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Functional morphology and physiology of slowly adapting pulmonary stretch receptors.

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Functional Morphology and
Physiology of Slowly Adapting
Pulmonary Stretch Receptors
Department of Anatomy, Physiology, and Cell Biology, School of Veterinary
Medicine, University of California–Davis, Davis, California
Since the original work by Hering and Breuer (1868) on slowly adapting
pulmonary stretch receptors (SARs), numerous studies have demonstrated
that these receptors are the lung vagal afferents responsible for eliciting the
reflexes evoked by moderate lung inflation. SARs play a role in controlling
breathing pattern, airway smooth muscle tone, systemic vascular resistance, and heart rate. Both anatomical and physiological studies support
the contention that SARs, by their close association with airway smooth
muscle, continuously sense the tension within the myoelastic components of
the airways caused by lung inflation, smooth muscle contraction, and/or
tethering of small intrapulmonary airways to the lung parenchyma. As a
result, the receptor field location within the tracheobronchial tree of a SAR
plays an important role in its discharge pattern, with variations in airway
transluminal pressure and airway smooth muscle orientation being important modulating factors. The disruption of airway myoelastic components in
various pulmonary diseases would be expected to alter the discharge pattern of SARs, and contribute to changes in breathing pattern and airway
smooth muscle tone. Anat Rec Part A 270A:11–16, 2003.
2003 Wiley-Liss, Inc.
Key words: vagus nerve; slowly adapting pulmonary stretch
receptors; control of ventilation
SARs are a category of neural afferent endings that
innervate the tracheobronchial tree. Their original designation was based on the observation that an increase in
airway wall tension increases receptor discharge, i.e.,
there is a rhythmic pattern of discharge during eupneic
breathing (dynamic property), and this increase in discharge slowly adapts as airway wall tension is maintained
(static property). The rhythmic discharge of eupneic
breathing is characterized by a mounting discharge during inspiration and a declining discharge during expiration. The pattern of SAR discharge during eupneic breathing and lung inflation is a direct consequence of their
anatomical location within the tracheobronchial tree and
the orientation of their receptor endings in relation to
airway wall structures. The first documented role for
SARs was as the afferent “input” for evoking the HeringBreuer inflation reflexes. These reflexes are characterized
by an early termination of inspiration when the lungs are
inflated during inspiration, and a prolongation of the expiratory pause when a prolonged inflation is applied at the
end of inspiration (Fig. 1). In addition, these receptors
have been implicated in the regulation of airway smooth
muscle tone, the regulation of systemic vascular tone and
heart rate, and the pathophysiology of restrictive lung
Historically, SARs have played an interesting role in
physiology. Hering and Breuer’s (1868) description of the
vagus nerves’ function in the “self steering” of breathing is
arguably the first description of a negative feedback loop
playing a role in the regulation of a normal body function.
With our current understanding of biological systems and
*Correspondence to: Edward S. Schelegle, Ph.D., Department
of Anatomy, Physiology, and Cell Biology, School of Veterinary
Medicine, University of California–Davis, One Shields Ave.,
Davis, CA 95616. Fax: (530) 752-7690.
Received 24 April 2002; Accepted 5 September 2002
DOI 10.1002/ar.a.10004
homeostatic mechanisms, it is hard to imagine a time
when the notion of a feedback loop would be novel. The
studies of Hering and Breuer (1868) were followed by the
descriptions of Stirling (1876), Krause (1876), and Berkeley (1893) of myelinated nerves within the lung that are
distributed to the bronchial smooth muscle. Later, Larsell
(1921) and Larsell and Dow (1933) described afferent
nerve endings terminating in bundles of airway smooth
muscle in rabbit, dog, and human lung. They described
coarse fibers that end in plate-like masses in airway
smooth muscle bands. The terminal branches of these
nerves terminate between and wrap around the smooth
muscle. Smaller bands of muscle are partially encircled by
the terminal twigs, with their terminal knobs located between individual muscle cells.
In the same year that Larsell and Dow reported their
anatomical studies of the human lung, Adrian (1933) published his studies on the afferent impulses in the vagus
nerve and their affect on breathing. This was the first
study of the discharge pattern of single vagal afferent
fibers arising from the lung. Adrian reported that the
main group of sense organs in the lung behave no differently than the muscle spindles and stretch receptors
found in other parts of the body. This main group of sense
organs shows a serial discharge of impulses when they are
stretched, and adapt very slowly. Adrian (1933, p. 355)
stated that “[T]he stretch receptors in the lung resemble
those in skeletal muscle in their effect on the central
nervous system. Both influence it to cut short the movement which has stimulated them, and in so doing prevent
the inconvenience or damage which might from unrestrained motor activity.” Adrian’s studies were followed by
those of Knowlton and Larrabee (1946), in which they
analyzed the discharge pattern of pulmonary volume receptors. Knowlton and Larrabee (1946) identified two distinct pulmonary volume receptors: SARs and rapidly
adapting receptors (RARs). It was thus 65 years after the
findings of Hering and Breuer (1868) were reported that
the afferent arm of the feedback loop they described was
physiologically identified, and 78 years after that the nomenclature we use today to identify these fibers as SARs
was devised. The description of the discharge pattern of
SARs following numerous stimuli reported by Knowlton
and Larrabee (1946) and later by Widdicombe (1954a, b)
form the foundation on which all further studies of the
physiologic function of SARs are based. The early studies
of Widdicombe (1954a, b), in which reflex responses were
isolated to different areas of the tracheobronchial tree,
and the newly developed technique of nerve cooling was
used to produce selective conduction block of nerve fibers
when combined with the extensive study of single-fiber
discharge patterns under numerous conditions, provided
us with initial insights into the full physiologic function of
SARs. These initial studies provided the first information
(and the impetus for numerous physiologic studies) concerning 1) the distribution of SARs within the tracheobronchial tree; 2) the effect of airway distribution on discharge pattern and physiological response; 3) the response
of SARs to changes in airway resistance and lung compliance, and in turn their influence on airway smooth muscle
tone; and 4) the response of SARs to changing CO2 levels
delivered to them. The remainder of this review will
briefly examine the later studies that extended these observations, and conclude with a discussion of the possible
role of SARs in disease. These mostly physiological studies
occurred in parallel with anatomical studies (Elftman,
1943; von During et al., 1974; Yamamoto et al., 1995) of
the innervation of the airway smooth muscle by the afferent end organs (originally described by Larsell (1921)).
The study of Bartlett et al. (1976) provided the best localization of functional SARs to airway smooth muscle. As a
result, these anatomically described afferent endings remain the presumptive end organs responsible for the discharge pattern of SARs recorded in the vagus and only
grossly localized to the tracheobronchial tree.
In order to identify the specific receptors and stimuli
that play a role in setting breathing patterns and evoking
the Hering-Breuer inflation reflexes, several investigators
(Widdicombe, 1954a; Miserocchi et al., 1973; Miserocchi
and Milic-Emili, 1975; Bartlett et al., 1976; Ravi, 1986)
attempted to quantitate the relative distribution of SARs
within the lower airways. These investigators used a combination of single nerve fiber recording techniques with
locally applied stimuli to determine the anatomical location of the receptor being studied. The results of these
studies indicate that a considerable variation between
mammalian species exists in the distribution of SARs
along the tracheobronchial tree. Using the combined observations of Miserocchi et al. (1973) and Bartlett et al.
(1976) in dogs, the distribution of SARs is 18.8% in the
extrathoracic trachea, 34.4% in the intrathoracic trachea,
9.0% in the bronchus, and 36.1% in the intrapulmonary
airways. Similarly, using the combined observations of
Ravi (1986) and Widdicombe (1954b) in the cat, the distribution SARs is 0.8% in the extrathoracic trachea, 2.1%
in the intrathoracic trachea, 13.2% in the extrapulmonary
bronchus, and 83.9% in the intrapulmonary airways.
Keller et al. (1989) reported that in the guinea pig, 92% of
the SARs identified were located in small intrapulmonary
airways and only 8% were located in the large airways,
including the trachea, main bronchi, and lobar bronchi.
Given their location in the tracheobronchial tree, and
the different forces acting upon them during the ventilatory cycle, it is not surprising that extra-/intrathoracic and
extra-/intrapulmonary SARs have different patterns of
discharge. In addition, these different populations of receptors respond differently to applied lung inflation and
deflation. Intrathoracic SARs have a rhythmic pattern of
discharge during eupneic breathing that is characterized
most often by a mounting discharge during inspiration
and a declining discharge during expiration. In contrast,
extrathoracic tracheal receptors exhibit a more irregular
pattern of discharge and may exhibit in a few receptors a
mounting discharge during expiration. The large group of
SARs with inspiratory rhythmic discharge pattern has
been further characterized based on whether they continue to discharge during expiration. Sant’Ambrogio and
Sant’Ambrogio (1982) discussed the different terminology
used to describe these receptor populations. For the purposes of this review, we use the terminology first proposed
by Paintal (1973) and refer to SARs with discharge activity during expiration as “low-threshold” receptors and
those that are silent during expiration as “high-threshold”
receptors (Fig. 2). SARs demonstrating these discharge
patterns have been shown in cats (Ravi, 1986), dogs (Miserocchi and Sant’Ambrogio, 1974), and rats (Bergren and
Peterson, 1993; Davies et al., 1996).
In addition to the observed differential distribution of
low- and high-threshold receptors in extra- and intrapulmonary airways, extra- and intrapulmonary SARs have
Fig. 1. Response to lung hyperinflation applied at the end of inspiration in a dog with (A) vagus nerves intact and (B) after bilateral vagotomy. Note the prolonged expiration with (A) the vagus nerves intact,
indicating the presence of the Hering-Breuer inflation reflex. Note that (B)
after bilateral vagotomy the Hering-Breuer reflex is absent, and that prior
to and after hyperinflation, respiratory frequency is decreased and tidal
volume (VT) is increased. This illustrates not only the role of the vagus in
the Hering-Breuer inflation reflex, but also the influence of the vagus
nerves in determining the eupneic breathing pattern. VT, tidal volume;
ABP, arterial blood pressure; PTP, transpulmonary pressure.
been shown to respond differently to positive and negative
pressures applied to the airway. Miserocchi and
Sant’Ambrogio (1974) found that 58% of extrapulmonary
receptors in the dog showed a plateau in discharge frequency in response to an applied airway pressure above 10
cm H2O. Of these receptors, 88% were located in extrapulmonary airways, with 100% being located in airways ⬎ 1
mm in diameter. The remaining type of SARs described
had an increasing discharge frequency to applied airway
pressures up to 30 cm H2O. Of these receptors 57% were
located within intrapulmonary airways and showed a
more even distribution throughout the airway levels studied. In comparison, a negative pressure applied to the
airway has been shown to selectively activate extrathoracic SARs (Bartlett et al., 1976; Widdicombe, 1954b).
Considering the large variation in the distribution of
SARs, and their varying pattern of discharge, it becomes
important to understand the relative contribution these
different populations of receptors have on reflex responses, including the control of breathing. Interestingly,
despite their relatively high percentage in the dog, extraand/or intrathoracic tracheal receptors do not appear to
contribute significantly to inflation reflexes or the control
of breathing (Russell and Bishop, 1976; Lloyd, 1979; Lloyd
and Cooper, 1980; Rao et al., 1981). In rabbits, however,
tracheal receptors may act to delay the activation of the
Fig. 2. Response of (A) a low-threshold SAR and (B) a high-threshold
SAR (high amplitude spikes) to the application of 15 cm H2O inflation
pressure to the airway in an anesthetized, closed-chest, mechanically
ventilated rat. Bar at the bottom of figure represents 2 sec. Note the
presence of expiratory discharge activity in the (A) low-threshold SAR
prior to inflation. AP, action potential; PTP, transpulmonary pressure.
inspiratory off-switch and facilitate post-inspiratory endexpiration diaphragm activity, and thus act to modulate
the reflex response evoked by SARs lower in the airway
(Agostini et al., 1985). Whether such differential influences on the control of breathing exists for any of the other
profiles of SARs located through the airway tree (i.e., highor low-threshold, deflation-sensitive, etc.) is unclear.
Coleridge and Coleridge (1986) proposed that low-threshold receptors, which have a low continuous discharge rate
during expiration and are primarily located in large bronchi in the cat (Ravi, 1986), contribute more to setting
expiratory time than high-threshold receptors.
Inhibitory effects of changing end-tidal CO2 on SARs
have now been observed in dogs and other mammalian
species (Mustafa and Purves, 1972; Schoener and Frankel,
1972; Sant’Ambrogio et al., 1974; Bradley et al., 1976;
Kunz et al., 1976; Coleridge et al., 1978; Bystrzycka and
Nail, 1980; Mitchell et al., 1980) with intrapulmonary
high-threshold receptors being the most affected (Ravi,
1985). The results of these studies indicate that this inhibitory effect is limited to end-tidal CO2 below normal. In
contrast, Green et al. (1986) demonstrated that when pulmonary arterial CO2 was altered while maintaining tidal
volume and breathing frequency constant, the inhibitory
effect of CO2 on SAR discharge extends above as well as
below normal resting pulmonary arterial CO2.
The inhibition of SAR discharge by CO2 has been shown
to be independent of changes in pulmonary mechanics
(Mustafa and Purves, 1972; Sant’Ambrogio et al., 1974;
Coleridge et al., 1978; Green et al., 1986). The possibility
that an elevated PCO2 acts by increasing hydrogen ion
concentration at the receptor location is supported by
those studies that show that treatment with acetazolamide
attenuates the CO2-induced inhibition (Sant’Ambrogio et al.,
Fig. 3. Schematic of SAR input traveling in the vagus nerve (vagus n.)
into the nucleus tractus solataris (NTS), and the inhibitory influence on
neurons in the nucleus ambiguus (NA) and the nucleus paraambiguus
(NPA). The inhibitory influence on the NPA decreases the output from the
spinal motor nucleus (SMN), decreasing the motor output to the respiratory muscles (illustrated is the motor output via cervical spinal nerves
3–5 (phrenic nerve) supplying the diaphragm). The inhibitory influence on
the NA decreases the output via the parasympathetic nerves (PSN)
traveling in the vagus nerve to airway ganglia (AG) and decreasing the
parasympathetic motor output to airway smooth muscle (ASM). Also
shown are the excitatory influence of increasing ASM tension, and the
inhibitory influence of elevated airway and pulmonary arterial CO2 on
1974; Ravi, 1985). Matsumoto et al. (1999, 2000) suggested
that the CO2-induced inhibition of SARs does not involve a
reduced influx of Na⫹ through voltage-gated Na⫹ channels,
but may involve the activation of 4-aminopyridine-sensitive
K⫹ channels on the nerve terminals of SARs.
Numerous investigators have demonstrated an increase
in peak inspiratory and/or mean expiratory discharge activity of SARs located below the trachea in several species
following the administration of bronchoconstrictive agents
(Widdicombe, 1954a; Bartlett et al., 1976; Davenport et
al., 1981b; Matsumoto et al., 1990) and vagal parasympathetic efferent stimulation (Matsumoto, 1996). These interventions have been shown to act through the contraction of airway smooth muscle, and not by a direct
stimulation of the SAR terminal ending (Matsumoto et al.,
1990, 1992, 1993; Matsumoto and Shimizu, 1994; Matsumoto, 1996). In addition to the direct effect of airway
smooth muscle contraction upon SAR activity, receptors
located peripherally to a site of airway constriction also
exhibit an increase in discharge frequency due to resistive
loading of the airway (Davenport et al., 1981a) (it has also
been shown that an increase in SAR activity relaxes airway smooth muscle by reducing parasympathetic tone to
the airway (Widdicombe and Nadel, 1963a, b)). Widdicombe and Nadel (1963b) suggested that SARs play a role
in a negative feedback mechanism that acts to limit increases in parasympathetic tone to the airway, and optimize the reciprocal relationship between dead space and
airway resistance.
The role that phasic activity of SARs plays in determining normal airway tone, and how this may be altered in
disease states, such as asthma, have become areas of
active study. Recent studies suggest that SARs play important roles in the regulation of breathing pattern and/or
airway tone in pathological conditions wherein their sensitivity to normal stimuli is increased due to bronchoconstriction (Widdicombe, 1954a; Bartlett et al., 1976; Davenport et al., 1981b; Matsumoto et al., 1990), airway
obstruction (Davenport et al., 1981a), or decreases in lung
compliance (Yu et al., 1991). Koller and Ferrer (1973)
observed an increase in SAR activity following allergen
challenge in a guinea pig model of asthma. More recently,
Mansoor et al. (1997b) showed that vagal afferent fibers do
not contribute to mild alterations in breathing patterns
observed in rats with elastase-induced emphysema,
whereas they appear to significantly influence breathing
pattern and altered pulmonary reflexes in rats with bleomycin-induced pulmonary fibrosis (Mansoor et al., 1997a;
Schelegle et al., 2001).
Pulmonary fibrosis is characterized by an increased collagen content of the lung parenchyma that is often associated with chronic inflammation. The increase in lung
collagen results in a decrease in lung volume and compliance. In addition, pulmonary fibrosis may produce a decreased diffusing capacity that can result in hypoxia and
hypercapnia. These alterations in lung mechanics and gas
exchange are usually associated with a rapid shallow
breathing pattern at rest and during exercise, and the
sensation of dyspnea. Guz et al. (1970) first hypothesized
that lung vagal afferents with receptor endings within the
airways and parenchyma play a role in the development
and maintenance of this abnormal breathing pattern. This
hypothesis now seems reasonable given our new knowledge of reflexes evoked by SARs in response to experimentally induced alterations in lung compliance and to exogenous inflammatory mediators (Coleridge and Coleridge,
1986; Mansoor et al., 1997a).
Using selective conduction blocking techniques, Mansoor et al. (1997a) examined the influence of lung vagal
nonmyelinated and myelinated afferents in the rapid shallow breathing pattern present in rats with bleomycininduced pulmonary fibrosis. Mansoor et al. (1997a) found
that an alteration in the phasic and/or tonic impulse activity of SARs and/or RARs contribute to the observed
rapid shallow breathing in this model of lung fibrosis. In a
subsequent study, Schelegle et al. (2001) examined the
impulse activity of pulmonary vagal afferents in rats with
bleomycin-induced lung fibrosis. Bleomycin treatment resulted in a significant increase in the volume sensitivity of
high-threshold SARs, while it blunted the sensitivity of
these fibers to increasing transpulmonary pressure. In
addition, the activity of high-threshold SARs during the
deflation phase of expiration was significantly reduced in
bleomycin-treated rats. These observations are consistent
with previous observations of the effects of acutely induced decreases in lung compliance on SAR discharge
patterns in cats and rabbits (Yu et al., 1991). Yu et al.
(1991) found that a 30% reduction in lung compliance
resulted in a significant increase in SAR discharge at peak
inflation of the ventilator cycle in an experiment in which
inflation volume was held constant across treatments.
The increase in responsiveness of SARs to lung inflation
volume induced by bleomycin would lead to an increased
SAR input to the brainstem at any given lung volume, and
would therefore act as an inspiratory “off switch” at a
lower inflation volume and contribute to a reduced tidal
volume and possibly a shorter inspiratory time. Mansoor
et al. (1997a) observed a significant reduction in the average expiratory frequency for SARs as well, and suggested that a decrease in tonic expiratory activity of SARs
may also contribute to the previously observed shortening
of expiratory time in this model of chronic pulmonary
Widdicombe (1964) pointed out the wide variation in
thresholds and potencies of the Hering-Breuer inhibitory
reflex in research animals, and the perceived lack of influence that SAR discharge has on resting breathing pattern in man. While we have learned much in recent years,
our knowledge is far from complete. Most investigators
now believe that in most species, once a certain volume
threshold is achieved, the “inspiratory off-switch” provided by stretch receptor input controls tidal volume and
inspiratory time. In addition, the expiratory discharge of
these receptors may act to determine expiratory time and
thus influence breathing frequency at rest—at least in
some species. On the other hand, the role that normal
phasic activity of SARs plays in determining normal airway tone is poorly understood. Also poorly understood is
the function of SARs in the regulation of breathing pattern and/or airway tone under conditions (such as exercise) in which tidal volume is increased, and the role these
receptors play when their activity changes due to bronchoconstriction, airway obstruction, or decreases in lung compliance (Fig. 3). Manning et al. (1992) observed that the
sensation of air hunger induced by the inhalation of increased CO2 in humans is modulated by volume feedback
from the lung, with greater lung volumes being associated
with a reduced rate of air hunger. This observation is
consistent with the notion that while SARs may not play a
role in setting eupneic breathing patterns in humans,
their pattern of discharge in lung disease may act to
modulate sensations of air hunger and dyspnea. Because
of the immense clinical importance of these issues, much
work remains to be done.
The authors thank William Walby for his assistance in
preparing and editing the manuscript.
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slowly, morphology, stretch, pulmonaria, receptors, function, physiology, adapting
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