dose that eventually reaches the airway smooth muscle (ASM). However, agonist must traverse a variety of tissue obstacles to reach the ASM, during which the agonist is subjected to both enzymatic breakdown and removal by the bronchial and pulmonary circulations. This raises the possibility that a significant fraction of the deposited agonist may never actually make it to the ASM. To understand the nature of this effect, we measured the time course of changes in airway resistance elicited by various durations of methacholine aerosol in mice. We fit to these data a computational model of a dynamically contracting airway responding to agonist that diffuses through an airway compartment, thereby obtaining rate constants that reflect the diffusive barrier to methacholine. We found that these barriers can contribute significantly to the time course of airway narrowing, raising the important possibility that alterations in the diffusive barrier presented by the airway wall may play a role in pathologically altered airway responsiveness.

scholarly journals Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs

2004 ◽  
Vol 97 (5) ◽  
pp. 1946-1953 ◽  
Author(s):  
Christopher J. Danek ◽  
Charles M. Lombard ◽  
Donald L. Dungworth ◽  
P. Gerard Cox ◽  
John D. Miller ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Radio Frequency ◽  
Airway Smooth Muscle ◽  
Airway Responsiveness ◽  
Airway Wall ◽  
Smooth Muscle Contractility ◽  
Airway Narrowing ◽  
Radio Frequency Energy ◽  
Before And After ◽  
Percent Decrease

We delivered controlled radio frequency energy to the airways of anesthetized, ventilated dogs to examine the effect of this treatment on reducing airway narrowing caused by a known airway constrictor. The airways of 11 dogs were treated with a specially designed bronchial catheter in three of four lung regions. Treatments in each of the three treated lung regions were controlled to a different temperature (55, 65, and 75°C); the untreated lung region served as a control. We measured airway responsiveness to local methacholine chloride (MCh) challenge before and after treatment and examined posttreatment histology to 3 yr. Treatments controlled to 65°C as well as 75°C persistently and significantly reduced airway responsiveness to local MCh challenge ( P ≤ 0.022). Airway responsiveness (mean percent decrease in airway diameter after MCh challenge) averaged from 6 mo to 3 yr posttreatment was 79 ± 2.2% in control airways vs. 39 ± 2.6% ( P ≤ 0.001) for airways treated at 65°C, and 26 ± 2.7% ( P ≤ 0.001) for airways treated at 75°C. Treatment effects were confined to the airway wall and the immediate peribronchial region on histological examination. Airway responsiveness to local MCh challenge was inversely correlated to the extent of altered airway smooth muscle observed in histology ( r = −0.54, P < 0.001). We conclude that the temperature-controlled application of radio frequency energy to the airways can reduce airway responsiveness to MCh for at least 3 yr in dogs by reducing airway smooth muscle contractility.

Airway smooth muscle orientation in intraparenchymal airways

1997 ◽  
Vol 82 (1) ◽  
pp. 70-77 ◽  
Author(s):  
M. Lei ◽  
H. Ghezzo ◽  
M. F. Chen ◽  
D. H. Eidelman
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Serial Sections ◽  
Airway Wall ◽  
Transverse Axis ◽  
Mean Values ◽  
Airway Narrowing ◽  
Human Specimen ◽  
The Mean ◽  
Airway Tree

Lei, M., H. Ghezzo, M. F. Chen, and D. H. Eidelman.Airway smooth muscle orientation in intraparenchymal airways. J. Appl. Physiol. 82(1): 70–77, 1997.—Airway smooth muscle (ASM) shortening is the central event leading to bronchoconstriction. The degree to which airway narrowing occurs as a consequence of shortening is a function of both the mechanical properties of the airway wall as well as the orientation of the muscle fibers. Although the latter is theoretically important, it has not been systematically measured to date. The purpose of this study was to determine the angle of orientation of ASM (θ) in normal lungs by using a morphometric approach. We analyzed the airway tree of the left lower lobes of four cats and one human. All material was fixed with 10% buffered Formalin at a pressure of 25 cmH2O for 48 h. The fixed material was dissected along the airway tree to permit isolation of generations 4–18 in the cats and generations 5–22 in the human specimen. Each airway generation was individually embedded in paraffin. Five-micrometer-thick serial sections were cut parallel to the airway long axis and stained with hematoxylin-phloxine-saffron. Each block yielded three to five sections containing ASM. To determine θ, we measured the orientation of ASM nuclei relative to the transverse axis of the airway by using a digitizing tablet and a light microscope (×250) equipped with a drawing tube attachment. Inspection of the sections revealed extensive ASM crisscrossing without a homogeneous orientation. The θ was clustered between −20° and 20° in all airway generations and did not vary much between generations in any of the cats or in the human specimen. When θ was expressed without regard to sign, the mean values were 13.2° in the cats and 13.1° in the human. This magnitude of obliquity is not likely to result in physiologically important changes in airway length during bronchoconstriction.

Nerve growth factor-enhanced airway responsiveness involves substance P in ferret intrinsic airway neurons

2006 ◽  
Vol 291 (1) ◽  
pp. L111-L118 ◽  
Author(s):  
Z.-X. Wu ◽  
R. D. Dey
Keyword(s):  
Smooth Muscle ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Treatment Group ◽  
Substance P ◽  
Airway Smooth Muscle ◽  
Airway Responsiveness ◽  
Tracheal Smooth Muscle ◽  
Control Group ◽  
Nerve Growth

Nerve growth factor (NGF), a member of the neurotrophin family, enhances synthesis of neuropeptides in sensory and sympathetic neurons. The aim of this study was to examine the effect of NGF on airway responsiveness and determine whether these effects are mediated through synthesis and release of substance P (SP) from the intrinsic airway neurons. Ferrets were instilled intratracheally with NGF or saline. Tracheal smooth muscle contractility to methacholine and electrical field stimulation (EFS) was assessed in vitro. Contractions of isolated tracheal smooth muscle to EFS at 10 and 30 Hz were significantly increased in the NGF treatment group (10 Hz: 33.57 ± 2.44%; 30 Hz: 40.12 ± 2.78%) compared with the control group (10 Hz: 27.24 ± 2.14%; 30 Hz: 33.33 ± 2.31%). However, constrictive response to cholinergic agonist was not significantly altered between the NGF treatment group and the control group. The NGF-induced modulation of airway smooth muscle to EFS was maintained in tracheal segments cultured for 24 h, a procedure that causes a significant anatomic and functional loss of SP-containing sensory fibers while maintaining viability of intrinsic airway neurons. The number of SP-containing neurons in longitudinal trunk and superficial muscular plexus and SP nerve fiber density in tracheal smooth muscle all increased significantly in cultured trachea treated with NGF. Pretreatment with CP-99994, an antagonist of neurokinin 1 receptor, attenuated the NGF-induced increased contraction to EFS in cultured segments but had no effect in saline controls. These results show that the NGF-enhanced airway smooth muscle contractile responses to EFS are mediated by the actions of SP released from intrinsic airway neurons.

Determinants of airway smooth muscle shortening in excised canine lobes

1995 ◽  
Vol 78 (2) ◽  
pp. 608-614 ◽  
Author(s):  
M. Okazawa ◽  
S. Vedal ◽  
L. Verburgt ◽  
R. K. Lambert ◽  
P. D. Pare
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Wall ◽  
High Concentration ◽  
Airway Narrowing ◽  
Wall Area ◽  
Muscle Shortening ◽  
Mechanical Factors ◽  
Airway Dimensions ◽  
Wall Geometry

There is marked heterogeneity of airway narrowing in intraparenchymal airways in response to bronchoconstricting stimuli. We hypothesized that this heterogeneity results from variations in the structure of the airway wall. Freshly excised dog lung lobes were inflated to transpulmonary pressures (PL) of between 5 and 15 cmH2O, and an aerosol containing a high concentration of carbachol was administered. The lobes were fixed and processed for light-microscopic examination and morphometric analysis of membranous airway dimensions. The relationships of smooth muscle shortening to PL and airway dimensions were analyzed using multiple linear regression. The results show that airway smooth muscle shortening was greater at lower PL and in airways with larger internal perimeter and a greater number of folds per internal perimeter and that it was less in airways with greater inner wall area. We conclude that the magnitude and variability of airway smooth muscle shortening and airway narrowing in response to maximal constricting stimuli are influenced by mechanical factors related to airway wall geometry.

Augmentation of bovine airway smooth muscle responsiveness to carbachol, KCl, and histamine by the isoprostane 8-iso-PGE2

2004 ◽  
Vol 287 (5) ◽  
pp. L1035-L1041 ◽  
Author(s):  
Adriana Catalli ◽  
Luke J. Janssen
Keyword(s):  
Oxidative Stress ◽  
Cystic Fibrosis ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Airway Responsiveness ◽  
Tracheal Smooth Muscle ◽  
Cholinergic Stimulation ◽  
Functional Responses ◽  
Prostanoid Receptor ◽  
Tp Receptors

Isoprostanes are generated during periods of oxidative stress, which characterize diseases such as asthma and cystic fibrosis. They also elicit functional responses and may therefore contribute to the pathology of these diseases. We set out to examine the effects of isoprostanes on airway responsiveness to cholinergic stimulation. Muscle bath techniques were employed using isolated bovine tracheal smooth muscle. 8-Isoprostaglandin E2 (8-iso-PGE2) increased tone directly on its own, although the magnitude of this response, even at the highest concentration tested, was only a fraction of that evoked by KCl or carbachol. More importantly, though, pretreatment of the tissues with 8-iso-PGE2 (10 μM) markedly augmented responses to submaximal and even subthreshold concentrations of KCl, carbachol, or histamine, whereas maximal responses to these agents were unaffected by the isoprostane. The augmentative effect on cholinergic responsiveness was mimicked by PGE2 (0.1 μM) and by the FP agonists PGF2 (0.1 μM) and fluprostenol (0.1 μM), but not by the EP3 agonist sulprostone (0.1 μM) or the TP agonist U-46619 (0.1 μM). Antagonists of EP1 receptors (AH-6809 and SC-19920, 10 μM) and TP receptors (ICI-192605, 1 μM) had no effect on 8-iso-PGE2-induced augmentation of cholinergic responsiveness. We conclude that 8-iso-PGE2 induces nonspecific airway smooth muscle hyperresponsiveness through a non-TP non-EP prostanoid receptor.

scholarly journals Airway Smooth Muscle Dynamics and Hyperresponsiveness: In and outside the Clinic

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Peter B. Noble ◽  
Thomas K. Ansell ◽  
Alan L. James ◽  
Peter K. McFawn ◽  
Howard W. Mitchell
Keyword(s):  
Smooth Muscle ◽  
Lung Function ◽  
Airway Smooth Muscle ◽  
Underlying Mechanism ◽  
Protective Mechanisms ◽  
Functional Abnormality ◽  
Airway Narrowing ◽  
Asthmatic Patients ◽  
Muscle Dynamics ◽  
Health And Disease

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.

Chronic inflation of ferret lungs with CPAP reduces airway smooth muscle contractility in vivo and in vitro

2008 ◽  
Vol 104 (3) ◽  
pp. 610-615 ◽  
Author(s):  
Z. Xue ◽  
L. Zhang ◽  
Y. Liu ◽  
S. J. Gunst ◽  
R. S. Tepper
Keyword(s):  
Smooth Muscle ◽  
Mechanical Stress ◽  
Chronic Stress ◽  
Airway Smooth Muscle ◽  
Structural Changes ◽  
Airway Responsiveness ◽  
Wall Structure ◽  
Airway Wall

The mechanical stress imposed on the lungs during breathing is an important modulator of airway responsiveness in vivo. Our recent study demonstrated that continuous positive airway pressure applied to the lungs of nonanesthetized, tracheotomized rabbits for 4 days decreased lower respiratory system responsiveness to challenge with ACh (Xue Z, Zhang L, Ramchandani R, Liu Y, Antony VB, Gunst SJ, Tepper RS. J. Appl Physiol 99: 677–682, 2005). In addition, airway segments excised from the lungs of these animals and studied in vitro exhibited reduced contractility. However, the mechanism for this reduction in contractility was not determined. The stress-induced decrease in airway responsiveness could have resulted from alterations in the excitation-contraction coupling mechanisms of the smooth muscle cells, or it might reflect changes in the structure and/or composition of the airway wall tissues. In the present study, we assessed the effect of prolonged chronic stress of the lungs in vivo on airway smooth muscle force generation, myosin light chain phosphorylation, and airway wall structure. To enhance the potential development of stress-induced structural changes, we applied mechanical stress for a prolonged period of time of 2–3 wk. Our results demonstrate a direct connection between the decreased airway responsiveness caused by chronic mechanical stress of the lungs in vivo and a persistent decrease in contractile protein activation in the airway smooth muscle isolated from those lungs. The chronic stress also caused an increase in airway size but no detectable changes in the composition of the airway wall.

Airway narrowing and response to simulated deep inspiration in bronchial segments from subjects with fixed airflow obstruction

2020 ◽  
Vol 128 (4) ◽  
pp. 757-767
Author(s):  
Alvenia Cairncross ◽  
Robyn L. Jones ◽  
John G. Elliot ◽  
Peter K. McFawn ◽  
Alan L. James ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Volume Fraction ◽  
Airflow Obstruction ◽  
Deep Inspiration ◽  
Airway Wall ◽  
Airway Narrowing ◽  
Fixed Airflow Obstruction

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 FEV1 %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.

A model of the mechanics of airway narrowing

1990 ◽  
Vol 69 (3) ◽  
pp. 849-860 ◽  
Author(s):  
B. R. Wiggs ◽  
R. Moreno ◽  
J. C. Hogg ◽  
C. Hilliam ◽  
P. D. Pare
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Dose Response ◽  
Fluid Dynamic ◽  
Tracheobronchial Tree ◽  
Wall Thickening ◽  
Airway Wall ◽  
Pulmonary Resistance ◽  
Airway Narrowing ◽  
Muscle Shortening

To examine the interaction between airway smooth muscle shortening and airway wall thickening on changes in pulmonary resistance, we have developed a model of the tracheobronchial tree that allows simulation of the mechanisms involved in airway narrowing. The model is based on the symmetrical dichotomous branching tracheobronchial tree as described by Weibel and uses fluid dynamic equations proposed by Pedley et al. to calculate inspiratory resistance during quiet tidal breathing. To allow for changes in lung volume, we used the airway pressure-area curves developed by Lambert et al. The model is easily implemented with a spreadsheet and personal computer that allows calculation of total and regional pulmonary resistance. At each airway generation in the model, provision is made for airway wall thickness, the maximal airway smooth muscle shortening achievable, and an S-shaped dose-response relationship to describe smooth muscle shortening. To test the validity of the model, we compared pressure-flow curves generated with the model with measurements of pulmonary resistance while normal subjects breathed air and 20% O2-80% He at a variety of lung volumes. By simulating progressive airway smooth muscle shortening, realistic pulmonary resistance vs. dose-response curves were produced. We conclude that this model provides realistic estimates of pulmonary resistance and shows potential for examining the various mechanisms that could produce excessive airway narrowing in disease.

Sign in / Sign up

Export Citation Format

Share Document