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MILNE LECTURE:
LOWER AIRWAY OF THE HORSE
Structure and Function of the Tracheobronchial
System
N. Edward Robinson, B. Vet. Med., PhD, MRCVS
The tracheobronchial tree delivers and distributes air within the lung. Normally it provides a low
resistance to airflow. Airway smooth muscle, the mucociliary system, the bronchial circulation, and
cough provide neurally mediated protection of the lung from environmental challenges. Disease
involves an exaggerated response of these mechanisms so that the airways become obstructed,
distribution of ventilation is abnormal, and hypoxemia develops. Author’s address: Dept. of Large
Animal Clinical Sciences, G-321 Veterinary Medical Center, Michigan State University, East Lansing,
MI 48824-1314. r 1997 AAEP.
1.
Introduction
The tracheobronchial tree is a system of branching
tubes that begins distal to the larynx and ends at the
level of the respiratory bronchioles. These conducting airways deliver air to the alveolar ducts and
alveoli where gas exchange occurs. Diseases of the
tracheobronchial tree are common. Viral respiratory diseases in young horses damage the mucociliary system and have effects on mucus secretion and
regulation of smooth muscle. In racing animals,
airway inflammation is clinically associated with
poor performance and probably is due to a combination of infection and environmental contaminants in
stables. Severe airway obstruction in older animals
is the result of repeated exposure to dusts and molds
and other contaminants in both stables and pastures. In these older heaves-affected animals, alterations in mucus secretion and smooth muscle tension
are clearly associated with airway inflammation.
This paper describes the structure and function of
the tracheobronchial tree as it relates to the patho-
genesis, diagnosis, and treatment of tracheobronchial disease in the horse.
In order to obtain sufficient oxygen during racing,
a horse moves large volumes of air per minute in and
out of its lungs by means of the tracheobronchial
tree. The tracheobronchial tree provides a frictional resistance that opposes airflow and must be
overcome by the work of the respiratory muscles.
In addition, the tracheobronchial tree forms the
anatomic dead space that does not participate in gas
exchange. Ideally, the horse needs a wide airway to
provide a low resistance but this would result in an
unacceptably large dead space. In its evolution, the
horse has had to compromise between its needs for
an open airway for ease of gas delivery and the needs
for low dead space in order to have efficient gas
exchange.
In addition to delivering air for gas exchange, the
tracheobronchial tree protects the lung from inhaled
irritants such as dusts and pollutant gases, from
antigens, and from infectious agents. The defense
NOTES
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LOWER AIRWAY OF THE HORSE
mechanisms of the airways include cough, the mucociliary system, phagocytes, smooth muscle, and
the bronchial circulation. These mechanisms prevent penetration of inhaled materials deeper into
the lung and assist in the neutralization and elimination of such materials. Defense mechanisms are
invoked to varying degrees in diseases of the tracheobronchial tree, and much of what we recognize
as disease is an overreaction of these defenses so
that the air passages are obstructed by bronchospasm, mucus accumulation, and airway wall thickening. This airway obstruction causes difficult
breathing, impairs gas exchange, and reduces the
horse’s performance.
2.
Functional Anatomy of the Airways
The equine tracheobronchial tree branches in a
monopodial manner. In each region of lung corresponding to a lobe, there is one major bronchus,
which divides multiple times. At each branch point
the daughter airway is much smaller than its parent,
which progresses almost directly to the periphery of
the lung. This branching pattern may be important
in the distribution of inhaled particles. For example, the inhalation of foreign particles into the
main bronchus of the caudal lobe could direct such
material to the caudal part of the lobe. This may
explain in part why the lesions of exercise-induced
pulmonary hemorrhage occur in the most caudal
part of the lung.
Airways are lined by a mucous membrane, consisting of the epithelium and lamina propria, under
which are varying amounts of smooth muscle and
cartilage (Fig. 1). In the trachea and bronchi, the
epithelium is pseudostratified and columnar and
consists of secretory goblet cells, ciliated cells, and
cells with microvilli that participate in fluid and
electrolyte exchange. The epithelial cells provide
the mechanisms for mucociliary clearance. Submucosal glands also contribute secretions to the mucus
blanket of the large airways. In the bronchioles the
epithelium is simple cuboidal. The secretory cell is
the Clara cell, and there are no goblet cells. Beneath the epithelium of the airways, the lamina
propria contains a variety of sensory and motor
nerves and blood vessels. These vessels are a plexus
of the bronchial circulation and provide nutrients to
the airway wall, aid in heating and humidifying air,
and participate in the inflammatory response in
airway disease. Cartilage provides firm support to
the wall of the airways greater than 1–2 mm in
diameter. In the trachea, U-shaped cartilages form
most of the airway wall, and smooth muscle simply
bridges the space between the tips of the cartilage
dorsally. In the bronchi, cartilage plates encircle
most of the airway but gradually become thinner and
disappear toward the periphery. Simultaneously,
the smooth muscle progressively encircles the airway until, in airways less than 1 mm in diameter,
there is no cartilage and smooth muscle completely
surrounds the airway. The small airways that lack
88
(a)
(b)
Fig. 1. (a) Anatomy of the bronchial wall showing epithelium,
lamina propria, smooth muscle, and cartilage. A plexus of bronchial vessels (V) lies beneath the epithelium. Submucosal glands
are interspersed in the smooth muscle layer. (b) Small airway
from a horse with airway disease. Numerous goblet cells are
visible in the epithelium (Epi) and have contributed to a mucus
plug. Smooth muscle (SM) and cartilage (Ca) surround the
airway, which is partially narrowed by bronchospasm, which folds
the epithelium.
cartilage are kept patent by the pull of the surrounding alveolar septa that insert into their walls.
3.
Resistance to Airflow
During breathing, the respiratory muscles work to
stretch and enlarge the lung and to move air through
the air passages. Air movement is opposed by the
resistance of the airways, the magnitude of which is
determined primarily by the internal diameter of the
trachea, bronchi, and bronchioles. The trachea and
mainstem bronchi have a large diameter and therefore a much lower resistance than individual bronchioles. However, the diameter of the airways does not
decrease progressively at each division, especially in
the bronchioles where the parent and the daughter
bronchiole can have a similar diameter. Consequently, as air flows from the trachea to the thousands of bronchioles, it is moving through a system
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MILNE LECTURE:
with an increasing total cross-sectional area (Fig. 2).
This has several important consequences: (1) The
trachea and large bronchi constitute the largest
fraction of the airway resistance, and obstructions to
this region therefore result in severe respiratory
distress. (2) The bronchioles provide very little
resistance to flow and therefore bronchiolar obstruction must be diffuse to cause respiratory distress
in the resting animal. (3) Airflow velocity is high
and flow is turbulent in the large airways. Consequently, most of the sounds heard with a stethoscope
originate from the larger airways. (4) Airflow velocity is low and flow is laminar in bronchioles. Sounds
are generated in these airways only when turbulence
results from airway obstruction by mucus, and so on.
Because the bronchioles are held open by the tethering action of the surrounding lung, bronchiolar diameter increases and decreases as the lung inflates and
deflates, respectively. Turbulence is most likely to
occur when the bronchioles are narrowest. For this
reason, wheezes originating in the bronchioles are
best heard at the end of exhalation.
The effort being exerted by the respiratory muscles
against the resistance of the airways is evaluated by
measuring the change in pleural pressure during
breathing (DPpl). This is most conveniently done
by using an esophageal balloon.1,2 In the resting
horse with healthy lungs, DPpl is up to 10 cm H2O
during a tidal breath. During exercise, DPpl is
greater because larger volumes of air are being
moved through the airways in less time. When the
airways are narrowed by disease, DPpl must increase because airway resistance is high (Fig. 3).
In general, an increase in DPpl parallels the clinical
severity of airway obstruction in horses with heaves.
In addition to DPpl, other measures of airway
function include airway resistance (RL ) and dynamic
compliance (Cdyn ). Airway resistance reflects espe-
Fig. 3. In the normal resting horse, inhalation requires a decrease in pleural pressure (DPpl) to approximately 210 cm
H2O. When the airways are obstructed a greater effort is required to move air, and this is reflected in a lower pleural
pressure.
cially the function of the larger airways, whereas
Cdyn or its inverse, dynamic elastance, is more indicative of peripheral airway diameter. An increase in
RL and a decrease in Cdyn are primarily a result of
airway narrowing, which can be a result of bronchospasm, mucus obstruction, or airway wall thickening. In many obstructive diseases, these factors
coexist and have important interactions with one
another. Various indices from flow-volume loops
have also been used to evaluate airway obstruction.
Changes in flow-volume loops reflect changes in
breathing strategy that are necessary to maintain
gas exchange in the face of airway obstruction.3
4.
Regulation of Airway Smooth Muscle Contraction
The main regulator of airway diameter throughout
the tracheobronchial tree is airway smooth muscle.
In the healthy animal, smooth muscle is regulated
primarily by the autonomic nervous system and by
some interactions with the epithelium. In disease,
airway narrowing results from the release of chemical mediators that cause smooth muscle contraction
both directly and by interactions with nerves.
A.
Fig. 2. Diagram of the cross-sectional area of the tracheobronchial tree. Because this total area increases from the trachea to
the bronchioles and alveoli, airflow velocity slows. Consequently, airflow changes from laminar in the larger airways to
turbulent in the bronchioles.
LOWER AIRWAY OF THE HORSE
Neural Regulation of Airway Smooth Muscle
The classical descriptions of pulmonary innervation
include two efferent (motor) systems (sympathetic
and parasympathetic) and an afferent (sensory) system. Neural control of airway function is more
complex than previously thought.4 In particular,
the importance of nonadrenergic–noncholinergic
(NANC) nerves has become obvious in recent years.4–6
A recent review includes an extensive description of
the innervation of the equine lung.7
A schematic diagram of the nerves that regulate
airway smooth muscle contraction is shown in Fig. 4.
The primary excitatory innervation in the trachea,
bronchi, and bronchioles is provided by the parasympathetic system, which reaches the lung in the
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MILNE LECTURE:
LOWER AIRWAY OF THE HORSE
Fig. 4. Diagram of the efferent nerve supply to airway smooth
muscle. The parasympathetic and iNANC systems reach the
lung by means of the vagus nerve. Acetylcholine (ACh) is
released from parasympathetic nerves, and nitric oxide (NO) from
iNANC nerves. ACh binds to M3 receptors to cause smooth
muscle contraction. Sympathetic nerves release norepinephrine, which may bind to b2 adrenoceptors to relax smooth
muscle. It is more likely that the latter are activated by circulating catecholamines, including epinephrine (Ep) and NE.
vagus.8,9 Activation of this system releases acetylcholine, which binds to M3-muscarinic receptors on
airway smooth muscle.10 This in turn causes smooth
muscle contraction and bronchospasm. There is no
tonic parasympathetic activity in the horse; blockade
of muscarinic receptors by atropine does not cause
bronchodilation in normal animals.11 The parasympathetic system is activated when sensory receptors
in the airway mucosa are stimulated by inhaled
irritants, such as dusts and pollutant gases, or by
mediators of inflammation. A protective reflex is
initiated that gives rise to bronchospasm and increases mucus secretion.12 In some airway obstructive diseases such as heaves, a reflex activation of
the parasympathetic system is facilitated by the
presence of inflammation.13
The release of acetylcholine from parasympathetic
nerves is regulated by receptors on the nerve terminals. A prejunctional muscarinic receptor14–16 provides negative feedback that normally inhibits the
release of acetylcholine. In experimental allergic
airway disease, the function of this receptor is deficient so that increased release of acetylcholine contributes to bronchospasm.17 We have been unable
to find a similar defect in prejuctional receptor
function in horses with airway disease.15 An a2
adrenoceptor also inhibits acetylcholine release
and is probably activated during exercise to prevent parasympathetically mediated smooth muscle
contraction.18,19
Unmyelinated sensory nerves containing neuropeptides such as substance P also occur along the
airways, especially around blood vessels in the lamina
propria. When these sensory nerves are activated
by inhaled irritants or mediators of inflammation,
protective reflexes are initiated but in addition,
neuropeptides are released locally by means of an
90
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axon reflex. A local release of neuropeptides increases blood flow through the submucosal bronchial
plexus, increases vascular permeability, stimulates
mucus secretion, and causes neutrophil chemotaxis.
By initiating these changes, neuropeptides, such as
substance P, calcitonin gene-related peptide, and
neurokinin A, facilitate the inflammatory response
and contribute to airway obstruction.5,6,20,21 These
nerves form the excitatory nonadrenergic–noncholinergic (eNANC) system.
The inhibitory innervation of the airway smooth
muscle is provided by the sympathetic and inhibitory nonadrenergic–noncholinergic (iNANC) systems.8,22 Even though sympathetic nerves occur
throughout the airways,23 the norepinephrine that
they release has little direct effect on smooth muscle
b2 adrenoceptors except in the cranial trachea. It is
important to realize, however, that even though they
are not activated by norepinephrine released from
sympathetic nerves, b2 adrenoceptors are present on
smooth muscle throughout the airways.8,9 Activation of these receptors by circulating epinephrine
or therapeutically by specific b2 agonists, such as
clenbuterol, leads to smooth muscle relaxation. The
iNANC system is the primary inhibitory system to
horse airway smooth muscle. It provides inhibitory
innervation to the smooth muscle of the trachea
and large bronchi.8,24 Neurotransmission in the
iNANC system involves nitric oxide and also may
involve vasoactive intestinal peptide.20,22 The physiological role of the iNANC system is not well understood. In vitro studies have revealed an absence of
iNANC inhibition in airways from heaves-affected
animals.8,22
B.
Epithelial Factors
The epithelium produces factors that inhibit smooth
muscle contraction. Although the epithelium is a
source of inhibitory prostanoids such as prostaglandin E2 (PGE2 ),25 the epithelium-derived inhibitory
factor appears not to be a prostanoid.26,27 Discovery
of epithelium-derived inhibitory factors led to speculation that epithelial damage could lead to enhanced
smooth muscle contraction. However, in the horse
with chronic obstructive pulmonary disease, there
appears to be more rather than less epitheliumderived inhibition of smooth muscle contraction.24
C.
Mediators of Inflammation
Several inflammatory mediators can cause bronchospasm. Histamine, the preformed mediator that is
released from mast cells, causes bronchospasm28–30
by two mechanisms. By binding to histamine H1
receptors, it directly contracts equine airway smooth
muscle.31 In addition, concentrations of histamine
that cause only a small contraction dramatically
augment the response of smooth muscle to activation
of parasympathetic nerves.a Serotonin has similar
direct and indirect effects.32
Eicosanoids are metabolites of arachidonic acid,
which is released from cell membranes in response to
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MILNE LECTURE:
many types of stimuli. The cyclo-oxygenase metabolites of arachidonic acid, the prostanoids (PG), have
varied effects, depending on which prostanoid is
produced and the receptor to which it is coupled.
In the normal airways, PGE2 is the primary cyclooxygenase product being produced, especially in the
epithelium.25 PGE2 inhibits smooth muscle contraction.33 In airway disease in other species, the bronchoconstrictor prostanoid PGD2 is produced in
increased amounts.34 Leukotrienes, products of the
5-lipoxygenase metabolism of arachidonic acid, have
a variety of actions in airways such as neutrophil
chemotaxis, increased mucus secretion, and bronchospasm. In the horse, aerosol administration of LTB4
causes neutrophil accumulation in the lung,35
whereas the cysteinyl leukotrienes (LTC4, LTD4, and
LTE4 ) cause airway smooth muscle contraction and
respiratory distress.a,31,35 The effects of leukotrienes on airway smooth muscle are most consistent
in the peripheral airways.
5.
Mucociliary System
The tracheobronchial tree is lined by a layer of
mucus-containing liquid that is transported toward
the larynx by the action of cilia. Although the
function of this mucociliary apparatus is altered by
many diseases, there have been few specific studies
of this system in horses. Wanner et al.36 recently
compiled an excellent review of mucociliary clearance in health and disease.
The mucociliarly system comprises a periciliary
layer of fluid of low viscosity in which cilia beat.
This is overlain by rafts or sheets of mucus in which
foreign material becomes entrapped. These fluid
layers originate in the goblet cells and submucosal
glands from serous and mucous secretory cells.
Beating of cilia is due to the interactions between
microtubules within the cilium and includes an
effective stroke, rest, and recovery stroke. During
the effective stroke, the cilium is extended so that
the claws at its tip engage the mucus rafts that float
on the periciliary fluid. In recovery, the cilium is
bent and moves caudad within the periciliary fluid.
Several factors are important in maintaining normal
mucociliary clearance. If the periciliary fluid depth
is not sufficient, the cilium becomes entangled in the
mucus layer during the recovery stroke. Such a
situation may occur in a dehydrated animal. If the
periciliary layer is too deep, the tip of the cilium
misses the mucus raft during the effective stroke.
The latter may occur when there is an excessive
amount of secretion by the mucus apparatus. Mucus viscosity is also critical for normal clearance.
If mucus viscosity is increased, for example by the
presence of neutrophil or bacterial DNA (purulence),
clearance can be impaired.
Mucociliary clearance rates in horses have been
measured by use of scintigraphy. Clearance is delayed when the horse’s head is elevated by cross
tying and is increased when the head is lowered.37
Clearance is also delayed by the administration of
LOWER AIRWAY OF THE HORSE
xylazine or detomidine.38 Viral respiratory infections, especially equine influenza, also slow clearance rates.39 In the case of influenza, clearance
rates do not return to normal for up to 1 month.
These factors that depress mucociliary clearance are
likely to make horses more susceptible to bacterial
infections.
A.
Ciliary Beating
The cilia on the surface of airway epithelial cells beat
spontaneously and continuously, but their rate of
beating changes in response to agonists that change
the intracellular concentrations of cAMP and Ca21.
Administration of b2-adrenergic agonists increases
cAMP and increases the rate of ciliary beating. Increases in intracellular Ca21 also increase beat frequency and occur in response to deformation of the
epithelial surface and to cholinergic agonists such as
acetylcholine. The net effect of inflammation is
most likely a reduction in ciliary beat frequency.
Leukotrienes and some prostanoids increase beat
frequency; other substances, including the plateletactivating factor, hydrogen peroxide, eosinophil major basic protein, neutrophil elastase, neutral
protease, and complements C3a and C5, decrease
the rate of beating.
B.
Mucus Secretion
Mucus is secreted from goblet cells and submucosal
glands (Fig. 5). Secretion is increased by cholinergic, a- and b-adrenergic, and peptidergic neurotransmitters. Autonomic reflexes originating in tracheal
and bronchial submucosal irritant receptors and C
fibers promote mucus secretion. Long-term stimulation of secretion leads to an increase in the number
of goblet cells and the size of submucosal glands.
Mucus is secreted in a condensed form and then
becomes hydrated into a tangled polymer gel. The
properties of this gel determine the viscosity of
the mucus. Cholinergic stimulation makes mucus
less transportable, whereas adrenergic stimuli have
no effect. High viscosity (low transportability) is
associated with low water content, high serum protein content (inflammation), and high DNA content
(purulence).
Allergen challenge promotes mucus hypersecretion and increases the transport of fluid and electrolytes across the epithelium toward the airway lumen.
Most inflammatory cell products increase mucus
secretion. Leukotriene C4 and leukocyte products,
such as neutrophil elastase, promote mucus secretion; histamine causes water transport toward the
airway lumen; and reactive oxygen species increase
glycoconjugate release.
C.
Mucociliary Function in Disease
Viruses that damage the tracheobronchial epithelium, e.g., influenza, decrease mucociliary clearance
dramatically, presumably because of epithelial injury and shedding. Recovery takes several weeks.
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LOWER AIRWAY OF THE HORSE
with sympathetic and peptidergic nerve fibers23,43
that are involved in the regulation of blood flow and
of vascular permeability.
7.
(a)
(b)
Fig. 5. Mucus apparatus of the airways: (a) Alcian blue–
periodic acid Schiff stain showing goblet cells in epithelium and
the submucosal gland. Bronchial vessels (V’s) are prominent in
the lamina propria. (b) Immunohistochemical stain for mucosubstances. Mucus is clearly visible in goblet cells (G’s) and is being
extruded onto the surface (SMuc).
ary clearance by increasing mucus secretion and
decreasing ciliary function. Some bacteria must
attach to cilia to impair clearance, whereas others,
notably Pseudomonas aeruginosa, produce soluble
products that can impair ciliary beating and increase mucus secretion.
Anesthesia disrupts mucociliary function in part
because the cuff of the endotracheal tube damages
the epithelium. Clearance is also disrupted downstream from the cuff but the degree of impairment
depends on the type of surgery. In humans, abdominal surgery is more deleterious to clearance than is
orthopedic surgery.
6.
Bronchial Blood Flow
The bronchial circulation, a branch of the systemic
circulation, provides nutrient blood flow to the walls
of the airways down to at least 1 mm in diameter.40
Within the airway wall, bronchial blood vessels form
two plexuses, a submucosal plexus and a peribronchial plexus. In addition, some species, including
the horse, have an extensive network of bronchial
blood vessels just below the epithelium. These vessels most likely participate in the warming and
humidification of air, in thermoregulation,41 and in
the inflammatory response of the airways.42 The
subepithelial network of vessels is richly supplied
92
Cough
Cough is a mechanism to clear foreign material from
the intrapulmonary airways. Cough is initiated
by stimulation of irritant receptors located within
and just below the epithelium. These receptors
are most numerous in the lower trachea and in the
large bronchi, i.e., in the airways that are most
effectively cleared by coughing. When irritant receptors are activated, the following sequence of events
occurs. After inhalation, the glottis closes and the
expiratory muscles, especially the abdominal
muscles, contract. This raises the pressure within
the thorax and compresses the air within the lung.
The glottis then opens and the compressed air is
expelled at high velocity through the tracheobronchial tree. The clearance of large airways is facilitated because the high intrapleural pressure
compresses these airways and reduces their crosssectional area. As a result, flow velocity in the
compressed airways is very high and this serves to
blast out foreign material.
Cough is initiated when the irritant receptors are
deformed by the presence of material on the epithelial surface. This can be foreign bodies or accumulated secretions. Deformation of cough receptors
also occurs when smooth muscle contracts. For this
reason, cough can be a sign of bronchospasm and is
sometimes relieved by use of bronchodilator drugs.
Airway disease results in cough for several reasons:
mucociliary clearance frequently is impaired so that
mucus accumulates in the airways, the sensitivity of
irritant receptors is increased by inflammation, and
epithelial desquamation exposes irritant receptors
more directly to the airway lumen. The latter occurs in the presence of viral respiratory diseases,
and recovery of the normal epithelial surface may
take up to 5 weeks.
8.
Airway Wall Thickness
Structural changes within the airway wall, which
result in airway wall thickening, may play an important role in airway obstruction.44–49 Moderate
amounts of airway wall thickening, which have little
effect on baseline caliber, can markedly accentuate
the effects of smooth muscle shortening on the
degree of airway narrowing. These effects are
greater when the airway wall thickening is localized
to the peripheral rather than the central airways.
Recently, Broadstone et al.50 demonstrated thickening of the airway wall in horses with chronic obstructive pulmonary disease.
9.
Consequences of Airway Obstruction
As stated above, obstructions of the large airways
cause severe respiratory distress because these air
passages form the narrowest point in the tracheobronchial system. Foreign bodies would provide
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MILNE LECTURE:
such an obstruction. In most chronic airway diseases, inflammation is most intense in the bronchioles, which are obstructed by a mixture of bronchospasm, mucus plugging, and airway wall thickening.
If the obstruction is diffuse and severe, airway
resistance may be sufficiently increased to result in
signs of respiratory distress in the resting animal.
Such is the case in the horse with severe heaves.
More commonly, obstruction is less severe so that
there are no signs of respiratory distress in the
resting animal. However, animals with low-grade
bronchiolitis (small airway disease) may not perform
adequately. This is because the small airway obstruction results in uneven distribution of ventilation within the lung.
The distribution of ventilation is one of the main
factors determining the gas-exchange efficiency of
the lung. Uneven ventilation distribution leads to
ventilation–perfusion mismatching, which results in
hypoxemia. When small airways are obstructed,
ventilation distribution becomes more uneven as
respiratory rate increases. Exercise requires an
increase in respiratory rate, and therefore small
airway disease most likely leads to uneven ventilation distribution during exercise. It is highly likely
that it is this uneven distribution of ventilation that
is the cause of poor performance in horses with
low-grade inflammatory airway disease.
This research was supported by grants from 3M
Animal Care Products and Bayer AG.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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3. Petsche VM, Derksen FJ, Robinson NE. Tidal breathing
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