The Respiratory System of the Guinea Pig:
Emphasis on Species Differences
NATHAN R. BREWER, DVM, PHDI
Comparative study of the respiratory system of common laboratory animals will reveal unique species variations in basic
structure/function
relationships and cellular response to biogenic products. These variations are of interest to animal
researchers, laboratory animal veterinarians, and others with an
interest in selection of animal models for directed studies. The
guinea pig is a useful model for assessing lung function impairment and bronchial reactions. The guinea pig, and the mixed
breed Basenji-Greyhound type dog, are the best characterized
animals that manifest airway hyperresponsiveness and reactions
that resemble asthma in humans (1-3).
In the guinea pig, alveolar development is almost complete at
birth (4). In the rat, alveolar growth takes place mostly after birth
with a critical period of rapid growth between days 4 and 13 (5,
6). In the guinea pig, malnutrition during gestation can cause
pulmonary hypoplasia (i.e., reduction in the lungweight-to-body
weight ratio and in total lung DNA) that is irreversible. Postnatal body weight changes (lung weight-to-body weight ratio and
lung DNA) caused by malnutrition are reversible (7,8).
Gross Anatomy of the Airway
The nasal hairs of the guinea pig are approximately 1.8 x 10-3
cm in diameter and approximately 35.4 x 10-3cm long (9). Gross
anatomic features of the pharyngeal area in the guinea pig, as in
all hystricomorphs, are complicated (10, 11). The soft palate is
continuous with the base of the tongue, and there is a small
opening from the oropharynx to the remainder of the pharynx,
the palatal ostium (Figure 1). To perform endotracheal intubation, the tube must be threaded through the palatal ostium, a
process that requires training (10, 12, 13). The mandible of the
guinea pig, unlike that of other mammals of similar size, is widely
flared caudally, allowing easy access to upper airway structures
(14). The eustachian tube complex in guinea pigs is easily accessible, and the animal is a useful model for study involving
nasopharynx
AND
LEON
J. CRUISE,
DVM, PHD2
coordination of swallowing, breathing, and middle ear aeration.
The muscular elements underlying tubal-palatal function in
guinea pigs are more distinct and spacially separated than those
in macaques or humans (14).
The guinea pig has no laryngeal ventricle, and the vocal cords
are poorly developed. The trachea of guinea pigs with mean body
weight of 400 g is a mean ± SEM 3.51 ± 0.88 cm long and a mean
± SEM 0.21 ± .05 cm in diameter (9), although Phalen and
Oldham reported that a I-kg guinea pig had a trachea measuring 5.7 cm long and 0.4 cm in diameter (15). The guinea pig
trachealis muscle is relaxed by high doses of methylxanthine, a
drug that induces contractions in many smooth muscles (16).
The airway of many mammals, including humans, has bronchial
divisions that stem from the trachea in a dichotomous order. In
rodents, the primary bronchi stem from the trachea in the shape
of a wishbone, and the intralobular airways branch from the primary bronchi laterally (Figure 2) .All of the in trapulmonic air tubes
stemming from the bronchi are bronchioles. Bronchioles differ
from bronchi by absence of cartilage, simplification of epithelium,
and absence of goblet cells and submucous glands. In the guinea
pig, there is but one order of bronchioles (17). The bronchioles
give rise to respiratory bronchioles, distinguished from bronchioles by the presence of alveoli. The respiratory bronchioles give
rise to terminal sacs with outpockets of alveoli. In 400-g guinea
pigs, the bronchioles, alveolar ducts, and alveolar sacs are about
the same diameter (0.01 to 0.015 cm), and the alveoli are approximately 0.008 cm in diameter (9).
There is a paucity of connective tissue in the lung of the guinea
pig, and there are no intralobular septa or secondary individual
lobulations. The lung tissue is extremely fragile and excess pressure must be avoided when performing artificial respiration,
including pressures used to inflate lungs during intratracheal
fixation, or bronchoalveolar lavage. Artificial respiration is best
performed by alternately tilting th_eanimal's head up and down.
The lack of septation between lobules allows extensive collateral
ventilation, limiting the possibility'ofatelectasis development to
an obstructive bronchus.
In most mammals, the smooth muscle in the bronchial tree is
last molar
HARD
PALATE
palatoglossal
arch
SOFT
velopharyngeal
PALATE
recess
palatal ostium
tongue
FIG. 1. The oropharyngeal region of the guinea pig.
Animal Resources Center, University of Chicago, 5841 Maryland Ave., Chicago,
fL, 606371 Veterinary Services, College of Medicine, Howard University, Washington, D.C., 20059
100
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1997by the
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Laboratory Animal Science
FIG. 2. The upper airwaydivisionsin human and rodent.
Volume 36, No.1
/
January 1997
more prominent in the distal, smaller bronchi. This observation
is species variable, and the guinea pig has the most prominent
smooth muscle, compared with all other mammals examined.
The muscle is spirally arranged, much like the arrangement in
the pulmonary arterioles in the ox. The bronchi of sheep are
heavily muscled, but unlike those in the guinea pig, the muscle
is less prominent in the distal airways. The muscle is so strong in
the guinea pig that the bronchi can be closed down more completely than they can in other animals.
Physiological Measurements of the
Respiratory System
Crosfill and Widdicombe (17) reported that, in guinea pigs
weighing 690 (430 to 1050) g: lung weight was 3.2 (2.4 to 4.1) g;
functional residual capacity was 4.75 (4.1 to 5.1) ml; specific gravitywas 0.40 (0.37 to 0.43) g/ml; tidal pressure swing was 3.2 (2.1
to 5.1) cm H20; minute volume was 0.13(0.08 to 0.19) L/min;
mean alveolar diameter was 83.43)lm; and value for the work of
breathing was 272 (179 to 390) gecm/min, absolute, with a value
of 0.52 (0.28 to 0.91)/g of body weight and 2,090 (1,560 to 2,880)
g cm/unit of ventilation. The lung epithelial fluid volume in the
guinea pig has been reported to be approximately 0.01 ml (18).
In the distal airways, the extent and structure of the capacitance
systems of the vessels in the lungs are poorly developed in the
guinea pig and cat, compared with good development in the
rabbit and sheep. The human is intermediate (19). The dead
space, that portion of the airway in which no appreciable air
exchange takes place, was reported to be 0.60 (0.52 to 0.66) ml
in guinea pigs (n=5) weighing 212 (190 to 230) g. In 8 guinea
pigs weighing 194 (180 to 230) g, the dead space was reported
to be 0.76 (0.51 to 0.93) g. End tidal CO2 tension, measured by
use of a rapid responding infrared CO2 analyzer, 8 guinea pigs
weighing 194 (180 to 230) g. was 37.5 (35 to 42) torrin. The
volume of CO2 excreted was 4.3 (3.1 to 5.2) ml/min (20). Gehr
(21) found that 15 guinea pigs with mean body weight of 429 g
had mean lung volume of 13.04 ml and alveolar surface area of
0.91 ± 0.11 m2 in close contact with capillary blood, the thickness of the tissue barrier being 0.43 ± 0.03 )lm and the capillary
surface area being 0.74 ± 0.09 m2• The diffusion capacity for
in the lung, in scientific international terms, was determined t~
be 0.0179 ml/s/mbar (torr = 1.3332 mbar). Weibel (22) determined the surface area of the lung ofa guinea pig to be 0.91 m2•
Weibel (23) also found the diffusion capacity for 02for the membrane portion of the tissue barrier to be 0.068 ml/s/torr/kg.
Ingenito, et al. (24) found dynamic elastance, the quality of recoil of the lung in terms of unit of pressure change per unit of
°
Table 1. Some respiratory
n
5
3
61
49
12
200
60
8
5
13
16
13
3
Body
weight
(g)
690 (430-1,050)
880 ± 12
1,000 ± 58
466 (274-941)
477 (274-941)
557 ±83
219 ± 32
209 ± 30
194 (180-230)
212 (190-230)
300-1.000
278 ± 56
520
450-750
Volume 36, No.1 / January 1997
Breaths
/min
Tidal
volume
(ml)
3.7 (2.3-5.3)
75
67
90.3 ± 69-104
44±6
84 ± 14
81 ± 13
81 (61-90)
83 (71-94)
82 ± 7.6
28
60
90
1.75 (1.0-3.9)
3.0 ±0.2
1.68 ± 0.39
1.7 ± .01
2 (1.7-2.5)
1.85 (1.6-2.1)
7ml/kg
7ml/kg
3 ± 2/kg
volume change, to be 1.94±0.19 cm H20/ml; air wall resistance
to be 0.10 ± .01; and tissue resistance to be 0.03 ± .004 cm H20/
ml/s. Boucher (25) found the transepithelial electrical potential in the guinea pig trachea to be 8 mV; and in the bronchus,
to be 4 mY. These quantities are about half the values reported
in the rat. Table I gives some recorded values for the guinea pig
respiratory system.
Cells of the Airway
Of the cell types in the lung, approximately 40 in number,
fibroblasts are the most numerous. Fibroblasts are structural cells
that are influenced by and release cytokines. Cytokines are intermediate molecular mass polypeptides of 7 to 40 kDa that have
functions which include growth and differentiation (33). Among
the cytokines released by fibroblasts are interferon
B-1,
interleukin 6, interleukin 8, monocyte chemotactic factor, colony
stimulating factors, and tumor necrosis factor (33).
The next most numerous cell type is the pulmonary endothelial cell, part of the pulmonary capillary bed, the largest vascular
bed in the body. It covers 70 m2 in the human adult (34), and
accounts for approximately 30% of the cells of the lung (35).
The lining cells of the trachea are pseudostratified, simplifying to cuboidal epithelium in the bronchioles. In the guinea
pig, about half of the cells in the trachea are ciliated, and the
proportion of ciliated cells decreases distally. At the terminal
bronchi, about 15% are ciliated (36). The ciliated cells contain
a species-variable carbohydrate-rich material, are rich in mitochondria, and have a high metabolic rate. There are as many as
200 cilia on the luminal surface ofa ciliated cell (36), and each
cilium exerts about 1,500 beats each minute (37). Each ciliated
cell has been calculated to produce work each minute comparable to lifting its own weight 2.6 miles (38).
Goblet cells are numerous in the guinea pig; they are rare in
the mouse, rat, and hamster. Numbers increase with contamination, and they secrete a species-variable acidic mucoid substance
(32). Serous cells, those which secrete a neutral mucoid substance, have not been found in guinea pigs. They are common
in the rat (39).
Clara cells, non ciliated epithelial cells with high metabolic rate,
vary widely in distribution, numbers, and form between species.
They have not been found in the trachea or major bronchi in
the guinea pig (40), unlike the situation in the rabbit, the hamster, and the mouse (41-43). In the guinea pig, about 73% ofthe
cells lining the bronchioles are Clara cells (44). The Clara cells
of the guinea pig, similar to those in many mammals, have cytoplasm that is heavily occupied with smooth endoplasmic
values of the guinea
Minute
ventilation
(ml/min)
pig
Vital
capacity
(ml)
Lung
compliance
(ml/cmH,O/
body weight)
21.1 ± 1.6
1.5 ± -0.14kg1
Total lung
cmH,o/ml/s
130/ kg (80-190)
155.6 (100-382.2)
154.1 (87-329)
140 ± 20
139 ± 30
137 ± 23
0.43 ± 0.08
0.20 ± 0.05
0.22 ± 0.05
0.16 ± 0.13
0.73 ± 0.21
0.69 ± 0.18
0.27 ± 0.09
0.63 ± 0.13
0.13 ± 0.01
640/kg
CON1KMPORARY
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1997 by the
American
Association
Reference
resistance
for Laboratory
Animal
17
26
26
27
27
28
29
29
20
20
20
30
31
22,23
32
Science
101
reticulum. Primate Clara cells have only rough endoplasmic
reticulum, and smooth endoplasmic reticulum is a minor constituent in Clara cells of the ox, dog, cat, and ferret (41).
Brush cells, those having an apical border of thick regular
microvilli about a third the length of cilia, are found in guinea
pigs (40), and in many other mammals. Their identification in
humans is not convincing (39).
Submucous glands, abundant in the human, and present in
murine rodents, have not been found in the guinea pig or the
hamster.
Five major cell types have been identified in the alveoli: type
I; type II, endothelial cells, interstitial cells, and macrophages.
The type II cell is the stem cell of the alveolar epithelium. When
type-I cells are effete, they are replaced by transformation of the
type-II cells. Type-I cells do not divide. Type-II cells synthesize
and secrete surfactant, a highly surface-active phospholipid mixture with high concentration of saturated phosphatidylcholine.
Evidence indicates that type-II cells are also involved in the defense against oxidative damage (44, 45). Lung tissue, especially
the alveolar type-II cells, are vulnerable to oxidative damage.
Protection by the zinc-containing enzyme superoxide dismutase
is vital. In the guinea pig, zinc is utilized in a carrier-mediated
process that is stimulated by arachidonic acid to form superoxide dismutase (45). Type-II cells also participate in metabolism
of some xenobiotes (46) and in fluid and electrolyte transport
(47). Type-II cells only cover about 3% of the surface of the alveoli although there are about twice as many as type-I cells.
Lung macrophages, derived from blood monocytes, are part
of the mononuclear phagocyte system, formerly called the reticuloendothelial system (48), and consist of alveolar macrophages,
tissue macrophages, and in many species, intravascular macro phages. Intravascular macrophages are not prominent in guinea
pigs or other rodents. Macrophages have high metabolic activity; they release many products, including cytokines, enzymes,
cyclooxygenase and lipoxygenase metabolites, antipropionases,
antioxidants, and coagulation factors (49). Alveolar macrophages are freely mobile
to scavenge
microbiotes
and
micro molecular debris. Interstitial macrophages, not directly
exposed to airborne particles, differ from alveolar macrophages
in the ability to replicate and synthesize DNA in vitro. In guinea
pigs, neutrophils, not macrophages, capture intravascular foreign bodies up to the size of erythrocytes. In the guinea pig, the
neutrophils adhere to endothelial cells, even under normal conditions, a characteristic in the species (50). Neutrophils ingest
foreign bodies and apparently migrate to the interstitium where
macrophages aid in foreign body removal (50).
Mast cells vary among species and between tissue, in numbers
and content. Rodent mast cells appear as electron-dense spheroidal structures, whereas human mast cells contain characteristic
crystalline inclusions in the form of scrolls, whorls, and lattices
(48). The guinea pig is unique in that smooth muscle fibers are
prominent in the pleura, and mast cells are found along the
smooth muscle of the plural surfaces in this species, being more
prominent in this area than in other parts of the lung (51, 52).
Mast cells contain histamine, leukotrienes, prostaglandins, platelet activity factor, and enzymes. The enzymes vary among species
and among tissues. Guinea pig, mouse, and rabbit mast cells
contain no tryptase (53). Human, dog, and monkey mast cells
throughout the body contain tryptase, which has not been found
in any other cells in these animals (53). Not all mast cells contain chymase. Only about 10% oflung mast cells contain chymase.
Chymase is rare in mast cells that are located in alveoli or airway
epithelium, but is common in lamina propria that is close to
airway submucosal glands.
Chymase cleaves angiotension I to produce angiotensin II, and
it cleaves and inactivates substance P (SP), vasoactive intestinal
peptide (VIP), calcitonin gene-related peptide (CGRP), brady102
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1997 by the American
Association
for Laboratory
Animal
Science
kinin (BK), and kallidinin (53). Mast cells are involved in
bronchoconstriction via liberation of histamine and leukotrienes,
a process substantiated by the finding that nedocromil sodium
and cromogylate sodium reduce the bronchoconstrictor action
of tachykinins (54).
The guinea pig mast cell differs from the guinea pig basophil
in that it is larger (approximately 10 to 40 11m), has a smaller,
more numerous granules, and is more variable in shape than
basophil granules (48). In the guinea pig, basophil degranulation is characterized
by the fusion of individual granule
membranes to form a large central cytoplasmic sac containing
the liberated granules.
Eosinophils, first described by Paul Ehrlich in 1888, are found
in loose connective tissue beneath the epithelial surface of the
respiratory tract. In the guinea pig, there are about 300 times as
many eosinophils in the tissues as there are in the circulating
blood (55). A hypersensitive strain of guinea pigs, the BHS strain,
contains a larger number of eosinophils in tissues. Interleukin 5
(IL-5) is essential for maturation of the eosinophil from its precursor, the eosinophilic
promyelocyte
(56, 57), inducing
proliferation, differentiation,
and activation of eosinophils.
Interleukin 5 plays a role in antigen-induced airway eosinophilia.
It increases eosinophil survival, activates eosinophils, and stimulates eosinophilopoiesis
(58, 59). An antibody to IL-5 blocks
allergic pulmonary eosinophilia (60). Eosinophils differ from
other leukocytes in ability to inactivate mediators released from
mast cells, and by ability to damage the larval stages of some
helminth parasites. Eosinophils and neutrophils contain histaminase, release of which inactivates histamine. The eosinophils also
contain an arginine-rich protein called major basic protein that
accounts for about 25% of the total cell protein content, the
release of which damages parasitic worms (61).
Pulmonary neuroendocrine cells (PNEC; K-cells; Feyter cells)
are the least abundant of the airway cells of the epithelium, representing about 0.1 % of the total lung epithelial cells (62). When
found in groups, they are called neuroendocrine bodies (NEB).
The NEB are intrapulmonary chemoreceptors that respond to
changes in oxygen tension (Po2) by releasing serotonin (63).
Guinea pigs genetically adapted to the high altitudes of the Andes
have significantly more NEB than do those at sea level (0.42 vs.
0.08/cm2) (64,65). The PNEC are also believed to have growth
properties in fetal tissue (66).
There is species variability in the peptides found in PNEC.
Gastrin-releasing peptide, the mammalian homologue of the
amphibian neuropeptide bombesin, is a small peptide found in
PNEC with amine precursor uptake and decarboxylation. Cell
properties. Leu-enkephalin, calcitonin, and gastrin-releasing
peptide have been identified in human PNEC.
Table 2 is a list of peptides found in PNEC of various species,
adapted from reference 67.
The Pulmonary Circulatory System
Right ventricular systolic pressure in the guinea pig is about
18 torr (132). The pulmonary trunk differs from that of the aorta
in that it is composed of short irregular branching elastic fibers
interspersed with smooth muscle and collagen. In the rat, the
pulmonary artery resembles the aorta in that it is composed of
long, parallel, concentric, elastic lamella (68,69). In this respect,
the guinea pig is more comparable to the human, monkey, dog,
and ferret, than is the rat (69) (Figure 3). The pulmonary artery
and its branches are thicker and heavily muscled in the guinea
pig and rabbit than in all other animals examined (68, 69).
Heavily muscled sections (muscle swellings) are prominent.
Muscle swellings are also found in the pulmonary artery of
the rabbit, opossum, and dolphin, and in the smaller branches
of the ox; they have not been described in other animals (68,
69). The pulmonary arteries of the guinea pig have a thin-walled
Volume 36, No.1 / January 1997
Table 2. Peptides in PNEC
Somatostatin
Eukephalin
Bombesin
Calcitonin
+
S
S
+
+
+
+
+
+
Human
Monkey
Ox
Sheep
Goat
Pig
Dog
Cat
Rabbit
Guinea pig
Rat
Mouse
Hamster
(+)
CGRP
+
+
+
+
+
+
Positive
=
CGRP
=
Calcitonin
(S) = Scarce
CCK = cholerystokinin
gene related peptide
+
+
+
+
+
+
+
+
+
+
+
+
S
(-) =
SP
Negative
60
}J
PULMONARY
49
VEIN
}J
220
176
132
88
44
22
22
DIAMETER
FIG. 3. Relationship
differen t species.
Volume 36, No.1 / January 1997
+
+
+
+
CCK
SP
+
+
S
S
+
S
S
+
S
S
+
+
+
+
+
+
(Blank)
+
+
+
+
S
S
S
S
+
= not done
= substance P
elastic segment, and branching is associated with abrupt changes
in lumen size and wall thickness. The guinea pig shares these
characteristics with the rat and the rabbit, and differs from the
human, dog, cat, and mouse in which the pulmonary arterial
tree is smoothly tapering (70).
Bronchial artery-pulmonary artery anastomoses in the guinea
pig, as in the rat and the rabbit, are large (400 to 600-flm diameter) and are found only near the hilum (71). Although present
in most species, pulmonary artery anastomoses have not been
observed in the pig, dog, cat, and rhesus monkey (71).
The capacitance systems in the blood vessels of the distal airwaysare poorly developed in guinea pigs and cats (71), compared
with those of rabbits, (72) and sheep (73).
Unlike the systemic circulation, where the arteriole is the prime
site of circulatory resistance, the pulmonary precapillary arterioles are less sphincteric, are more pliable, and passively expand
with increased flow volume, thus acting as storage vessels.
In the guinea pig, the pulmonary capillaries are smaller in the
center than in the periphery of the lung lobule-a
probable
contributing factor for the centrilobular location of emphysema
in the species (74). In guinea pigs and rats, the pulmonary capillaries arefenestrated (71). In dogs (75), sheep (73), and healthy
humans (76), such fenestrations are largely limited to capillaries that are associated with glands and neuroephitheal bodies.
Guinea pigs and rats are not subject to these limitations. Similar
to that in all animals with a thin pleura, the only blood supply to
the pleura of the guinea pig is from the pulmonary artery.
The guinea pig, rat, pig, llama, and ox have thick pulmonary
veins that have muscle swellings (Figure 3). The pulmonary veins
of the human, dog, cat, ferret, fox, goat, horse, monkey, and
rabbit have no muscle swellings and have thin fibrous walls (69).
53
Seratonin
Fetal
Adult
between vascular calibers and medial thickness in
All species tested undergo constriction of pulmonary blood
vessels in response to breathing low 02 tension (69,77). In time,
thickening of the medial smooth muscle of arterioles that envelop terminal and respiratory bronchioles takes place and causes
a chronic pulmonary hypertension; thickening varies with the
species. The guinea pig, dog, and sheep are hypo responders.
Rats and rabbits are moderate responders. Calves and pigs are
hyperresponders (69).
Adenosine is a potent vasodilator in most vascular beds (78),
but is capable of inducing an increase in pressure in the pulmonary artery in most animals (79). It is also reported to constrict
the guinea pig aorta (80). In the isolated pulmonary artery of
the guinea pig (81), adenosine causes initial contraction followed
by slowly developing relaxation (82).
Control of Respiration
Unlike the heart, the respiratory system cannot operate without
control by the nervous system via sensors in the brain stem. Control of rhythmicity is operative even in the absence of all peripheral
sensory input. Within the medulla are two bilateral aggregations
of neurons having respiration phase related activity,a dorsal respiratory group (DRG) and a ventral respiratory groups (VRG). In
the guinea pig, the DRG is located immediately ventral to the tractus solitarius, which is slightly different from the cat or the rat
where it is ventrolateral to the tractus solitarius (30). The VRG in
the guinea pig is less compact than the DRG. It is located within
and around the nucleus ambiguus. A unique cell type in the DRG
of the guinea pig, a pump-inhibited unit, exists (30). During autonomous ventilation, the pump-inhibited
unit stops firing
completely during the expiratory phase whenever the lungs are
inflated. Mild inhibitation associated with lung inflation has been
observed in the nucleus retroambigualis in other species (83,84),
but inhibition has not been observed in the DRG or VRG in species other than the guinea pig.
An excess of CO2 in the circulating blood of most mammals,
induced by exercise or because of an increase in CO2 in ambient
air, causes hyperpnea. The response to CO2 increase is species
variable. In the human, an increase of CO2 in the ambient air,
from the normal 0.03% to 3%, doubles the ventilation rate. Burrowing or diving mammals are more tolerant of CO2 increases
than are humans.
Ozone induces inflammation of the airways in guinea pigs that
is mediated by neuropeptides which are released from sensory
nonadrenergic-noncholinergic
nerve fibers. Capsaicin reduces
ozone-induced airway inflammation in guinea pigs (85). Adrenergic and cholinergic fibers are not involved.
Chronic hypoxia, as would develop at high altitudes causes pulmonary artery hypertension through vasoconstriction. In guinea
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103
pigs, administration of heparin given ten days prior to exposure
to hypoxia reduces the amount of hypertension that develops (86).
Acute hypoxia may elicit a modest hyperventilatory response
from the carotid and aortic receptors. The response reflects only
the P02 in the blood, not the 02 content. Thus, air containing
21 % 02 and 0.1 % CO, resulting in blood content that is about
50% of normal, but with P02 that is normal, would not cause a
response from the carotid sinus (87).
There are mechanoreceptors in the larynx and trachea that respond to attempts to insert an endotracheal or esophageal catheter
with a strong laryngeal spasm. There also are reflexes initiated by
tension on the gut during an operative procedure that can cause
laryngeal spasm (88,89). The trachaelis muscle relaxes after stimulation of the sympathetic nerves in the guinea pig, but relaxation
after sympathetic stimulation of the trachaelis muscle does not
take place in the rabbit, rat, or monkey (90). Functional
nonadrenergic inhibitory nerves were not found in the rat, but
were found in the guinea pig, rabbit, and monkey (90).
Post-mortem massive bronchoconstrition takes place in guinea
pigs after excision of the lungs or exsanguination (91). Hyperpnea also causes airway tissue to constrict, greatly increasing airway
and tissue resistance in the guinea pig (2). The hyperpnea airway resistance suggests that the guinea pig may be a good model
for exercise-induced asthma in humans.
About 80% of afferent fibers in the vagus nerve from the lungs
are unmyelinated, and are termed C-fibers. The C-fibers are small
diameter (0.3 to 1.3 !lm) slow-conducting (0.5 to 2.3 m/s) fibers
containing SP), neurokinin A (NKA), VIP, and CGRP that are associated with axon reflex effects. Pep tides have been synthesized
and specific antagonists have been developed (92). The peptides
released from the C-fibers that are most conspicuous in guinea
pigs are those that cause bronchoconstriction. Afferent C-fibers
elicit a classicalpulmonary chemoreflex in many mammals-bradycardia, apnea, and decrease in blood pressure (93). Of animals
tested (guinea pigs, rats, rabbits, dogs, and cats), only in guinea
pigs is the classic response to capsaicin administration not evoked.
In the guinea pig, hyperpnea develops instead of apnea, there is
no bradycardia, and the hypotension evoked is slight (93).
In the guinea pig, the trachea is well innervated, but the small
airways have little or" no innervation (94). In this respect, it is
comparable to that in the human (95). It differs from that in the
human in that there is an adrenergic as well as a nonadrenergic
inhibitory pathway and a cholinergic excitatory pathway. No
adrenergic nerves have been found to have a function in the rat.
The bronchi of guinea pigs are more sensitive to the constrictor
action of serotonin (5-hydroxytryptomine, 5-HT) than are those
of the dog or the normal human. The tracheobronchial tree of
the normal human is rarely affected by 5-HT, but asthmatic patients are severely affected. The resting tonus of the isolated
guinea pig trache is decreased by indomethacin, a cyclooxygenase
inhibitor, whereas the isolated human bronchus has a transient
decrease followed by an increase (96).
In the guinea pig, nonadrenergic-noncholinergic
fibers are inhibitory in the lungs (85). In guinea pig airways, the
non adrenergic-non cholinergic component of vagal stimulation is
important in plasma leakage because pretreatment with atropine,
propranolol, or hexamethonium does not affect the leakage (97).
Parasympathetic and sympathetic fibers enter the pulmonary
plexus in which the parasympathetic ganglia are embedded. In
the preganglionic fibers, acetylcholine (ACh) activates nicotinic
receptors on ganglion cells, and are inhibited by ganglion blockers
like hexamethonium. In the postganglionic fibers, ACh activates
muscarinic receptors on target cells, such as airway smooth muscle,
and is antagonized by atropine. Thus, ACh triggers two classes of
receptors, nicotinic ACh and muscarinic ACh receptors.
Muscarinic receptor density is high in mammalian airways. In
guinea pig airways, these receptors appear to be located in sym104
CON1'1.j'vIPORARY TOPICS
© 1997 by the American
Association
fOf
Laboratory
Animal
Science
pathetic ganglia (98, 99), whereas in human airways, they seem
to be present on cholinergic nerves, and are probably localized
in parasympathetic ganglia (100). The bronchi of guinea pigs
are more sensitive to the constrictor action of acetylcholine than
are those of other mammals examined (rat, rabbit, cat, dog, pig,
monkey, human [101]). The sensitivity varies among strains. A
hypersensitive strain (BHS) has more muscarinic receptors in
the lung, and has high sensitivity to acetylcholine and to certain
leukotrienes (102).
There are at least five subtypes of muscarinic receptors, and
all five have been cloned and sequenced (103). At least three
subtypes playa role in the lung. The M-1 receptors, antagonized
by pirenzepine (100), facilitate transmission through parasympathetic
ganglia and enhance
ACh reflexes. They are
predominantly located in the central nervous system and automatic ganglia, accounting for a high proportion of muscarinic
receptors in humans and guinea pigs (99, 100). The M-2 subtype predominates in the human and bovine trachea (99), is
located on postganglionic ACh nerves, and inhibits ACh release.
Stimulation ofM-2 receptors with the agonist pilocarpine inhibits the release of ACh and decreases bronchoconstriction.
Gallamine, a ganglionic blocking agent, blocks M-2 receptors
acting opposite to pilocarpine. Although it abolishes bradycardia induced by ACh, it potentiates bronchoconstriction induced
by ACh (104). Three subtypes (M-1, M-2, M-3) predominate in
guinea pigs (105). In guinea pigs, the M-1 receptors appear to
be located in sympathetic ganglia (98), whereas in the human,
they appear to be located in parasympathetic ganglia (100). The
release of ACh from vagal nerve endings constrict airways by
stimulation ofM-3 receptors on airway smooth muscle. The constriction is retarded by activity of the M-2 muscarinic receptors.
When the M-2 receptors lose activity, as may happen during viral infections (104), ozone exposure, or antigen inhalation, the
lung is subjected to bronchoconstriction
(105). The M-3 receptors, uninhibited by M-2 receptor activity, mediate the contractile
responses to bronchoconstricition
(106).
The lungs of most mammals contain both a-excitatory and B-inhibitory adrenoceptors, but only B-adrenoceptors are found in the guinea
pig lung. The B-adrenoceptors respond to epinephrine and are antagonized by propanoloL They activate adenylyl cyclase,the enzyme
that couples to one of the stimulating nucleotide-binding regulatory
proteins, the Gs protein, resulting in intercellular accumulation of
cyclicadenosine monophosphate (129).
Species differences exists in the 8-adrenoceptors subtype. The
predominant subtype in the guinea pig (107) and ox (108) tissues is the 82 subtype, whereas in the pig and mouse, the 8)
subtype predominates (109). In human airway smooth muscle,
only 82-adreno-ceptors are found (110). In the rat, no adrenergic nerves have been found to have any direct function in the
lung. The 82-adrenergic agonists inhibit release of mediators from
mast cells and basophils, increase movement of chloride ions
and water in to the bronchial lumen (Ill), and increase beating
frequency of the cilia (112).
Leukotrienes, first discovered in leukocytes, are of several classes
(A, B, C, D, and E) and are usually derived from arachidonic acid,
an acid with four double bonds. The bronchoconstrictive slowreacting substance of anaphylaxis (SRS-A) found in guinea pig
and human lung, has been identified as LTD4 (113). The LTB4
and LTD 4 are equipotent at inducing dose-related contractions of
guinea pig parenchyma (114). An antagonist ofLT (and ofSRSA), PPL 55712, is effective against LTC4 and LTE4but has no effect
against the actions ofLTB4 (114) the release ofTXi\ from perfused lungs by LTC4 and LTD4, suggesting that LTs exert their
action via generation ofTXi\ (114).
The LTC4 andLTD4 are about 100 times more active in guinea
pig lungs than in human lungs, and more than 1,000 times more
active than in rabbit or rat lungs (114).
Volume
36. No.1
/ January
1997
Tachykinins are a family of neuropeptides widely distributed
in the central and peripheral nervous systems. They increase
smooth muscle contraction, increase mucous gland secretion,
cause postcapillary venule leakage and edema, and participate
in the proliferation of epithelial cells from their stem cell precursors and migration of these cells to the damaged region (115).
Included in the family are SP, NKA, NKB, NKY, and NPK. In
most instances, the activity is mediated by specific receptor on
target cells. The activity and the receptor vary among species
and among different vessels of the same species.
Substance P is located in chemosensitive C-fiber afferents in the
respiratory tract, under or within lining epithelium, around blood
vessels, within the bronchial smooth muscle layer, and around local tracheobronchial ganglion cells (116). It is active in the control
of bronchial smooth muscle tone and vascular permeability. It induces a tracheal smooth muscle constriction oflong duration, but
transmural field stimulation of the guinea pig trachea only yields
a rapid atropine-sensitive contraction followed by a long-lasting
relaxation. In field stimulation of the peripheral bronchi of the
guinea pig, a long-lasting atropine-resistant contraction is induced
that is dependent on capsaicin-sensitive nerves, and is blocked by
an SP antagonist (116).
The guinea pig trachea contains the agonist receptor NK-l,
the receptor that mediates SP, and NK-2, the receptor that mediates NKA. In the hamster, the only receptor that mediates
contractions to neurokinin is the NK-2 receptor 117). A cyclic
hexapeptide, AWFGLM (single letter representation of amino
acids), blocks receptors mediating action in hamster trachea,
but not guinea pig trachea (117). There are noNK-l or NK-2
receptors in the airway of rats (118). The NK-l receptor antagonist CP 99,994 is 40 to 75 times more potent in inhibiting plasma
extravasation induced by SP in the guinea pig airways, compared
with rat airways (119). The NK-l receptor antagonist RP67,580
has preferential treatment in the rat (120).
Substance P is under close regulation by neutral endopeptidase (enkephalinase)
located on airway epithelium
(85).
Inhibition of endopeptidase, by thiorphan or angiotensin-converting enzyme (ACE), greatly aggregates SP, increasing its
pathogenicity (53). The response to NEP suppression is less in
hamsters, and is not observed in mammals other than rodents
(121). In nonrodent species, stimulation of airway C-fibers is
cholinergic and is abolished by atropine.
Neurotensin is a tridecapeptide, ELYENKPRRPYlL*,first isolated from the bovine hypothalamus, that induces vasodilatation
and hypotension. It causes bronchoconstriction
in guinea pigs
by direct action on the bronchial smooth muscle, whereas in
humans and other species, the action is by indirect mechanisms,
putatively involving cholinergic nerves and products released
from mast cells (54). That mast cells are involved is substantiated by the finding that nedocromial sodium (a drug that reduces
the release of histamine and leukotrienes from mast cells) reduces the bronchoconstrictor
effect (54). In rats, indirect
bronchoconstriction
is reduced by atropine and methysergide
(a serotonin
antagonist
[54]).
In
guinea
pigs,
bronchoconstriction
is not affected by atropine, but is reduced
by the NK-2 receptor antagonist CP96345.
Hyperpnea-induced bronchoconstriction may be mediated by
tachykinins in guinea pigs. In humans with asthma, hyperpneainduced bronchoconstriction
is common.
Histamine content and activity vary widely among species and
among tissues of the same individual. It causes a marked constriction of the guinea pig tracheal muscle, a moderate
constriction in cat tracheal muscle, and has no effect on rabbit
tracheal muscle (122). An interesting difference exists in release
of histamine between the guinea pig and the rat. The rat does
not require oxygen for anaphylactic release of histamine, whereas
oxygen deficiency completely inhibits histamine release in the
Volume 36, No.1
/ January
1997
guinea pig. In the guinea pig, release of histamine is an energydependent process (123). The marked bronchospasm seen in
guinea pigs after histamine inhalation is not seen in healthy
humans, but in asthmatic humans, it causes a severe bronchoconstrictor effect. Important differences in anaphylaxis exist
between the guinea pig and other mammals. In the guinea pig,
an antigen-antibody reaction is associated with the liberation of
histamine. In the rat and the mouse, the most important chemical liberated in an anaphylactic reaction is 5-HT. Anaphylaxis
affects guinea pigs principally by bronchospasm, an effect intensified by the heavy muscular coat of the bronchioles in that
species, and not observed as the primary response in other species. In the rabbit, the pulmonary artery, heavily muscled in that
species, is most sensitive to chemicals released by anaphylaxis,
and may lead to constriction so severe that right-sided heart failure may result (124). In the dog, an important effect is spasm of
the hepatic vein, heavily muscled in that species, causing engorgement of the splanchnic
pool with typical ecchymotic
hemorrhages of the intestine, similar to the effect in humans. In
the rat, the effect of anaphylaxis is vascular engorgement of the
gastrointestinal tract due to capillary dilatation, as opposed to
smooth muscle spasms in other species (123).
Prostaglandins
(PGs), thromboxanes
(TXs), leukotrienes
(LTs), and lipoxins (LXs) are eicosanoids, consisting of 20 carbon atom compounds (eico = 20) that have a common link to
essential fatty acids. Prostaglandins, first found in secretions of
the prostate gland, are 20 carbon fatty acids containing a five
carbon ring.
The PGs and TXs released by guinea pig lung tissues are
greater than those released by lungs of the human or the rat
(125). Thromboxane B2' the metabolite ofT~,
is the dominant cyclooxygenase product in guinea pig lung, whereas human
and rat lungs form equivalent amounts of TXB2, and PGF1a, the
spontaneous hydrolysis product of prostacyclin (126).
Cyclooxygenase is one of a complex of ubiquitous enzymes
that are involved in the synthesis of prostaglandin from arachidonic acid. Its activity is inhibited
by indomethacin,
an
aspirin-like drug that is most effective in neutralizing the effects of cyclooxygenase. Indomethacin decreases the resting
tonus of the isolated guinea pig trachea, whereas in the human
isolated trachea, the tonus undergoes a transient decrease followed by an increase (127).
Vasoactive intestinal peptide, a 28-amino peptide, largely found
in cholinergic efferent fibers, causes relaxation of bronchial smooth
muscle in many species (94), and is a potent vasodilator. Of the
mammals studied (pig, ox, rat, dog, rabbit, guinea pig, and human), only guinea pig VIP differs in its amino acid sequence (128).
Guinea pig VIP is less potent than "common" VIP as a smooth
muscle relaxant. Guinea pig receptors recognize common VIP with
high affinity, but rat lung receptors are not as receptive to guinea
pig VIP as they"are to common VIP (128).
Angiotensin-converting enzyme, a carboxypeptidase of about
180 KDa, converts angiotensin 1 to angiotensin II. The enzyme
is found in the plasma of guinea pigs in higher amounts than in
the plasma of any of the other mammals examined (129). Guinea
pig plasma is also rich in another membrane-bound carboxypeptidase (130). These enzymes modulate the activity of bradykinin,
histamine, serotonin, and acetylcholine in one passage through
the lungs. The high activity of ACE in the guinea pig is such that
an intravenous injection of the potent vasoconstrictor bradykinin given to guinea pigs is impotent (130).
Platelet-activating factor (PAF) is a phospholipid having potent hypotensive, inflammatory, and smooth muscle contractile
activities. It is formed within the intracellular membrane through
acetylation of the phosphorylcholine ether precursor in the presence of calcium. Alveolar macrophages are an important source
of PAF; it can cause aggregation of platelets and the dilatation
CONTEMPORARY
TOPICS©
1997 by the American
A~sociation
for Lahoratory
Animal Science
105
of blood vessels, even at low concentrations (0.1 nM). The PAF
recruits and activates eosinophils, aggregates polymorphonuclear
cells and releases arachidonic acid from them, and can induce a
long lasting increase in bronchial hyperresponsiveness with bronchospasm, plasma protein extravasation, and hypersecretion, to
which guinea pig airway tissues are extremely sensitive. The
guinea pig responsiveness is probably due to capsaicin-sensitive
sensory fibers (129-131).
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