Vol. 93, Issue 2, 629-635, August 2002
Postnatal alveolar development of the rabbit
Jana
Kovar1,2,
Peter D.
Sly1,3, and
Karen E.
Willet1
1 Centre for Child Health Research, University of
Western Australia, Perth, Western Australia, 6872; and
2 Department of Anatomy and Human Biology and
3 Department of Paediatrics, University of Western
Australia, Perth, Western Australia, 6907 Australia
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ABSTRACT |
Previous studies
of alveolarization have used rats or lambs; however, neither closely
reflects human alveolar development. We characterized alveolar
development in rabbits (n = 3-7 /group) at 28 days
gestation (dg) to 9 mo to determine whether they followed the human
pattern more closely. The right lung was made up of 30% alveolar and
50% duct space at 28 dg to 3 days and of 50 and 30%,
respectively, at 14 days to 9 mo. Tissue fraction and alveolar wall thickness decreased by 40% 28 dg to birth. At birth, ~4.5% of
the number of alveoli seen at 9 mo were present, with alveolar number
increasing progressively well into adulthood. The rate of alveolar
formation was high around birth, decreasing progressively with age.
Alveolar volume increased more than twofold (28 dg to birth) and
continued to increase postnatally to 16 wk. Surface fraction decreased
by 17% (28 dg to 3 days), after which it remained uniform. Our
findings suggest that the timing of onset of alveolarization in humans
and rabbits is similar and that rabbits may be used to model postnatal
influences on alveolar development.
alveolar number; alveolar volume; alveolar wall thickness; surface
fraction
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INTRODUCTION |
ALTHOUGH STUDIES OF LUNG
GROWTH and development in humans are limited by the availability
of normal lungs, ~10% of alveoli are thought to be present at birth
(3). However, the end point of alveolar formation remains
unclear, with estimates ranging from 6 mo to 8 yr of age (7, 10,
34, 35, 38). The small sample size and the apparently large
variation in the total adult number of alveoli (200-600 million)
(34) have limited definitive conclusions. Rats and sheep
are commonly used as models for human postnatal alveolar development;
however, the majority of rat alveoli are formed entirely postnatally in
the first 2 wk of life (4, 5), and sheep already have most
of their alveoli at birth (8). Thus, in terms of the
timing of onset of alveolarization, the rat and sheep may not be the
most suitable model for postnatal human alveolar development.
The rabbit has been used extensively in respiratory research as a model
for studying the impact of antenatal steroids (12, 27, 28)
and surfactant replacement (9, 11, 14-16, 19, 21) and
for the comparison of lung mechanics between immature and mature lungs
(17, 22-24, 29-33). The aim of this study was to
comprehensively characterize the postnatal alveolar development of the
rabbit and to determine whether it may be a suitable model for human
postnatal alveolar development.
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MATERIALS AND METHODS |
Tissue preparation and sampling.
This protocol was approved by the TVW Telethon Institute for Child
Health Research animal experimentation committee. New Zealand White
rabbits (n = 3-7 per group) between 28 days
gestation (dg) and 9 mo of age were weighed and given a lethal overdose
(5 ml/kg ip) of pentobarbital sodium (325 mg/ml). The age groups
studied were 28 dg, birth, 1 day, 3 days, and 1, 2, 4, 6, 8, 12, 16, 24, and 36 wk. Lungs were excised, and inflation was fixed overnight with 4% paraformaldehyde at 20 cmH2O. Fixed lung volume
(FLV) was measured by volume displacement (20). The right
lung was removed and divided into the anterior azygos and right
anterior and right posterior lobes. A sample was systematically removed in the sagittal plane from the center of each lobe. All morphometric measurements were performed blind on 5-µm hematoxylin- and
eosin-stained sections.
Volume fractions.
Volume fractions of lung parenchyma [parenchymal fraction (PF)]
(alveoli and alveolar ducts), nonparenchyma (conducting airways and
blood vessels), and pleura were estimated from photographic enlargements ×23 of 5-µm sections by superimposing a cycloid point counting grid (74 lines/148 points). Volume fraction is defined as Pi/Pt, where
Pi is the number of test points in contact with
the structure of interest (e.g., parenchyma) and Pt is the
total number of points hitting the reference space (total of all
compartments). Parenchymal volume (PV) in the right lung was derived
from fixed lung volume as follows
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Parenchymal morphometry.
A Sony 3CCD color video camera interfaced with a Leica DMLS microscope
and a Macintosh 8100/80AV computer were used to capture 10 random
nonoverlapping digitized images from each 5-µm section. The final
magnification of the images was ×220. A linear point counting grid (21 lines/42 points) was superimposed onto the images, and the number of
points falling on alveoli, ducts, or septal tissue and the number of
air-tissue tissue-air intercepts were counted. Alveolar (AF),
duct (DF), and tissue fractions (TF) were calculated by using
Pi/Pt. In transverse
sections, alveoli were identified as those structures opening onto a
common airspace (alveolar duct). The relative size and the presence of
secondary alveolar septa distinguished alveolar ducts from
alveoli. In cross sections, alveoli were identified on the basis of
size (~50-150 µm; see Fig.
1) and shape (circular).
Irregular or ambiguous structures (on average 8%) were rejected. The
total number of alveoli (NT) in the right lung was
calculated by the following formula
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where NV is the number of alveoli per
unit volume. The method described by Weibel (37)
was used to calculate the alveolar numerical density by the following
formula
where NA is number of alveoli per unit
area, 
is a shape constant describing alveolar shape (1.55), and
D is a distribution variable of the characteristic linear
dimension of the alveoli (equal to 1). The average alveolar volume for
each age group was calculated by
The average surface area of alveoli (SAA) was
determined by multiplying the surface fraction by lung volume and the
PF
where
where Io is the number of intercepts with the air
tissue interface, NL is the number of test
lines, LL is the length of the test line within
the reference volume, and NF is the number of fields counted.
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Fig. 1.
Representative photomicrographs of 5-µm hematoxylin- and
eosin-stained sections of the right lung at 28 days gestation (dg)
(A), 7 days (B), 4 wk (C), and 6 mo (D) of age. Scale bars = 100 µm.
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Alveolar wall thickness was estimated as volume per unit area of
alveolar surface according to the formula TF/SV, where TF is the volume fraction of alveolar wall tissue.
The data from each of the three lobes of the right lung were pooled,
and the means ± SD were derived for each age group. The effect of
age on lung development was assessed by using a one-way ANOVA; in cases
in which the data did not pass either a normality or an equal variance
test, a Kruskal-Wallis one-way ANOVA on ranks was performed.
Significance was accepted with a P < 0.05.
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RESULTS |
Body weight increased exponentially over the age range studied,
with the highest rate of increase after 4 wk of age (Fig. 2A). Right lung volume (Fig.
2B) increased 20-fold between birth and 16 wk
(P = 0.001), plateauing thereafter. Specific lung
volume (lung volume/body wt) (Fig. 2C) decreased rapidly
during the first few postnatal weeks and did not change after
4-6 wk.
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Fig. 2.
A: growth. Body weight recorded at time of
death. B: lung growth. Right lung volume measured by volume
displacement. C: specific lung volume. Ratio of right lung
volume to body weight. Data are means ± SD for animals between 28 dg and 9 mo of age. Age*, x-axis is log10 of
(age + 10) in days. Note that at 9 mo animals weighed 5,000+ g.
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Morphometric changes around birth.
Between 28 dg and birth, there was an increase in the percentage of
lung made up of alveolar ducts from 30 to ~50%. The volume fraction
of alveoli remained at ~30% until postnatal day 3 (Fig. 3A). Both wall tissue volume
in the right lung and alveolar wall thickness decreased by 40% between
28 dg and birth (Fig. 3, B and C, respectively)
(P = <0.001). Alveolar volume increased more than
twofold in the last 3 days of gestation (see Figs. 1 and 5).
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Fig. 3.
A: alveolar and duct fractions. Percentage of
the right lung that is made up of either alveolar ( ) or
duct ( ) space. B: tissue fraction.
Percentage of the right lung that is made up of tissue space.
C: alveolar wall thickness. Alveolar wall thickness
estimated for the right lung. Data are means ± SD for animals
between 28 dg and 9 mo of age.
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Postnatal changes in morphometry.
From 3 days to 1 wk, the proportion of alveolar and duct space changed,
and by the second week the proportion had reversed, with ~50% of the
right lung now comprising alveolar space and only 30% comprising duct
space (Fig. 3A; see Fig. 1). Between birth and 9 mo of age,
the percentage of tissue in the right lung was relatively constant at
~22% (Fig. 3B). After birth, wall thickness increased
progressively (by 36% from birth) until a maximum was reached at
6 wk (P = <0.001). Between 6 wk and 9 mo of age,
alveolar wall thickness dropped by 30% (P = 0.005)
(Fig. 3C).
Total alveolar number (Fig.
4A) appeared to increase
progressively over the age range studied (see Fig. 1) (Kruskal-Wallis ANOVA, H = 69.966, df = 12, P < 0.001).
However, between 28 dg and birth, alveolar number decreased
significantly (P < 0.05). The increase in alveolar
number between 28 dg and 9 mo was described by a logarithmic equation
as follows
The rate of change in alveolar number with age (as described by
the derivative of the above equation) is shown in Fig. 4B.
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Fig. 4.
A: total alveolar number. Total number of
alveoli estimated for the right lung. B: rate of alveolar
formation. Rate of change in alveolar number with age. C:
total alveolar number/body weight. Alveolar number in the right lung
standardized for body weight. Data are means ± SD for animals
between 28 dg and 9 mo of age.
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When standardized to body weight, alveolar number (Fig.
4C) decreased rapidly between 28 dg and postnatal week
4, thereafter remaining relatively constant (P = 0.051).
Average alveolar volume was quite variable at all ages and postnatally
continued to increase to 16 wk of age (P = <0.001) (Fig. 5, Fig. 1).
Total alveolar surface area in the right lung increased progressively
over the age range studied. Between 28 dg and the first week of life,
surface area doubled (P = <0.001) and continued to
increase a further 10-fold between the first week and 9 mo (P = <0.001) (Fig.
6A). The specific surface area
(surface area/body wt) showed a similar pattern to specific lung volume
and specific alveolar number, with a rapid decline between birth and 4 wk (P = <0.001), not changing thereafter
(P = 0.066) (Fig. 6B). Surface area
per unit volume of lung parenchyma, or surface fraction (Fig. 6C), decreased by 17% between 28 dg and 3d, after which it
remained fairly uniform over the age range studied.
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Fig. 6.
A: alveolar surface area. Total surface area
of alveoli estimated for the right lung. B: alveolar surface
area/body weight. Alveolar surface area in the right lung standardized
for body weight. C: surface fraction. Surface area per unit
volume estimated for the right lung. Data are means ± SD for
animals between 28 dg and 9 mo of age.
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DISCUSSION |
Rabbits are commonly used in respiratory research in studies
modeling human lung development, premature infants, and respiratory diseases. However, little is known about the normal pattern of lung
development in this species. The aim of the present study was to
comprehensively characterize the postnatal alveolar development of the
rabbit to determine whether it is an appropriate model for human
postnatal alveolar development.
Lung volume.
Right lung volume (Fig. 2B) plateaued at 16 wk of age,
having increased 20-fold from birth. This finding is consistent with a
review by Thurlbeck and Angus (36) who reported a 26-fold increase in lung volume in humans between birth and adulthood, with the
greatest rate of growth being in the first 2 yr. Interestingly, in the
present study, specific lung volume (Fig. 2C) decreased rapidly between birth and 4 wk and then plateaued. The rapid decline in
specific lung volume during the first postnatal month indicates that
the increase in body weight greatly exceeds the increase in lung volume
during this time. This is followed by a period in which the lung volume
and body weight increase in proportion to one another. Burri et al.
(6) found that, in rats, lung volume varies almost
directly with body weight for the first 10 days of life, but thereafter
lung volume increases more slowly (to the 0.7th power) than body weight.
Lung morphometry.
The percentage of the right lung that was made up of alveolar duct
decreased from ~50 to 30% by 2 wk of age and remained at this
proportion over the age range studied (Fig. 3A). This
decrease in duct fraction reflects the bulk alveolar formation that
occurred between day 3 and 2 wk of age (increase from 30 to
50% alveoli). Interestingly, duct fraction increased before it
decreased (35 to 50% between 28 dg and birth, at which level it
remained until almost 1 week of age) suggesting a surge in duct
formation in late gestation. This is also paralleled by a significant
reduction in alveolar number between 28 dg and birth (Fig.
4A).
In the present study, we found that alveoli continued to form
progressively well into adulthood (Fig. 4A). Although total alveolar number increased, alveolar airspace fraction within the lung
remained unchanged after 1 wk of age. Intuitively, then, the number of
ducts present must also be proportionately increasing in either number
and/or size. This would challenge what we know about lung development
from rat studies because these suggest that ducts stop forming soon
after birth and any alveolar formation beyond 2 wk of age does
not involve septation of ducts but by an as yet unidentified mechanism
(13). In 1950, Short (25) found that the
formation of septa in rabbits ceases some time between the 10th day and
the 3rd month after birth; however, this observation came from indirect
and outdated measurements on perfused rather than on inflation-fixed
lungs (via the trachea) at a constant pressure.
The rat has been used extensively as a model of lung development. At
birth, the rat lung is predominantly made up of ducts and saccules
(immature alveoli). Within a discrete 9-day period beginning 4 days
after birth, bulk alveolar formation takes place (4, 5).
This process is regulated by glucocorticoids and is sensitive to
exogenous glucocorticoid, as Massaro's studies have shown
(13). During this period, alveoli form via
septation and elongation of secondary septa, followed by vascular
maturation (5). Parallel to this is another type of
alveolar formation that continues through to adulthood
(13). This second type of alveolar development does not
appear to be hormone sensitive and does not involve the classic
processes of septation (1). It is possible that this
phenomenon occurs in the rabbit because our data show that alveoli
continue to increase well into adulthood.
Surface fraction (Fig. 6C) decreased slightly until 3 days,
after which time it remained uniform. With lung volume and surface area
increasing continually over the age range studied, this would suggest
that new alveoli are continually formed to maintain an equal surface
density over time. As an individual grows, the oxygen demands become
greater; hence, there is a need for the alveolar surface area to
increase appropriately with age (Fig. 6A).
Alveolar wall thickness (Fig. 3C) showed a transient drop of
40% between 28 dg and birth, coinciding with the prenatal fall in
tissue fraction (also 40%) (Fig. 3B), followed by a gradual rise to a maximum at 6 wk. This indicates that a large proportion of
wall thinning occurs before birth in the rabbit. This is in contrast to
rat studies, which show that alveolar wall thinning follows septation,
in the second to third week after birth. The overall tissue mass is
thought to decrease dramatically as secondary septa elongate to form
alveoli and as the microvasculature matures (4, 5). It is
possible that this phenomenon is ongoing in the rabbit because new
alveoli are continually being formed, but perhaps our methods are not
sensitive enough to detect these subtle changes. Early in postnatal
development we do show evidence that the new alveoli that are being
formed are thick walled to start with and thin gradually over time.
This can be seen from the changes occurring between days 3 and 7, when a surge in alveolar formation (70% increase in
alveolar number) coincides with a 24% increase in wall thickness.
After this time, however, the lower rate of increase in alveolar number
were not associated with a detectable change in wall thickness.
Both the increase in alveolar number and the increase in alveolar size
during development contribute to an increasing alveolar surface area.
We found that alveolar volume increased more than twofold from 28 dg to
birth and continued to increase postnatally to 16 wk of age. The
largest increase in size occurred between the first and second week
(Fig. 5).
The rabbit would appear to be an appropriate model for studying the
onset of alveolarization in humans. Data from our present study show
that at birth rabbits have ~4.5% of the number of alveoli present at
9 mo. We found the rate of alveolar formation was highest around birth
and decreased progressively to 9 mo of age (Fig. 4B). There
is, however, more doubt about the suitability of the rabbit for
modeling the cessation of alveolarization. Human studies have suggested
that the end of alveolarization occurs anywhere between 6 mo and 8 yr
of age, with Thurlbeck (35) suggesting that there is a
period during which the bulk of alveoli form (0-2 yr) followed by
a period of slower addition of alveoli. The data from the present study
suggest a progressive increase in the number of alveoli well into
adulthood. However, our aim was to determine the suitability of the
rabbit as a model of alveolar development in early life, to study the
effects of potential adverse influences on normal lung growth and development.
There are several limitations to the morphometric techniques we have
used that need to be considered. The first is that we are extrapolating
three-dimensional structures (alveoli) from two-dimensional sections.
This limitation could introduce possible errors relating to differences
in alveolar size. The probability of a structure appearing in any
two-dimensional plane is proportional to its size whereby the larger
the structure, the greater the likelihood of it appearing in an image
or section (26). Our counting is therefore biased in favor
of larger alveoli, and alveolar number may be overestimated in lungs
with larger alveoli and conversely may be underestimated in lungs with
small alveoli.
On the whole, the number of alveoli that we count per counting frame is
similar (ranging from 25-35) after birth. On average we count 30 alveoli in a given area (0.35 mm2). If we overestimate this
count by 5%, total alveolar number will change by 7.5% (i.e., 1.6 vs.
1.7 million). If a 10% error occurs, this will change the total
alveolar number by 15% (i.e., 1.6 vs. 1.8 million). We observed that
the total alveolar number increased from ~2 million to 43 million
over the age range we examined; hence, errors of a few hundred thousand
may change the overall magnitude of our data. However, we would not
expect the overall pattern of development to change.
Furthermore, we make assumptions on alveolar shape on the basis of
values derived from the mature lung, which may also lead to errors in
estimates of alveolar number (37). The shape coefficient () relates volume to cross-sectional area and is inversely related to 
, the ratio of diameter to length (height) (37). In
immature (shallow) alveoli, in which the ratio of diameter to height is large, would be expected to be smaller. Using a shape coefficient devised for mature lungs in young animals may therefore lead to an
overestimation of alveolar number. On the other hand, Randell et al.
(18) measured and calculated alveolar shape constants for
rats at birth, at 7 and 21 days, and after hyperoxic treatment by using
the three-dimensional serial reconstruction technique and found no
significant differences despite marked changes in alveolar size. This
would imply a proportional growth of alveolar diameter with respect to
septal height. This evidence of an alveolar shape "template" was
also supported by Blanco and Frank (2), who said that
alveoli are formed by a predetermined shape (close to a hemisphere) and
that any enlargement with time is isotropic. Hence, there is still some
debate as to the extent (if any) that changes in alveolar shape may
have on morphometric measurements. There are no published data in
immature lungs either estimating an alveolar shape constant or
examining the appropriateness of = 1.55, and it is difficult
to quantify; however, if there is a change in alveolar shape we would
expect the shape constant to be smaller given that in immature
(shallow) alveoli the ratio of diameter to height is larger. For
example, if the shape constant were to decrease by 5%, this would
translate to an increase in total alveolar number by 5%, and similarly
with a 10% decrease in the shape constant used, a 10% higher total
alveolar number would be calculated.
The assumption that the distribution variable D is equal to
1 may be unlikely in the developing lung given that during this time a
wide variation of alveolar size would be anticipated because of the
simultaneous presence of developed and developing alveoli (35).
In summary, the data from the present study suggest that rabbits may be
a suitable animal model for studying the effects of potential adverse
influences on lung growth in early life.
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ACKNOWLEDGEMENTS |
We thank Medical Research Fund of Western Australia and
the Asthma Foundation of Western Australia for their financial support of this study.
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FOOTNOTES |
Address for reprint requests and other correspondence: J. Kovar, Division of Clinical Sciences, TVW Telethon Institute for Child
Health Research, P.O. Box 855, West Perth, Western Australia, 6872 (E-mail: janak{at}ichr.uwa.edu.au).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
April 19, 2002;10.1152/japplphysiol.01044.2001
Received 16 October 2001; accepted in final form 17 April 2002.
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