Pulmonary Perspective

Airway Smooth Muscle

The Appendix of the Lung
Wayne Mitzner
Department of Environmental Health Sciences, Division of Physiology, Johns Hopkins University, Baltimore, Maryland
It is well accepted that many organs in the human body no longer
provide evolutionary advantage and appear to be lacking known
function. These include the appendix, most body hair, wisdom
teeth, male nipples, and external ear muscles, to name just a
few. Even worse, many such organs, such as the appendix or
wisdom teeth, can be the source of serious pain and medical
problems. In this perspective, it is suggested that airway smooth
muscle falls into this categorythat of an organ with no essential
physiologic function that can lead to serious medical problems.
The function of smooth muscle in the airway wall has been
speculated on for many years, but when looked at closely from
a functional perspective, there really seems to be no need for
airway smooth muscle. Indeed, most of the proposed reasons
for presence of airway smooth muscle have not been based
on experimental validation. In a recent discussion, Seow and
Fredberg (1) commented that there is no known disease entity or
physiologic decit associated with loss of airway smooth muscle.
They further suggested that perhaps airway smooth muscle was
a vestigial remnant of its common embryologic origin with the
gastrointestinal system, having no modern function. This conjec-
ture, however, is in stark contrast to much classical thinking. In
his extensive review article (2), Macklin could not imagine that
such a system was there for no physiologic purpose, stating that
Organized as it is, into a very complex system, this muscle
would seem of the utmost functional importancein fact quite
indispensable in respiration.
In this discussion, we consider the validity of 10 possible roles
for airway smooth muscle that have appeared in the literature
over the past 125 years. The emphasis will not be on whether
smooth muscle is indispensable inrespiration, but rather whether
it is needed at all. These possible roles consist of the following:
(1) peristalsis to assist exhalation, (2) peristalsis to assist mucus
propulsion, (3) peristaltic contraction in the fetal lung to gener-
ate uid pressure, (4) promoting lymphatic and venous ow,
(5) ventilation/perfusion matching, (6) protecting the peripheral
lung, (7) protecting airway structure, (8) stabilizing airways,
(9) enhancing the effectiveness of cough, and (10) optimizing
anatomic dead space volume.
PERISTALSIS TO ASSIST EXHALATION
The several imagined functions of airway peristalsis were specu-
lations based largely on the common embryologic origin of the
(Received in original form December 1, 2003; accepted in final form January 20, 2004)
Supported by NIH HL-66020.
Correspondence and requests for reprints should be addressed to Wayne Mitzner,
Ph.D., Division of Physiology, Room W7006, 615 North Wolfe Street, Baltimore,
MD 21205. E-mail: wmitzner@jhsph.edu
Am J Respir Crit Care Med Vol 169. pp 787790, 2004
Originally Published in Press as DOI: 10.1164/rccm.200312-1636PP on January 23, 2004
Internet address: www.atsjournals.org
airway tree and the gastrointestinal tract, where peristalsis and
its neural control is a clearly essential property. Active contrac-
tion of bronchial smooth musculature that might contribute to
exhalation was emphasized by Miller (3). His anatomic analysis
of airway smooth muscle showed a three-dimensional geodesic
arrangement analogous to a lazy tongs device for mechanical
extensions in the axial direction. He also suggested an expiratory
wave of peristaltic smooth muscle contraction starting from the
periphery to aid in exhalation. This concept of bronchi aiding
exhalation was endorsed later by Macklin (2), who stated that
it seems not so much to infer that the bronchial musculature
is an essential in respiration, for it is involved in both the opening
and the closing of the pulmonary bellows. This concept continues
to linger to this day with a recent suggestion that respiratory-
related bronchial rhythmic constriction can facilitate gas exchange
in the dog (4). However, the magnitude of such an effect, if it
exists, must be quite small and of little physiologic signicance.
Gas exchange in the lung can be performed quite well with fully
relaxed airway smooth muscle.
PERISTALSIS TO ASSIST MUCUS PROPULSION
The idea that slow peristaltic contraction of the smooth muscle
would provide an important means of clearing airway mucus
was rst described by Bullowa and Gottlieb (5), who used X-rays
to follow the movement of barium sulfate capsules and other
physical objects out of the lungs of dogs. Reinbergs subsequent
radiographic observation of clearance of a Bismuth instillate
in animals and humans supported this initial work (6), and his
interpretation of these observations was supported by Macklin
(2). However, these early radiographic observations of serpentine
contrast density more likely represented periodicity of mucociliary
clearance or artifacts of the method (7). These speculations about
such peristalsis were properly criticized in an extensive review
article by Widdicombe (8), who concluded that condent state-
ments that peristalsis is important in expectoration and bronchial
evacuation are a poor substitute for experimental studies. In-
deed, with more modern measurements, there have not been any
experiments that have shown airway smooth muscle peristalsis to
have any functional consequences. The ability of ciliated airways
to clear mucus obviates any need for peristalsis, and where there
is too much mucus for efcient movement by this mechanism,
coughing becomes the more productive means.
PERISTALTIC CONTRACTION IN THE FETAL LUNG TO
GENERATE FLUID PRESSURE
A potential role for rhythmically contracting airway smooth
muscle in fetal lung development has been suggested in a recent
study (9). These investigators observed peristaltic-like con-
tractions in airways in fetal rabbit and pig lung explants. They
suggested that such contractions might contribute to fetal lung
growth, particularly airway differentiation and branching. Al-
788 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 169 2004
though their work clearly shows the capacity for fetal airway
smooth muscle contraction, it is still not clear that this plays an
essential role in lung development. In addition, the proposed
peristaltic wave needed for this function would be in the periph-
eral direction, opposite to what was proposed as necessary by
the early anatomists for exhalation and mucus clearance. Al-
though the role of lung liquid pressure and fetal lung stretch
from lung uid secretion is well documented (10, 11), why the
airways might need active smooth muscle to counteract this
luminal pressure is not clear. It would therefore seem that the
effect of peristaltic fetal airway smooth muscle contraction would
at best be contributory to the normal pressure generated by uid
secretion. In an air-lled postnatal lung, of course, it could have
no function.
PROMOTING LYMPHATIC AND VENOUS FLOW
In the original Handbook of Physiology chapter on airway
smooth muscle, Krahl speculates that it may be surmised that
this effect of bronchial musculature on venous and lymphatic
channels must play an important role in propelling the vascular
uids toward the hilus of the lung (12). He based this creative
speculation on histologic observations indicating enlarged ves-
sels around contracted airways. However, for such airway
smooth muscle contraction to serve as an effective pump, not
only would it have to occur in a rhythmic fashion, but also it
would require valves to direct the ow. Unfortunately, there are
no valves, nor is there evidence of such rhythmic strong airway
smooth muscle contractions in vivo. Furthermore, even if such
rhythmicity were important, interstitial pressure variations that
occur with normal ventilation would likely be more than suf-
cient (13).
V

/Q

MATCHING
One might think that the potential need for airway smooth
muscle to optimize V

/Q

matching is a modern idea. However,

almost a century ago, Keith (14) suggested that airway muscle
contraction not only might affect the distribution of ventilation
but also that the decreased alveolar pressure on inspiration distal
to a narrowed airway might dilate the capillaries and increase
perfusion. Of course, we now know that the simultaneous de-
crease pleural pressure would largely prevent such vascular dila-
tion, and even if it did not, such an increased perfusion with a
decreased ventilation would not serve any teleologic advantage.
V

/Q

could potentially be affected by the local CO

2
concentration,
as low CO
2
is known to contract airway smooth muscle, and
elevated CO
2
may cause relaxation. However, the sensitivity of
airways to CO
2
reductions in the normal range is quite low,
having little effect till it falls to less than 2% (15). Although this
may possibly occur with hyperventilation or with local vascular
obstruction, it does not seem to be an essential function of
normal living. Indeed, even in the most extreme situation of
complete obstruction of left or right main pulmonary artery,
ventilation to the obstructed lung was only reduced by approxi-
mately 25% (16). Such an experimental observation is consistent
with the understanding that resting ventilation distribution is
largely controlled by regional lung distensibility rather than air-
way resistance (17). Thus, a need for airway smooth muscle to
regulate airway resistance seems even less relevant in this regard.
Nevertheless, at least one study measuring nitrogen washout
in normal subjects has suggested that loss normal vagal tone
promotes ventilation heterogeneity (18). These results may have
been partially related to the loss of elastic recoil after atropine,
but perhaps more importantly, there is no indication that such
ventilation changes would be linked to similar changes in perfu-
sion. Thus, it is even possible that V

/Q

distribution could have

improved after atropine, an idea supported by results showing
a more uniform apex to base ventilation distribution (and hence
a poorer match with perfusion distribution) after methacholine
challenge (19). Furthermore, in another study in asymptomatic
subjects with asthma, the distribution of ventilation was found
to be unaffected by relaxation of spontaneous tone with isopro-
terenol (20).
PROTECTING THE PERIPHERAL LUNG
Noxious particles or gases are known to have the capacity to
either directly or indirectly lead to airway smooth muscle con-
traction (2123). Thus, the question naturally arises whether
this constriction might serve some protective function, having
evolved to prevent further penetration to the already exposed
airway (24). Although such speculation may seem supercially
reasonable, when viewed in the context of the living organism,
it quickly breaks down. To maintain life, one must continue to
ventilate, and thus, a uniform constriction limiting peripheral
ventilation of all airways would not be possible for very long.
If the insult were local, then there could be reduced ventilation
to that region. However, such a reduction in ventilation to one
region would lead to signicantly altered ventilation and deposi-
tion to the rest of the lung (25). In fact, Macklem and colleagues
have concluded that a redistribution of ventilation would likely
lead to a more peripheral deposition in the unconstricted region
(26), thereby negating any benecial effect of the original protec-
tive function.
PROTECTING AIRWAY STRUCTURE
There has been some recent discussion hypothesizing that nor-
mal airway tone is required to protect the airway from overdis-
tension that might occur with normal breathing. Without normal
airway tone, the airway may become distorted, promoting bro-
proliferative pathology (27). Although there is no experimental
evidence directly testing such a hypothesis, it seems that the
airway structure itself is built to inherently resist overdistension.
As shownby James andcolleagues (28), the basement membrane
provides a relatively nondistensible natural limit that can be
used to compare airway size. Computed tomographic imaging
has also shown this natural limit to exist in vivo when there is
no airway tone (29), and thus, unless breathing near this elastic
limit leads to airway inammation, this proposed role of airway
smooth muscle seems unlikely.
STABILIZING AIRWAYS
The notion that intraparenchymal airway smooth muscle con-
traction might stabilize the airways and prevent airway collapse
seems to y in the face of logical thought. If one contracts an
airway in vitro (30, 31) or in vivo (32), the airway will continue
to narrow until it is closed. This concept of contraction stabilizing
airways seems to have originated from the work of Olsen and
colleagues (33) and later supported by Coburn and colleagues
(34). Olsen and colleagues studied both tracheal and bronchial
segments in vitro. It is relatively easy to see how contraction of
the trachealis could in fact protect the tracheal lumen from
obstruction with external compression by limiting invagination
of the tissue between the ends of the C-ring cartilage; however,
even maximal contraction of the trachealis by itself would never
lead to tracheal collapse. The situation with intraparenchymal
bronchi, however, is quite different. Given the fact that large
cartilaginous airways can close in vivo with sufcient methacho-
line (32), it is hard to imagine an excised airway remaining patent
with 20 cm H
2
O negative transmural pressure. Yet this is what
Pulmonary Perspective 789
Olsen and colleagues showed in contracted bronchi. The only
explanation that seems plausible is that their measurements of
absolute volume in the bronchial segments were in error and
that their airways were at much lower absolute volume than
calculated. Indeed, more recent histologic measurements (35) do
not support this concept that airway smooth muscle contraction
protects or otherwise limits narrowing of intraparenchymal air-
ways. At any transmural pressure, contracted airways were found
to have smaller luminal areas than relaxed airways.
ENHANCING THE EFFECTIVENESS OF COUGH
Somewhat related to this possible ability of airway smooth mus-
cle to stabilize airways is its potential role in optimizing airow
velocity to enhance coughing effectiveness (24, 36). It is well
accepted that airway narrowing that occurs during coughing can
increase velocity at the ow limiting segments, thereby aug-
menting clearance of mucus from the airway (37). This airway
narrowing normally results fromdynamic compression at specic
sites along the airway tree. Thus, it may seem that airway smooth
muscle could be activated to cause localized airway narrowing
in anticipation of a cough, but there is little experimental evi-
dence to support such a role (38). Although reex bronchocon-
striction and coughing occurs on inhalation of dust and irritant
gases, the afferent receptors do not originate from intraparen-
chymal airways (39). Thus, were a large inhaled particle to de-
posit in a bronchus, there would not be a localized reex bron-
choconstriction to help expel it. In other pathologic situations
such as bronchiectasis with enlarged airways, where coughing
effectiveness is often impaired (40), contraction of smooth mus-
cle is either not used or not effective in correcting this limitation.
Furthermore, regional dynamics during coughing are quite com-
plex, and too much airway narrowing must also lower the local
regional ow. For this reason, Leith has suggested that bronchodi-
lators may actually improve the effectiveness of coughing by in-
creasing expiratory ow rates (36). Thus, an active role for airway
smooth muscle in coughing presently seems quite uncertain.
OPTIMIZING ANATOMIC DEAD SPACE VOLUME
Macklin (2) and later von Hayek (41) thought that an important
role of airway smooth muscle was to play an active role in
regulating the volume of the anatomic dead space. The design
of the lung is such that anatomic dead space must be small
enough to allow adequate alveolar ventilation, yet not so small
as to make the airways so narrow to make breathing difcult.
This design compromise in the human lung was discussed in
detail by Widdicombe (8), who calculated theoretical graphs to
show how evolution has optimized the work of breathing, with
a dead space of approximately 20% of the normal tidal volume
and a breathing frequency of approximately 15 per minute. Is
there any reason that it should be necessary to change this ratio?
Were there some pathology that prevented taking normal tidal
breaths, perhaps then it would be advantageous to decrease the
dead space. At the other extreme, with heavy exercise, the tidal
volume, and alveolar ventilation increase and with higher ow
rates, the airway resistance may become limiting. Dilation of
the airways in this situation might thus be advantageous. Al-
though the work of breathing is clearly a function of dead space,
the sensitivity to dead space changes is not very strong (8).
While this function of active dead space regulation is indeed a
legitimate reason for airway smooth muscle, it begs the question
of how such a feedback system might be regulated. What is the
sensor that determines that dead space needs to be altered? It
would have to be an extraordinarily complex feedback system
taking into consideration ventilation, work of breathing, blood
gases, airway resistance, etc. Furthermore, simply breathing at
higher mean lung volume during exercise would by itself tend
to dilate the airways to near maximal size.
CONCLUSIONS
In summary, it thus it seems clear that none of these potential
functions of airway smooth muscle are essential to normal lung
physiology. If airway smooth muscle were eliminated, then the
airways might enlarge slightly, but there would be no other
obvious physiologic consequence. The intrinsic elasticity of the
airways would still allow the airway tree to distend with inspira-
tions and relax with expiration. This review thus strongly sup-
ports the speculation that airway smooth muscle is indeed a
vestigial organ (1), analogous to the appendix, which also has
no known function, but can cause serious medical problems.
Such being the case, if there were a way to treat airway smooth
like an inamed appendix, that is, to effectively cut it out, then
asthma, like appendicitis, could be cured. Airway inammation
with associated secretions may still be present, but without an
ability to translate inammatory signals into airway smooth mus-
cle contraction, dyspnea would be greatly minimized. Such pro-
cedures would obviously not involve surgical excision but may
possibly involve pharmacologically targeting airway smooth
muscle with a directed toxin, genetically impairing the contractile
apparatus of airway smooth muscle, or physicochemical disrup-
tion of the airway wall. Future therapies directed to this goal
may provide alternative and effective newtreatments for asthma.
Conflict of Interest Statement : W.M. has an NIH grant to examine the potential
side effects of thermal injury of the airways and the grant has a subcontract to
Broncus Technologies that makes the device that is used for this purpose, but
W.M. receives no financial compensation from the company.
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