Respiration Physiology 120 (2000) 167 – 177

www.elsevier.com/locate/resphysiol

The lung of the marmoset (Callithrix jacchus): ultrastructure

and morphometric data
A. Barbier a, H. Bachofen b,c,*
a
Department of Anesthesiology, Uni6ersity of Berne, Inselspital, CH-3010 Berne, Switzerland
b
Department of Medicine, Pulmonary Di6ision, Uni6ersity of Berne, Inselspital, CH-3010 Berne, Switzerland
c
Department of Anatomy, Uni6ersity of Berne, Inselspital, CH-3010 Berne, Switzerland

Accepted 14 February 2000

Abstract

Owing to its small size (body weight 300–400 g), its modest demands on animal husbandry, and in particular its
relatively long life-span (up to 12 years) the common marmoset (cotton ear marmoset: Callithrix jacchus (Cj)) might
be a useful animal model to study the adaptive capacity to different energetic demands, adverse environmental
influences such as air pollution, and aging of the lung. In order to describe the gas exchange apparatus of healthy
marmosets as a basis for further pulmonary research, the lungs of three young adult animals have been analysed both
qualitatively and quantitatively (by morphometry) at the light and electronmicroscopic level. Qualitatively, there is a
general similarity in the architecture and structure of lung parenchyma between marmosets and other mammals.
Quantitatively, the alveolar surface area was found to be 7662 9 1647 cm2. Capillary surface area and volume were
6000 91549 cm2, and 1.01 90.34 ml, respectively. The harmonic mean thickness of the air-blood barrier was
0.51790.117 mm. These morphometric parameters allowed to estimate the diffusing capacity for oxygen at
0.029990.0134 ml O2 (sec mmHg) − 1. In comparison with mammals of similar body size (rats, quinea pigs) it appears
that the marmoset has a higher gas exchanging capacity of the lung, which might reflect the ‘athletic’ activity of this
small primate. An incidental finding worth mentioning is the individual variability of septal structures due to
variations in capillary blood volume and hematocrit. The distinction between such functional variations and subtle
pathologic alterations of lung tissue requires a morphometric analysis at the electron-microscopic level. © 2000
Elsevier Science B.V. All rights reserved.

Keywords: Diffusing capacity, morphometry; Gas exchange, morphometric diffusing capacity; Mammals, marmoset (Callithrix
jacchus); Morphometry, lung structure

1. Introduction

The common marmoset (cotton ear or white ear

* Corresponding author. Tel.: +41-31-6323055; fax: + 41- marmoset: Callithrix jacchus (Cj)) is a New World
31-6329833. monkey which inhabits South and Central Ameri-
E-mail address: hans.bachofen@insel.ch (H. Bachofen) can forests; the most numerous populations are

0034-5687/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 0 3 4 - 5 6 8 7 ( 0 0 ) 0 0 1 0 5 - 5
168 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177
found in the Amazon basin. Their small body size
(weight 300–400 g, length 18 – 23 cm), the modest
demands on animal husbandry, and their rela-
tively long life-span (\ 10 years) make them most
suitable for biomedical research (Ingram, 1975;
Hiddleston, 1976). With regard to the lung, this
small primate might well serve for studies of the
adaptive capacity of the respiratory system in
relation to different energetic demands (Weibel,
1973; Taylor and Weibel, 1981; Weibel et al.,
1981, 1987), or to investigate the influence of
adverse environmental factors such as air pollu-
tion on pulmonary structures. A detailed study of
anatomy and histology (at the light microscopy
level) has been done by Surribas and von Lawze-
witch, (1987). So far, however, neither ultrastruc-
tural features nor morphometric data of lung
parenchyma have been published. It was the ob-
jective of this study to qualitatively describe and
quantitatively define the gas exchange apparatus
of marmosets as a basis for further experimental
pulmonary research.
2. Material and methods
The lungs of three marmosets have been
analysed: the basic data of these animals (a gener-
ous gift of Ciba Geigy, Basel) are given in Table
1. The animals have been raised in the primate
center. After induction of deep anaesthesia with
0.1 ml Atropin, 0.5% s.c., 0.5 ml Saffan® (Alfax-
olonum 9 mg, Alfadolon-aceticum 3 mg per 1 ml;
Pitman–Moore), 0.05 ml Valium 10® i.m., the
animals were tracheotomized and a cannula was
inserted into the trachea for instillation of glu-
Table 1
Basic data of marmosetsa
Cj 3518 Cj 3519 Cj 3520
Age (months) 31 32 20
Sex M F F structure, i.e. the surface densities of alveolar and
Mb (kg) 0.300 0.289 0.320
VL (ml) 17.8 18.6 17.8
VL/Mb (ml/kg) 59.3 64.4 55.6
a
Mb, body mass; VL, volumes of fixed lungs as determined
by volumetry; VL/Mb = mass specfic lung volume.
taraldehyde into the lung. The lungs were fixed
using the standard technique (Weibel, 1970, 1970/
71, 1980, 1984). After laparotomy, a pneumotho-
rax was set on either side by incision of the
diaphragm. The collapsed lungs were then in-
stilled with a 2.5% potassium phosphate buffered
glutaraldehyde solution (pH 7.4, total osmolarity
350 mOsm) at a constant pressure head of 25 cm
water above the sternum. At the end of the instil-
lation the tracheal cannula was tightly ligated to
maintain the intrapulmonary fixative volume. Af-
ter a period of 20 min, the chest organs were
removed in toto and completely submerged in
glutaraldehyde solution for several days. Finally,
the lungs were seperated from the other chest
organs, and the volumes of right and left lung
determined separately by volumetry (Scherle,
1970). Both right and left lungs of each animal
were embedded in gelatin (ordinary quality),
placed in a tissue slicer, and cut into five to seven
equidistant slices, apical to basal (Michel and
Cruze-Orive, 1988). Randomly selected blocks
from each slice were processed for light, transmis-
sion and scanning electron microscopy following
standard procedures (Weibel, 1984). Morphomet-
ric analysis of level I and II (Weibel, 1980) were
skipped. Considering the data obtained in other
species of mammals, a volume of non-par-
enchyma of 15% of the total lung volume was
assumed (Burri and Weibel, 1971; Gehr et al.,
1981a; Weibel et al., 1981). This assumption may
introduce a negligible error for lungs fixed with
the standard procedure (Weibel et al., 1981). For
level III morphometry 1 mm sections were cut
from four different Epon blocks from each slice
and stained with toluidine blue. Using an auto-
matic sampling stage microscope (Weibel, 1970)
provided with a multipurpose test system M100
(5), :200 fields per lung were analysed at a
magnification of 400× for estimating the volume
density of alveolar septa in parenchyma.
At level IV the parameters of internal septal
capillary surfaces, the volume densities of capil-
laries and red blood cells, the volume densities of
septal tissue and its components (endothelial and
epithelial cells, interstitial space), and the har-
monic mean thickness of the tissue and the
 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177
Fig. 1. Light microscopy of alveolar lung.
plasma barriers were estimated on transmission
electron micrographs (at least 100 pictures per
lung) with a magnification of 10 000× using a
coherent square lattice test system. The variables
obtained by point counting, and intersection and
intercept counting allowed the computation of the
alveolar and capillary surfaces, the volumes of
capillaries and septal tissue, the hematocrit in
lung capillaries, the mean harmonic thickness of
the tissues and the plasma barrier, and hence of
the diffusion capacity (Weibel, 1970, 1970/71,
1980, 1984). For the estimation of the diffusion
capacity of the lung the traditional model with
three resistances in series was used (Weibel, 1970,
1970/71): tissue barrier (t), blood plasma barrier
(p), and erythrocyte (e).
1
/DL = 1/Dt + 1/DP + 1/De
where
Dt = Kt · (SA +Sc)/2tht
DP =KP · Sc/thp
De = u · Vc
169
where (SA denotes total alveolar surface area; Sc
total capillary surface area; Vc capillary volume;
tht, thp harmonic mean thickness of tissue and
plasma barrier; Kt, KP permeability coefficients
for O2 (both are assumed to be equal with 5.5 ×
10 − 10 cm2 sec − 1 mmHg − 1); and u the rate of O2
binding by whole blood which amounts to 0.1193
mlO2 (ml sec mmHg) − 1 times the morphometric
hematocrit (Weibel et al., 1981).
3. Results
3.1. Qualitati6e findings
There is a general similarity in the architecture
and structure of lung parenchyma between mar-
mosets and other mammals, and in particular
human lungs (Figs. 1–3). Small ‘islets’ of cartilage
occasionally can be observed in the walls of termi-
nal and even respiratory bronchioles (Fig. 4), a
finding which is well known in monkeys (Surribas
and von Lawzewitch, 1987; Tyler et al., 1988). As
to the three-dimensional configurations of these
cartilages, serial sections reveal that they are cres-
170 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177

Fig. 2. Electron micrograph of alveolar septa of marmosetlung. Note the high variability in shape of red blood cells.

Fig. 3. Scanning electron micrograph of peripheral air spaces (alveolar duct and alveoli) of marmoset lung.
 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177
Fig. 4. Peripheral airway (bronchiolus) with cartilage (heavy
arrow). Note that the bronchiolus is partially lined by capil-
laries (thin arrows). B: lumen of bronchiolus; A: alveoli.
cent-shaped. Occasionally, they form almost
closed rings. As in other species of monkeys, too,
the respiratory bronchioles are highly alveolar-
ized. Capillaries are frequently observed in the
walls of respiratory bronchioles and occasionally
bulge into the bronchiolar lumen (Fig. 4; Castle-
man et al., 1975; Tyler et al., 1988). Two further
particularities seem worth mentioning. First, the
pores of Kohn are conspicuously numerous, in
fact, the alveolar surface has a quite similar ap-
171
pearance as that observed in dog lungs (Fig. 5;
Weibel et al., 1981). Second, the shape of red
blood cells is conspicuous in that mono-concave,
cup-shaped erythrocytes prevail (Fig. 6). This ex-
plains the high variability in shape of cut erythro-
cytes on transmission electron micrographs (Figs.
2 and 7).
It is noteworthy that conspicuous differences in
the septal structure between animal Cj 3520 and
the other animals could be observed. Although all
three animals appeared to be ‘clinically’ healthy,
the capillary blood volume and hematocrit ap-
peared to be considerably lower in animal Cj 3520
(Fig. 7B); accordingly, capillary walls are less
distended as illustrated by frequent wrinkles of
the fused basement membranes, i.e. in the thin
parts of the blood gas barrier (Fig. 7C).
3.2. Quantitati6e findings
The morphometric data are given in Tables 2
and 3. It has to be noted that animals with about
the same body mass and lung volumes were cho-
sen such that a size adjustment was not required
for a comparison of the individual morphometric
data (Table 1). Accordingly, the volumes of the
tissue components of fine lung parenchyma, i.e.
the volumes of interstitium, and those of the
endothelial and epithelial cells were found to be in
a comparable range (Table 2). However, between
animals Cj 3518 and 3519 on the one hand, and
animal Cj 3520 on the other, there are consider-
able differences in the capillary volume, the capil-
lary hematocrit as estimated by morphometry,
and also in the capillary and alveolar surface
areas. These latter morphometric parameters es-
sentially determine the oxygen diffusing capacity
as an important index of the structure-function
relationship of lung parenchyma, and conse-
quently, the diffusing capacity was found to be
substantially lower in animal Cj 3520 (Table 3).
4. Discussion
A drawback of this study is the small number
of mammals examined. In fact, both regulative
and financial restrictions for experiments with pri-
172 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177

Fig. 5. Scanning electron micrograph of alveolar surface with dense network of capillaries protruding in the alveolar space. Note the
numerous pores of Kohn.

mates precluded the sacrifice of a larger number this species. It is noteworthy that even the alve-
of animals. Moreover, the sample appears to be olar size as estimated from the alveolar surface to
inhomogeneous. Since all animals were young volume ratio is quite similar to that of other
adults (age 20–31 months, average life-span 12
years) however, and since sex differences of lung
structure have never been detected in any species
of mammals so far, the differences with regard to
age and sex should not introduce an important
bias.
It was not a hypothesis of this study that the
building blocks of the marmoset lung are consid-
erably different from those of other mammals. In
fact, both morphologic and morphometric find-
ings show that the architecture and fine structure
of the pulmonary gas exchange apparatus of mar-
mosets are well comparable with those of other
mammalian species inclusive man (Weibel, 1973;
Gehr et al., 1978; Weibel et al., 1981). Obviously, Fig. 6. Scanning electron micrograph of alveolar septum seen
the concept of relative invariance of the building both in section and surface view. Note the particular mono-
blocks of fine lung parenchyma holds true also for concave, cup-shaped red blood cells.
 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177
Fig. 7. Differences in capillary appearance between animals Cj
3518 and 3519 on the other hand, and anemic (and probably
also hypovolumic) animal Cj 3520 on the other. (A) Animal Cj
3518 with high capillary hematocrit. (B) Low capillary hemat-
ocrit and volume in animal Cj 3520. Note the wrinkles in the
thin part of the blood-gas barrier (arrows). (C) Higher mag-
nification of barrier pleats in the same lung (arrows). EN:
nucleus of endothelial cell; E: erythrocyte.
primates ((Macacus irus (Gehr et al., 1981b), man
(Gehr et al., 1978)) in spite of considerable differ-
ences in body size and mass. However, differences
in the architecture of fine lung parenchyma be-
tween different species have been observed which
173
affect the oxygen diffusing capacity as an index of
the conductance of the flow of oxygen from the
alveolar air into the erythrocytes in the pul-
monary capillaries. Thus the morphometric deter-
mination of the diffusing capacity has been
applied for assessing structure-function relations
in the normal human lung (Gehr et al., 1978), and
adaptive variations in the mammalian respiratory
system in relation to energetic demands (Weibel et
al., 1987).
A comparison of the data shows that with
regard to this latter key-variable there is a consid-
erable difference between the animals Cj 3518 and
3519 on the one side, and animal Cj 3520 on the
other (Table 3). Three possibilities have to be
considered for an interpretation. First, one has to
scrutinize for problems of tissue preservation, or
fixation, respectively. An analysis of the vast num-
ber of slices shows, however, that the quality of
tissue preservation and fixation is well comparable
between the three animals. The ultrastructural
findings are well in line with previously etablished
criteria (Mathieu et al., 1978; Bachofen et al.,
1982; Weibel et al., 1982; Bachofen and Bachofen,
1990). Amongst other criteria the cellular and
subcellular elements were well preserved (Fig. 7A,
B), the cell barriers were intact, and there were no
signs of hemolysis. Furthermore, the morphomet-
ric data of tissue components (endothelial and
epithelial cells, interstitial tissue) were in a com-
parable range. Second, one has to question
whether animal Cj 3520 has suffered from an
inapparent lung disease. This hypothesis seems
remote in that neither inflammatory, nor fibrotic,
nor other pathological lesions could be observed.
And third, one might argue that the variations are
about the same as those observed in human lungs
(Gehr et al., 1978) being consistent with truly
individual differences of structural elements of
lung parenchyma, i.e. in differences of lung
growth.
However, some structures are by no means
invariable, but their dimensions and arrangement
are influenced by functional factors within the
structure-function relationship of the lung. Sev-
eral studies have examined quite different aspects
of this relationship, and in particular the func-
tional variability of the diffusing capacity (Weibel
174 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177

et al., 1973; Bachofen et al., 1983; Bur et al.,
1985), which has to be considered as a key
parameter for assessing the difference between
normal and pathological conditions of the gas
exchanging apparatus. As shown by the formula
in the method section, this morphometric parame-
ter is dependent on several morphometric vari-
ables such as alveolar and capillary area, capillary
volume, capillary hematocrit, and the thickness of
the gas-blood barrier. At this point, an important
methodic fact has to be called to mind. The lungs
of all three animals have been fixed using the
standard technique (Weibel, 1984), which is instil-
lation of a suitable fixative into the airways of a
collapsed lung. Lung instillation is usually started
before circulatory arrest, and it has been shown
that this procedure causes a significant increase in
capillary hematocrit and correspondingly in mor-
phometric estimates of diffusion capacity (Bur et
al., 1985). Furthermore, there is firm evidence that
the circulatory state, and in particular the pul-
monary capillary pressure and the hematocrit at
the time of fixation significantly affects important
parameters of alveolar and septal dimensions, and
hence the estimates of diffusing capacity (Weibel
et al., 1973; Vock and Weibel, 1993).
A comparison of animals Cj 3518 and 3519
with animal Cj 3520 suggests that the latter was in
a state of circulatory or hemorrhagic shock at the
time of fixation, in that both the capillary volume
and the capillary hematocrit were abnormally low
(in healthy marmosets the large vessel hematocrit

Table 2
Morphometric parameters of tissue and capillariesa

Cj 3518 Cj 3519 Cj 3520 Mean9SD

Vv (s, fp) 0.150 0.116 0.101 0.122+ 6 0.025

V(s) (ml) 2.27 1.83 1.48 1.86+ 6 0.40
V(c) (ml) 1.27 1.13 0.63 1.01+6 0.34
V(t) (ml) 1.00 0.70 0.85 0.85+ 6 0.15
V(ep) (ml) 0.33 0.24 0.27 0.28+ 6 0.05
V(end) (ml) 0.24 0.17 0.22 0.21+ 6 0.04
V(int) (ml) 0.43 0.29 0.37 0.36+ 6 0.07
S(A) (cm2) 9052 6925 5810 7262+ 6 1647
S(c) (cm2) 7308 6403 4289 6000+ 6 1549
t (mm) 1.105 1.011 1.463 1.193+ 6 0.239

a
Vv(s, fp), septum volume per volume of fine parenchyma (alveolar air and septa); V(s), volume of alveolar septa; V(c), capillary
volume; V(t), tissue volume; V(ep), volume of epithelial cells; V(end), volume of endothelial cells; V(int), volume of interstitium; S(A),
alveolar surface area; S(c), capillary surface area; t, V(t)/S(A), mean tissue thickness.

Table 3
Estimated diffusing capacities of measured lungsa

Cj 3518 Cj 3519 Cj 3520 6 SD

Mean+

Vv(ec, c) 0.54 0.50 0.310 0.45 9 0.12

tht (mm) 0.502 0.385 0.6180 0.517 9 0.117
thp (mm) 0.095 0.113 0.1470 0.118 9 0.026
uO2 mlO2 (ml sec mmHg)−1 0.0648 0.0602 0.0376 0.0542 90.0146
DMO2mlO2 (sec. mmHg)−1 0.0778 0.0731 0.0369 0.0626 90.0224
DeO2mlO2 (sec. mmHg)−1 0.0819 0.0686 0.0244 0.0583 9 0.0301
DLO2mlO2 (sec. mmHg)−1 0.0397 0.0353 0.0146 0.0299 90.0134
DLO /Mb mlO2 (kg sec mmHg)−1
2
0.132 0.122 0.0460 0.100 9 0.47

a
Vv(ec, c), morphometric hematocrit; tht, thp, harmonic mean thickness of tissue (t) and plasma (p); uO2, rate of oxygen uptake
by whole blood; DMO2, membrane oxygen diffusing capacity; DeO2, oxygen diffusing capacity into erythrocytes; DLO2, pulmonary
oxygen diffusing capacity.
 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177
Fig. 8. Allometric plot of Weibel between diffusing capacity
and body mass observed in mammmals (from Gehr et al.,
1981a). For particular comparison, note the values of diffusing
capacity in primates, i.e. man, monkey (Macacus irus) and
marmoset.
is between 44 and 52% (Hiddleston, 1976); the
capillary hematocrit probably is somewhat lower
(Aarseth, 1971; Sarelius and Duling, 1982)). The
cause of the circulatory problem of this appar-
ently healthy animal is not clear. However, nei-
ther a circulatory shock with splanchnic pooling
upon induction of anaesthesia, nor a hemorrhagic
shock due to an inadvertent lesion of a large vein
during preparation (laparatomy and bilateral inci-
sion of the diaphragm), nor a bleeding event
before the experiment, can be excluded (the large
vessel hematocrit has not been determined before
lung instillation with glutaraldehyde). In any case,
the morphometric results are well explainable in
view of previous experimental observations (Vock
and Weibel, 1993): the reduction of capillary vol-
ume observed in animal Cj 3520 resulted in a
similar decrease of the gas exchanging surface
area, a thickening of the blood-gas barrier, and
together with the low hematocrit in a substantial
reduction of the pulmonary diffusing capacity,
although the structural components of the lung
were normal. Thus, the present finding and the
data of Vock and Weibel (1993) obtained in rats
175
with hemorrhagic shock illustrate two important
problems to be considered for the morphometric
evaluation of lung parenchyma. First, in some
situations the ‘standard’ method of lung fixation
might not be standardized enough, but both mon-
itoring and control of the circulation prior to
fixation may prove necessary to ensure compara-
ble results. Second, a safe distinction between
normal and (subtle) pathologic conditions re-
quires an analysis at the electron microscopic level
which allows a quantitative assessment of invari-
able structures such as number and volumes of
cells and variable structures such as the capillary
volume and hence the septal volume and surface
area.
As to the gas exchange capacity of marmoset
lungs as reflected by the diffusing capacity, the
present findings fit well into the allometric plot of
Gehr et al. (1981b)Fig. 8). However, the log-log
plot obscures to some extent the differences be-
tween species. In fact, a comparison with mam-
mals of similar body mass (rats and quinea pigs)
shows that marmosets have a high pulmonary
conductance for oxygen (average DLO2/Mb of rats
(n= 3) 0.04, of guinea pigs (n= 15) 0.042, versus
0.100 mlO2 (kg·sec·mmHg) − 1 of marmosets. The
high capacity appears to be due, above all, to the
large lung size of marmosets. Whether this feature
reflects an adaptive variation of the respiratory
system to high energetic demands of this species
(Karas et al., 1987), is open to speculation. Obser-
vations of the activities suggest that marmosets
are a rather ‘athletic’ species. However, there are
no data of the oxygen demand, and specifically,
the maximal oxygen uptake of marmosets have
not yet been measured.
In conclusion, the present analysis shows that
the pulmonary gas exchange apparatus of mar-
mosets is well comparable with that of other
mammals inclusive man, and this with regard to
the architecture and fine structure, the dimensions
of the structural and functional units, and hence
the functional capacity. However, when compared
with mammals of similar body mass, lung vol-
umes and hence the gas exchange capacity appear
to be somewhat larger in marmosets. The inciden-
tal observation of a rather large individual differ-
ence in morphometric estimates of pulmonary
176 A. Barbier, H. Bachofen / Respiration Physiology 120 (2000) 167–177
diffusing capacity could be explained by the find-
ings of recent experiments (Vock and Weibel,
1993): evidently some morphometric parameters
are rather sensitive to the state of the circulation,
the blood volume, and the hematocrit at the time
of lung fixation. This implies that the standard
method of lung fixation should be improved by
monitoring of the circulation at the time of
fixation.
Acknowledgements
The generous gift of Ciba-Geigy, Basel, the help
of the careholders in professionally anaesthetizing
the animals, and the support given by Karl Babl,
U. Gerber, and M. Urbinelli are gratefully
acknowledged.
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