Critical roles of airway smooth muscle in mediating deep-inspiration-induced bronchodilation: a big stretch?

Abstract

Background
Deep inspiration (DI) has been shown to induce bronchodilation and bronchoprotection in bronchochallenged healthy subjects, but not in asthmatics. Strain-induced relaxation of airway smooth muscle (ASM) is considered one of the factors responsible for these effects. Other factors include the release or redistribution of pulmonary surfactant, alteration in mucus plugs, and changes in airway heterogeneity.

Main body
The present review is focused on the DI effect on ASM function, based on recent findings from ex vivo sheep lung experiments showing a large change in airway diameter during a DI. The amount of stretch on the airways, when applied to isolated airway rings in vitro, caused a substantial decrease in ASM contractility that takes many minutes to recover. When challenged with a bronchoconstrictor, the increase in pulmonary resistance in the ex vivo ovine lungs is mostly due to the increase in airway resistance.

Conclusions
Although non-ASM related factors cannot be excluded, the large strain on the airways associated with a DI substantially reduces ASM contractility and thus can account for most of the bronchodilatory and bronchoprotective effects of DI.

Full text

Yasudaetal. Respiratory Research (2023) 24:250
https://doi.org/10.1186/s12931-023-02538-8
REVIEW
Critical roles ofairway smooth muscle
inmediating deep-inspiration-induced
bronchodilation: abig stretch?
Yuto Yasuda1*, Lu Wang1, Pasquale Chitano1 and Chun Y. Seow1,2
Abstract
Background Deep inspiration (DI) has been shown to induce bronchodilation and bronchoprotection in bronchoch-
allenged healthy subjects, but not in asthmatics. Strain-induced relaxation of airway smooth muscle (ASM) is consid-
ered one of the factors responsible for these effects. Other factors include the release or redistribution of pulmonary
surfactant, alteration in mucus plugs, and changes in airway heterogeneity.
Main body The present review is focused on the DI effect on ASM function, based on recent findings from ex vivo
sheep lung experiments showing a large change in airway diameter during a DI. The amount of stretch on the air-
ways, when applied to isolated airway rings in vitro, caused a substantial decrease in ASM contractility that takes many
minutes to recover. When challenged with a bronchoconstrictor, the increase in pulmonary resistance in the ex vivo
ovine lungs is mostly due to the increase in airway resistance.
Conclusions Although non-ASM related factors cannot be excluded, the large strain on the airways associated
with a DI substantially reduces ASM contractility and thus can account for most of the bronchodilatory and bron-
choprotective effects of DI.
Keywords Ex vivo lung mechanics, Lung volume and airway diameter, Strain-induced airway dilation, Airway smooth
muscle, Bronchoprotection, Bronchodilation
Background
An unsettled debate in the field of airway smooth muscle
(ASM) and lung function is the role of ASM in mediating
bronchodilation induced by a deep inspiration (DI) [1,
2]. e debate emerged subsequent to a comprehensive
investigation [3] in isolated bovine, non-asthmatic bron-
chial segments, in which a stretch on the airway resulting
from a DI-mimicking pressure-change was insufficient
to reduce ASM contractility and account for the typi-
cal bronchodilation observed in non-asthmatic human
subjects [4]. Prior to this study, several studies identified
significant broncho-relaxation in exvivo porcine, non-
asthmatic airway segments subjected to a transluminal
pressure change comparable to that experienced dur-
ing a DI [5–7]. Etiology behind this discrepancy remains
uncertain. In lung slices, oscillatory radial strain has been
demonstrated to dilate previously constricted healthy
human airways [8], implying that the local airway-paren-
chyma interdependence could mediate DI-induced bron-
chodilation. Even though the interdependence does not
rely on the presence of ASM in the airways, it is critical
in transmitting the distension force from the parenchyma
to the airway and ultimately to the ASM. In isolated
Open Access
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Respiratory Research
*Correspondence:
Yuto Yasuda
Yuto.Yasuda@hli.ubc.ca
1 Centre for Heart Lung Innovation, St. Paul’s Hospital, Providence Health
Care, University of British Columbia, 1081 Burrard Street, Vancouver, BC
V6Z 1Y6, Canada
2 Department of Pathology and Laboratory Medicine, University of British
Columbia, Vancouver, BC, Canada
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Yasudaetal. Respiratory Research (2023) 24:250
porcine, non-asthmatic ASM strip preparations, the con-
tractility of the muscle also exhibits a linear decline com-
mensurate with the amplitude of the strain applied to it
[9]. Taken together, the aforementioned invitro studies
suggest that oscillatory-strain-induced ASM relaxation
may partially account for the observed bronchodilatory
response following a DI. However, the relatively large
amplitudes and the prolonged oscillation employed in
these in vitro studies to achieve physiologically signifi-
cant broncho-relaxation, has raised doubts regarding the
significance of ASM’s role in DI-induced bronchodila-
tion invivo. In exvivo sheep lungs, profound bronchodi-
lation has been observed as a consequence of a DI [10].
ese findings suggest that extrapulmonary factors, such
as neural reflexes, are unlikely to be accountable for DI-
induced bronchodilation. However, the studies failed to
shed light on the role of ASM in mediating such bron-
chodilation, as the extent of stretch on the airways (and
consequently ASM) remains unknown. To answer the
question of whether DI-induced bronchodilation could
result from stretching the ASM (thus reducing its con-
tractility), we need to know first how much ASM in intra-
lobal airways are stretched during a DI. is brief review
is focused on mechanisms related to ASM that may play
a role in DI-mediated reduction in bronchodilation. For a
broader discussion on other mechanisms, the readers are
referred to the recent reviews by Lutchen etal. [11] and
Camoretti-Mercado and Lockey [12].
Why are we interested inthephenomenon
ofDI‑induced bronchodilation?
It is well known that a DI reverses bronchoconstric-
tion in non-asthmatic human subjects [4]. However,
this bronchodilatory response to DI is largely absent in
asthmatic individuals [13], particularly those with severe
asthma [14]. When healthy subjects are prevented from
taking deep breaths for a duration of 20–30 min, they
develop asthma-like symptoms, which can be alleviated
by a DI [15]. DIs administered prior to bronchochallenge
in healthy subjects have also been shown to reduce the
extent of bronchoconstriction induced by the subsequent
challenge [14, 16–18]. is phenomenon is known as
the bronchoprotective effect of DI, which is also attenu-
ated in asthmatic individuals. e mechanism under-
lying DI-induced bronchoprotection may be different
from that of bronchodilation. Crimi etal. showed that
even in healthy human subjects, the bronchoprotective
effect of DIs is absent if the lung function measurement
is not preceded by a full lung inflation [19]. is observa-
tion was corroborated by studies using isolated porcine
bronchial segments [20] and mouse model [18]. What
exactly a full lung inflation does to make the lung respon-
sive to the bronchoprotective DI effect is not clear, but
the observations suggest that factors affecting lung com-
pliance that may or may not be related to ASM must be
involved.
Additionally, in asthmatic subjects, fast re-narrowing
of the airways has been observed following DI-induced
bronchodilation [21], suggesting that asthmatic ASM
may be different from healthy ASM in its response to
strain, although shortening velocity and active isometric
force of tracheal smooth muscle from human asthmatics
was found not to be different from that from non-asth-
matics [22, 23]. However, a more recent finding indi-
cates an increase in reactivity of intra-lobal bronchi from
human asthmatics compared with those of non-asthmat-
ics [23]. e difference in ASM between asthmatics and
non-asthmatics may also lie in their “robustness”, in that
the asthmatic muscle’s contractility is less affected by
mechanical strain [22], such as that associated with DIs.
e mechanism underlying the DI-induced bronchodi-
lation and bronchoprotection in non-asthmatic subjects
is unclear. e diminished or total lack of such response
observed by many studies in asthmatics, especially in
severe asthmatics, suggests that part of the asthma
pathophysiology lies in how a DI alters the lung func-
tion. erefore, it is crucial to elucidate the mechanisms
underlying the DI effect, particularly in terms of the role
of ASM in lung function. Restoring the DI effect in indi-
viduals with asthma could represent a significant break-
through in asthma treatment.
How much are intralobular airways distended
duringaDI?
In exvivo sheep lungs, by undertaking a deep inhalation
from functional residual capacity (FRC), correspond-
ing to a transpulmonary pressure of 7.5 cm H2O, to
total lung capacity (TLC), corresponding to a transpul-
monary pressure of 40 cm H2O, an approximate dou-
bling of exvivo lung volume has been established [10].
Assuming the lung to be homogeneous and isotropic in
its material properties, this volume increase corresponds
to an approximate 26% enlargement in airway diam-
eters, as calculated by a scaling factor of 21/3. However,
because the lung is neither homogeneous nor isotropic,
it is necessary to directly measure airway diameter in
intact lungs. To address this matter directly, Dong etal.
[24] employed computed tomography (CT) to measure
airway diameters and lung volumes at different transpul-
monary pressures. eir findings revealed a significant
increase in airway diameter and lung volume as the
transpulmonary pressure increased from 5 to 30 cmH2O,
with small airways exhibiting a much greater increase in
diameter compared to large airways (Fig.1). Specifically,
with a ~ 50% increase in volume, small airways showed an
average diameter increase of ~ 63%, whereas large airways
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Yasudaetal. Respiratory Research (2023) 24:250
displayed an average increase of ~ 18%. Across all meas-
ured airways, the average increase in diameter amounted
to ~ 46%. In the context of large airways, Brown et al.
observed a ~ 28% increase in canine airway diameter
when lung volume doubled from 40 to 80% of maximum
volume in unchallenged canine lungs [25]. However, in
histamine-challenged lungs, they noted that doubling the
volume resulted in a doubling of airway diameter. Similar
results were obtained by Sera etal. in mice [26, 27]. An
interesting observation from the aforementioned studies
is that, despite airway volume representing a tiny frac-
tion of the total lung volume, the fractional increase in
the volume of all airways (individually calculated as πr2 x
airway segment length) exceeded the fractional increase
in lung volume. e explanation of this seemingly para-
doxical observation could lie in the geometrical dis-
parities between airways and alveoli. Assuming that an
airway segment approximates a thin-walled tube, LaPlace
law dictates that the tension in the airway wall (Taw)
equals to the transmural pressure (Paw) multiplied by
the radius of the airway (raw), i.e., Taw = Paw x raw. In con-
trast, approximating an alveolus as a thin-walled sphere,
the tension in the alveolar wall (Tal) is determined by
the product of the pressure across the alveolar wall (Pal)
times the radius of the alveolus (ral) divided by 2, i.e.,
Tal = (Pal x ral)/2. Considering a static transpulmonary
pressure condition where Paw = Pal, it follows Taw = 2(Tal
x raw)/ral. Given that the alveolar radius is relatively small,
approximately 0.1 mm in humans [28], the wall tension
in an airway with a 2-mm radius, for example, would be
40 times greater than that in the alveolar wall under the
same transpulmonary pressure. Consequently, because of
the complex lung structure, airway walls experience sub-
stantially greater tension than alveolar walls in the same
lung under the same transpulmonary pressure. is phe-
nomenon may elucidate why airways can undergo greater
distention compared to lung volume when exposed to
distending pressure.
Can theamount ofstretch inASM seen duringaDI
reduce ASM contractility?
Previous studies have established that oscillatory strain
applied to ASM leads to a reduction in its active force,
even when the oscillation is applied prior to activation,
resulting in a decreased ability to generate force in subse-
quent contractions [9, 29]. ese observations have led to
a widespread postulation that the strain exerted on ASM
during a DI is responsible for the bronchodilatory and
bronchoprotective response. However, before accepting
this hypothesis, it is crucial to determine whether the
amount of stretch applied to ASM during a DI is signifi-
cant enough to impact the muscle’s contractility. Dong
etal. addressed this issue by first quantifying the amount
of strain on the airways during a DI and then applying the
same level of strain to isolated bronchial rings to evaluate
its effect on ASM contractility in an ovine model [24]. As
shown in Fig.2, the 46% average airway strain observed in
intact lungs during a DI, when applied to isolated bron-
chial rings, led to an immediate and substantial reduction
in ASM contractility. e depressed force required at
least 25 min to recover, indicating that the bronchopro-
tective effect of DI can have a prolong duration.
0.91.0 1.11.2 1.31.4 1.
51
.6
0.8
1.0
1.2
1.4
1.6
1.8
Relative airway diameter
Total airways
Small airways
Medium airways
Large airways
Relative lung volume
Fig. 1 The fractional change in intralobular airway diameter
at different lung volumes corresponding to transpulmonary pressures
from 5 to 30 cmH2O in ex vivo sheep lungs. The airways are grouped
into 3 sizes in terms of their diameters, small (< 3 mm), medium
(between 3–4 mm), and large (> 4 mm). Reproduced from Dong et al.
[24] with permission
Fig. 2 Active force generated by bronchial rings after 3 consecutive
stretches at a frequency of 0.25 Hz and strain amplitude of 46%
that matched the airway strain observed in intact lungs during a DI.
The oscillatory strain was applied just before time zero. *P < 0.05
and **P < 0.01 indicate statistical difference from the maximum
isometric force before oscillation (Fmax). Reproduced from Dong et al.
[24] with permission
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Yasudaetal. Respiratory Research (2023) 24:250
e bronchodilatory effect of DI was investigated by
Dong etal. [24] in a different set of experiments. In ovine
bronchial rings activated by acetylcholine (ACh), force
oscillation at a frequency of 0.25 Hz was applied to the
ASM. To mimic the stretch experienced by the bron-
chus during a DI, the amplitude of the force oscillation
was calculated based on the wall tension of the bronchus
resulting from a change in the transmural pressure from
5 to 30 cmH2O, taking into account the airway diameter
according to the LaPlace law. e relaxation in length of
the bronchial ring served as an indicator of bronchodi-
lation. Immediately after the force oscillation, there was
a large re-lengthening of the ring, followed by re-short-
ening (Fig.3). Importantly, the extent of the re-shorten-
ing depends on the duration of muscle (ACh-induced)
activation before the force oscillation was applied. e
longer the muscle had been activated, the less the extent
of re-shortening. is observation may have implications
for the bronchodilatory effect of DI, suggesting that the
longer the airways remain in an actively contracted state,
the stronger the bronchodilatory effect of DI.
Based on the data presented in Figs.2 and 3, it is clear
that the amount of stretch experienced by the airways
during a DI could be sufficient to account for at least a
part of the bronchodilatory and bronchoprotective effect
of DI observed in non-asthmatic human subjects [4, 16],
but it should be noted that this conclusion is based on
observations from ovine bronchial ASM and not that of
humans.
How dowe know thereduction inlung resistance
afteraDI isASM related?
In isolated sheep lungs, a DI maneuver has been shown
to lead to a significant decrease in lung resistance [10].
Lung resistance comprises two components: airway
resistance and resistance stemming from the viscoelastic
lung parenchymal tissue, also known as tissue resistance.
In lungs subjected to bronchochallenge, the increase in
airway resistance is primary attributed to the contrac-
tion of bronchial smooth muscle, while tissue resistance
is largely unrelated to ASM activity. is does not mean
that tissue resistance is not a significant component of
the lung resistance. In sheep lungs when bronchochal-
lenge caused the lung resistance to double, the airway
resistance and tissue resistance each made up about half
of the lung resistance when the resistance is measured at
0.25Hz [30]. Some early studies showed that broncho-
challenge caused a significant increase in tissue resist-
ance [31–33]. But a later study showed that this is likely
due to broncho-challenge-induced heterogeneity in air-
way constriction [34].
In the study of Dong etal. the effects of DI on airway
and tissue resistance in bronchochallenged sheep lungs
were specifically investigated [30]. ey found that in
these lungs, the airway resistance increased by ~ sixfold
after ACh challenge, and about half of this increase was
abolished by a DI. On the other hand, tissue resistance
was found to be insensitive to ACh challenge, meaning
its response to a DI was similar regardless of whether the
lungs were challenged or not. is finding in sheep lungs
indicates that the part of the lung resistance influenced
by ACh resides in the airways, presumably due to the
effect of ACh on ASM. e study suggests that the reduc-
tion in lung resistance following a DI is primarily ASM-
related, and the strain exerted on the airways during a DI
is likely responsible for the observed bronchodilation.
Other factors aected byaDI
From the previous discussion, it is evident that at least
a part of the bronchodilatory and bronchoprotective
effects of a DI can be attributed to the relaxation of ASM
induced by strain. However, it is important to note that a
Fig. 3 Length relaxation of bronchial rings during an isotonic
contraction after 3 cycles of force oscillation (0.25 Hz). The dashed
horizontal line represents acetylcholine (ACh)-induced shortening
of the ring preparation maintained over time (time control)
without interruption by the force oscillation. The oscillation
was applied during an isotonic contraction at three different times (5,
15, and 60 min) after the onset of contraction. The solid black
symbols represent measurements that are significantly different
from the time control with a P value < 0.01, and the gray symbols
represent measurements that are significantly different from the time
control with a P value < 0.05. The open symbols indicate no difference
from time control. Reproduced from Dong et al. [24] with permission
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Yasudaetal. Respiratory Research (2023) 24:250
DI may also affect lung resistance through other mecha-
nisms independent of ASM. For instance, it could impact
the release or redistribution of pulmonary surfactant,
alter mucus plugs, or modify the heterogeneity of air-
way tone or caliber [11]. Although in healthy ovine lungs
we found that airway heterogeneity is not significantly
altered by a DI [24]. However, under certain pathologi-
cal conditions, reducing airway heterogeneity may be
an important consequence of a DI. Airway heterogene-
ity could also be a species-specific issue. We have found
heterogeneity in ASM and airway wall area in both asth-
matic and non-asthmatic human donor lungs [35]. is
finding suggests that there could be heterogeneity in
airway constriction in both human asthmatics and non-
asthmatics. Given the complexity of lung structure and
the presence of numerous cell types, it is conceivable that
the bronchodilatory and bronchoprotective effects of DI
do not originate from a single locus within the lung.
ere are factors known to be influenced by DI but
directly or indirectly related to changes in ASM contrac-
tility. In asthmatic subjects, the reduction in resistance
following DI is inversely associated with the expression of
desmin, MLCK, and calponin in bronchial biopsies [36].
e number of mast cells in the ASM area and CD4 posi-
tive lymphocytes in the lamina propria are also related
to the lack of effectiveness of DI-induced reduction in
expiratory resistance in asthmatic subjects [37]. Inhaled
glucocorticoids are effective in restoring DI-induced
bronchoprotection in mild asthmatic subjects, although
their effect is reduced in severe asthmatic subjects [38].
Systemic steroids increase DI-induced bronchodilation
in mild to moderate asthmatic subjects [39]. ese pieces
of evidence suggest that the extent of the effect of DI is
inversely related to airway inflammation. In the context
of chronic obstructive pulmonary disease (COPD), the
bronchodilatory effect of DI is diminished in mild COPD
patients [40]. e loss of alveolar attachment observed in
COPD is associated with the reduced DI-induced bron-
chodilation [41].
Conclusions
Based on recently gathered evidence, the reduction in
ASM contractility resulting from DI is emerging as a
leading factor believed to mediate the effects of DI. Fig-
ure4 depicts this airway-centric view of the bronchodila-
tory and bronchoprotective effects of DI. However, it is
important to recognize that multiple mechanisms unre-
lated to ASM could also be involved. Further research is
warranted to explore and elucidate these aspects, with
the ultimate goal of developing novel drugs that target
ASM contractility.
Acknowledgements
This work was supported by grant funding from the Canadian Institutes of
Health Research (CIHR Project grant) and the Natural Sciences and Engineer-
ing Council of Canada (NSERC Discovery grant).
A. Bronchodilatory effect
MCh challenge Deep inspiration
Deep inspiration
MCh challenge
B. Bronchoprotective effect
Healthy subjects
Asthmatic subjects
MCh challenge Deep inspiration
Healthy subjects
Asthmatic subjects
Deep inspiration
MCh challenge
Fig. 4 A hypothetical airway-centric view of how a DI, taken after or before bronchochallenge, leads to bronchodilation (A) and bronchoprotection
(B), respectively
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Yasudaetal. Respiratory Research (2023) 24:250
Author contributions
YY and CYS summarized literature and drafted manuscript. LW and PC edited
the manuscript. All authors have read and agreed to the published version of
the manuscript.
Availability of data and materials
Data sharing is not applicable to this article. No new data were created or
analyzed in this study.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Received: 15 August 2023 Accepted: 14 September 2023
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