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Morphometric studies of the alveolar epithelium in dog lungs in vivo after increased rates of outward filtration.

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THE ANATOMICAL RECORD 205:39-45 (1983)
Morphometric Studies of the Alveolar Epithelium in Dog
Lungs In Vivo After Increased Rates of Outward
Departments of Anatomy, Medicine, and Physiology, UMDNJ-New Jersey Medical
School, Newark, NJ 07103
Increased pulmonary artery pressures and decreased albumin
concentrations were established in dogs, in vivo, by circulatory overload and by
plasmapheresis. Each change, occurring singly, would be expected to produce an
increase in outward filtration rate. The ultrastructure of the alveolar epithelium
after the production of this presumed increase in filtration was evaluated by
established morphometric techniques. The extent of extravascular fluid accumulation was assessed by multiple indicator-dilution studies and by light microscopic analysis. Previous studies from this laboratory (DeFouw and Berendsen,
1979; DeFouw, 1980) define increased alveolar surface densities, increased type
I cell vesiculation, and depleted type I1 cell lamellar body contents after increased
filtration had induced septal edema and alveolar flooding in isolated perfused dog
lungs. In the present study septal edema and alveolar flooding were not detected.
Nor were changes observed in either alveolar epithelial cells or in alveolar configurations. However, there was significant accumulation of extravascular fluid
in cuffs around extraalveolar vessels. These results are consistent with the interpretation that the initial stage of cardiodynamic edema formation, namely, perivascular cuffing, is not associated with structural aberrations of the alveoli or
their lining epithelial cells, in vivo. Since such changes were detected previously
in isolated lungs after development of the final stages of edema, namely, septal
fluid accumulation and alveolar flooding, additional studies of septal edema and
alveolar flooding in intact animals are necessary to establish functional correlates
to ultrastructural aberrations in severely edematous lungs.
Previous studies from this laboratory have
established that severe edema formation in
isolated perfused dog lungs is associated, in
part, with depletion of type I1 cell lamellar body
contents, elevations of alveolar surface densities, and increased vesiculation within type I
epithelial cells and in capillary endothelial cells
(DeFouw and Berendsen, 1979; DeFouw 1980).
That the alveolar epithelium and the surfactant system should be affected in the production of acute pulmonary edema is suggested by
two concepts: (1) that the lamellar bodies of
type I1 cells represent intracellular storage depots of pulmonary surfactant (Chevalier and
Collet, 1972;Massaro and Massaro, 1972; Smith
and Kikkawa, 19781, and (2)that vesicles contribute to macromolecule transport across the
alveolar epithelium (Dermer, 1970). Support
for this view can be found in the report of Harlan et al. (1966) on the detection of 14C-labelled
palmitic acid in tracheal foam from edematous
dog lungs. However, the mechanism whereby
the loss of surfactant to edematous fluid initiates a depletion of type I1 cell lamellar body
contents remains uncertain.
The present investigation describes morphometric analyses of dog lungs, in vivo, after
circulatory overload and plasmapheresis had
presumably produced increased rates of outward filtration from the microcirculation. Thus,
comparisons with the previous studies of isolated dog lungs are made possible.
Filtration rates from the pulmonary microcirculation are generally considered in relation
to the differences between plasma hydrostatic
and osmotic (oncotic) pressures. The importance of corresponding tissue pressures is rec-
0003-276W83/2051-0039$02.50 0 1983 ALAN R. LISS, INC
Received July 2, 1981;accepted Oct. 12,'82.
ognized but cannot be assessed. However, under the present conditions tissue hydrostatic
pressure could be expected to increase and tissue osmotic pressure to decrease. In the first
set of studies of this report hydrostatic pressures were elevated by circulatory overload,
while oncotic pressure remained essentially
unchanged; in the second set, oncotic pressure
was reduced under conditions of relatively stable hydrostatic pressure. Previous studies by
others have been shown that the respective
procedures produce marked elevation in pulmonary lymph flow rates from lungs, in vivo,
in response to a presumed but not directly measured increase in rates of outward filtration
(Uhley et al., 1967; Zarins et al., 1978).
Circulatory Overload Studies
Four mongrel dogs, with body weights of approximately 20 kg were anesthetized with pentobarbital (30 mgkg, IV) and given heparin
(25,000 IU) intravenously. The trachea was
cannulated and the lungs artifically ventilated
with humidified air containing 5% COz with
end-expiratory pressures of 5 cm HzO. A Swan
Ganz catheter was positioned in the pulmonary
artery via the right external jugular vein for
monitoring pulmonary arterial pressures. The
left femoral artery and vein were cannulated
for monitoring systemic arterial and venous
pressures. Indicator-dilutionstudies were carred
out as described elsewhere (Chinard, 1975; Per1
et al., 1976) in order to obtain measures of
tissue water accumulation from the extraction
of tritium oxide (THO) and from the extravascular lung water volume. A Wescor vapor pressure osmometer was used for determining osmolalities and a membrane osmometer was used
for determining oncotic pressures on plasma
samples obtained prior to and after the circulatory overload.
After the initial indicator-dilution run, an
infusion of 4% bovine serum albumin, containing red blood cells adjusted to a hematocrit of
25-30%, was pumped into the right femoral
vein at a rate of 50 cm3 minute-'. ARer approximately 6 liters of the infusion solution
had been administered and a second indicatordilution run had been recorded, the thorax was
opened via midsternal incision and the lungs
were fixed via tracheal instillation. The pulmonary trunk and aorta were ligated simultaneously with the onset of tracheal instillation of 2% glutaraldehye in 0.15 M bicarbonate
buffer at 30 cm HzO pressure. This procedure
was used to avoid artefacts of extravasation of
blood that we have noted when fixation was
initiated without blockage of the pulmonary
Plasmapheresis Studies
Four mongrel dogs, 20 kg approximate body
weight, were anesthetized and artifically ventilated as described in the circulatory overload
studies. Pulmonary arterial pressures and systemic oncotic pressures were also measured as
above. After the first indicator-dilution run,
the right femoral artery was connected to a
roller pump which assisted in bleeding the dogs
at 50 cm3 minute-l for 10-minute periods. The
500 cm3 of withdrawn blood was centrifuged
and the plasma removed. The red cells were
then reinfused as a suspension of 100-cm3cells
in 1,050 cm3 saline into the right femoral vein
a t 50 cm3 minute-'. Six bleedings and subsequent infusions were performed. The thorax
was incised and the lungs fixed as in the circulatory overload studies after the second indicator-dilution run.
Morphometric Analyses
The fixed lungs from the two experimental
groups were immersed in glutaraldehyde overnight and subsequently sampled via a stratified sampling technique which provided 24 tissue blocks from each of the lungs (Weibel, 1973).
A portion of each block was processed for light
microscopy and the remaining portions were
postfixed in 1%osmium tetroxide in 0.15 M
bicarbonate buffer, dehydrated in graded series of ethanols and propylene oxide, and
embedded in Epon. From the primary sample
of 24 blocks, ten blocks were randomly selected
and sectioned on a Sorvall MT2B Ultramicrotome at 70-80-nm thickness. The thin sections
were examined with a Philips 300 transmission electron microscope and micrographs of
the alveolar septa with final magnifications of
x 6,100, x 21,000, and x 81,500 were obtained for the morphometric analyses. Each of
the micrographs was analyzed with a multipurpose stereologic test grid composed of 168
test points and 84 test lines (Weibel, 1973).
Counts of test line intercepts with the alveolar
epithelial surface profiles and counts of test
points falling on type I epithelial cells were
obtained from micrographs a t x 6,100 to provide estimates of alveolar surface densities and
average thicknesses of the type I cells. Point
counting volumetry was used to estimate type
I1 cell organelle volume densities and type I
cell vesicle volume densities from the micrographs at x 21,000 and x 81,500, respectively.
A group of three normal mongrel dogs, approximately 20-kg body weights, were prepared for morphometric analyses in a manner
identical to that described for the experimental
groups. Statistical analyses of the normal and
experimental morphometric parameters were
performed by a one-way analysis of variance.
Comparisonsof the physiological data from the
experimental groups were performed with a
paired t test. For all statistical tests P < 0.05
was accepted as significant.
The multiple indicator-dilution studies were
undertaken in the overload and plasmapheresis series in order to obtain measures of the
increases of extravascular lung water expected
to result from the increased outward filtration.
Two parameters are reported here. The first,
the extraction of THO, indicates the extravascular volume of distribution of water relative
to the vascular compartment volume. This
measure is not affected by recruitment of vessels with extravascular volumes similar to those
of initially perfused vessels. If it increases, there
is fluid accumulation somewhere in the lungs.
In both the overload and plasmapheresis series
such an increase in the extraction of THO was
recorded in each experimental animal; however, the variability of the increases in the overload series was such as to limit the statistical
significance of the differences between the
means of the normal and overload data (Table
5). The second parameter, the extravascular
volume of distribution of water (calculated essentially from the product of the flow of blood
and the difference of the mean transit times of
tracer water and a vascular reference indicator) is expected to increase with recruitment
as well as with the development of edema. In
the overload group extravascular lung water
volume was increased but again with a variability limiting the statistical significance of
the differences between averages of the normal
and experimental data. An increase in extravascular lung water was not recorded in the
plasmapheresis series (Table 5).
In association with changes in the extraction
of THO and of the extravascular lung water
volume, changes in plasma hydrostatic and oncotic pressures in the experimental groups also
indicated increased rates of outward filtration
from the microcirculation. After circulatory
overload, mean pulmonary arterial pressure
increased from an average of 13 mm Hg in
control periods to an average of approximately
38 mm Hg. Colloid osmotic pressure, on the
other hand, remained in the range of 20-23
mm Hg (Table 3). Thus, the substantial increase in differences between hydrostatic and
osmotic pressures would insure an increase in
outward filtration provided that corresponding
moderating changes did not occur in the tissue
pressures. In the plasmapheresis group, mean
pulmonary aterial pressure was maintained a t
approximately 14-15 mm Hg while colloid osmotic pressure was decreased from an average
of approximately 22 mm Hg to a n average of
8 mm Hg (Table 4). Again, increased outward
filtration rates would be expected to occur with
these changes although the increases would be
less in the plasmapheresis group than in the
overload group because of the lesser increase
in the difference between pulmonary artery and
oncotic pressures.
Table 1 presents the stereologic parameters
which were measured on the type I alveolar
TABLE 1 . Average thicknesses of type I epithelial cells, type I cell vesicular volume densities, and alveolar surface
0.26 f .01
Type I thickness (pm)
8.2 f 1.7
Vesicle volume density
(% cytoplasm)
Relative vesicle distributions (% vesicle population)
16 f 5
67 f 8
17 f 4
Alveolar surface density
f 69.6
‘Mean values
one SD
0.25 * ,063
7.7 c 2.5
0.28 f .04
9.1 * 2.9
12 c 7
71 c 8
17 t 5
e 88.5
14 ? 2
69 % 3
17 f 2
f 45.5
epithelial cells. Average thicknesses of the type
I cells were unchanged after either circulatory
overload or plasmapheresis. The volume of type
I cell cytoplasma occupied by vesicles was also
unchanged and was estimated at approximately 8-9% in each of the groups. Moreover,
the intracellular distributions of vesicles were
similar in the normal and experimental groups:
70% of the vesicles were observed to be unattached to the cell surfaces and the remaining
30% were directly attached to either the luminal or abluminal membrane surfaces in the
single plane of tissue section. Table 1also presents the alveolar surface densities, defined as
cm2 alveolar surface per cm3 lung volume, for
the normal and experimental groups. The slight
changes in alveolar surface densities in the
experimental groups were not statistically significant.
Table 2 presents the estimates of organelle
volume densities from type I1 cells of the normal and experimental lungs. Organelle volume densities are defined as the proportion of
type I1 cell cytoplasm occupied by the respective organelles. As indicated, mitochondria1
volume densities were approximately 7-9% in
each case. Volume densities of the rough endoplasmic reticulum, including polyribosomes,
also remained essentially constant at approximately 7-10%. Likewise, the smooth endoplasmic reticulum, including the Golgi complex, occupied approximately &lo% of the type
I1 cell cytoplasm in the normal and experimental groups. The lamellar body volume
densities were decreased slightly from approximately 20% to 17-18% after both the plasmapheresis and circulatory overload procedures.
In addition to the preceding morphometric
results, examination of the alveolar septa demonstrated no fluid accumulation in the alveolar
TABLE 2. Organelle volume densities in the cytoplasm of
type II cells'
9.1 i 1.5
7.1 lr 3.5
Rough ER2
8.6 -c 1.5
Lamellar bodies 20.5 f 0.3
7.0 f 1.1
8.5 i 2.6
8.1 f 2.4
16.6 2 1.5
8.8 i 1.6
9.5 f 2.5
10.8 lr 2.8
18.4 i 2.8
'Mean values one SD.
2ER, endoplasmic reticulum
TABLE 3 . Hydrostatic and oncotic pressures in the
circulatory overload studies'
13.0 _t 1.5
Pulmonary artery pressure
19.5 i 4.3
Colloid oncotic pressure
Resultant pressure difference -6.4 i 2.9
37. C 6.1*
22.5 c 8.5
15.4 C 9.6*
'Mean values (mm Hg) f one SD. The pressure differences were
calculated for each of the runs and these differences were averaged.
'P < 0.05.
TABLE 4. Hydrostatic and oncotic pressures in the
plasmapheresis studies'
Pulmonary artery
Colloid oncotic
Resultant pressure
13.9 i 3.6
14.9 i 0.9
21.9 i 5.1
8.4 f 5.5*
6.7 -c 6.0*
'Mean values (mm Hg) t one SD. The pressure differences were
calculated for each of the runs and these differences were averaged.
*P < 0.05.
TABLE 5 . Cuffingof extraalveolar vessels and extractions of THO'
~ _ _ _ _
Normal lungs
Circulatory overload
Number of
vessels examined
with cuffs
of THO
0.49 i 0.08
0.68 t 0.14
0.65 _t 0.03*
lung water
cm3 . (100 gm lung)-'
42.9 2 13.3
111.2 i 73.2
34.6 f 15.5
'Values for the extraction of THO (means and standard deviations) were obtained from the multiple-indicatordilution studies carried out
in the animals subjected to circulatory overload and to plasmapheresis.We have pooled the control values in these studies and listed them
for normal lungs in the table to simplify the presentation of the data. In the overload experiments, the control values were 0.47 2 0.09
and for the plasmapheresis experiments 0.52 f 0.07. Similarly, the control values for extravascular lung water were 50.2 ? 11.1 and
35.7 ? 12.3.
*P < 0.05.
interstitium. Light micrographs, on the other
hand, containing branches of the larger pulmonary blood vessels and airways, showed fluid
accumulation within the perivascular connective tissue spaces in both the circulatory overload and the plasmapheresis groups. In the
normal lungs 18 extraalveolar vessels displayed cuffs from a total of 164 observed vessels. After circulatory overload 255 vessels possessed cuffs from a total of 455 observed vessels.
In the plasmapheresis group 110 of 171 observed vessels had fluid cuffs (Table 5 ) . Figure
1 illustrates a pulmonary artery and its surrounding fluid cuff in one of the circulatory
overload lungs. Thus, detectable edema fluid
accumulation was restricted to the extraalveolar interstitial spaces of the intact dog lungs
a h r circulatory overload and after plasmapheresis.
The results of the present morphometric
analysis of alveolar epithelial cells of dog lungs,
in vivo, differ from the results of similar analyses we have reported previously on isolated
perfused dog lung preparations. This difference is consistent with the interpretation that
increases in filtration from the pulmonary microcirculation are not associated with changes
in ultrastructural characteristics of the alveolar epithelium unless septa1 edema and alveolar flooding also occur.
The contention that filtration rates were increased in the present investigation is based
upon the marked increase in differences between hydrostatic and osmotic (oncotic) pressures of the circulating blood after both the
overload and plasmapheresis procedures. Although corresponding tissue pressures sur-
Fig. 1. The light micrograph from a lung of the circulatory overload group illustrates prominent penarterial fluid
cuffs surrounding the branches of the pulmonary artery. The
peribronchiolarconnective tissue sheath, on the other hand,
is not marked by interstitial fluid accumulation. The distention of the lymph vessel adjacent to the pulmonary artery
is consistent with the suggestion that lymph flow from these
lungs was increased.
rounding the microvasculature cannot be assessed, tissue hydrostatic pressure could be
expected to increase and tissue osmotic pressure to decrease under these conditions. Thus,
the effect of the marked changes in intravascular forces on filtration could have been moderated or even abolished by the presumed compensatory tissue pressure changes. The
increased extraction of THO in both the overload and the plasmapheresis series provides
evidence of increased outward filtration in those
experiments. That the extravascular lung water
volume also increased in the overload experiment is interpreted as an indication of recruitment. Since this parameter did not increase in
the plasmapheresis experiments, there was no
recruitment in that series, only excess fluid
accumulation. These findings and the findings
of increased numbers of extraalveolar vessels
with cuffs are mutually compatible. The interpretation that there was increased outward filtration in both the overload and in the plasmapheresis series is thus supported by both the
functional and the anatomical studies.
Since the procedures of circulatory overload
and plasmapheresis were also reported to be
associated with markedly increased pulmonary lymph flow in lungs, in vivo (Uhley et al.,
1967; Zarins et al., 1978), it is apparent that
pulmonary lymphatic capacity, in vivo, exceeds that in isolated lung preparations. That
is, comparable methods of alveolar septal edema
induction were effective in isolated perfused
dog lungs but ineffective in vivo. Moreover,
pulmonary lymphatic capacity, though not definitively known, is considerable, as tenfold increases in pulmonary lymph flow have been
reported (Staub, 1974). A finite lymphatic capacity is indicated, however, by the presence
of perivascular fluid cuffs surrounding the extraalveolar lung vessels after circulatory overload and plasmapheresis. This fluid accumulation is consistent with the anatomic
evidence presented by Lauweryns (1971) that
lymphatic vessels are present in the extraalveolar connective tissue spaces only. It is reasonable, if not established at this time, to consider that both the capacity of the extraalveolar
interstitium to accumulate fluid and the capacity of the lymphatic system to provide runoff must be overcome before septal edema and
subsequent alveolar flooding occur.
Previous studies from this laboratory have
described an association between alveolar interstitial edema and alveolar flooding with increased numbers of vesicles in type I epithelial
cells as well as in capillary endothelial cells.
Similarly, Gil and Magno (1980) observed increasedvesiculation in squamousepithelial cells
in fluid-filled rabbit lungs. The functional significance of this increased vesiculation, however, remains uncertain. The present study
clearly establishes that changes in the factors
which can be expected to provide increased filtration from the pulmonary microcirculation,
in vivo, are not associated with an increase in
type I cell vesiculation. Furthermore, intact
animals could possess adaptive responses to
increased filtration which are absent in isolated perfused lungs. Moreover, isolated lung
preparations, which are denewated, ventilated with positive pressure respiration, and
perfused in a nonpulsatile manner, could
themselves contribute to abnormal cellular responses under edematous conditions. In another study from this laboratory severely
edematous isolated lungs, perfused at 15°C also
failed to display increased vesiculation in type
I cells (Chinard and DeFouw, 1981). Apparently, septal edema and alveolar flooding in
isolated-perfused lungs do not influence type I
cell structure unless normal membrane fluidity and cytoplasmic viscosity are also maintained. Additional studies, possibly with ultrastructural tracers, may help to determine
whether type I vesiculation is a response to
abnormal fluid accumulation in the lung parenchyma and serves to limit expansion of the
alveolar interstitium. Our studies provide no
evidence that the vesicles provide a principal
mechanism by which fluid accumulates in the
alveoli during the alveolar flooding stage.
In previous studies from this laboratory increased alveolar surface densities after septal
edema and alveolar flooding in isolated dog
lungs were detected. Similar increases in alveolar surface areas in saline-filled lungs were
reported by Gil et al. (1979). As suggested by
these authors, after alveoli become fluid filled,
their configurations are no longer influenced
by interfacial tensions; therefore, tissue pressures would primarily determine alveolar
shapes and hence, surface densities. In addition, alveolar interstitial fluid accumulation
could affect tissue tensions normally created
by the fibrous and cellular components of the
septa. Thus, pressure differences between the
septal tissues and intraalveolar fluid could also
strongly influence alveolar configurations. The
results of the present study are consistent with
the purported role of these determinants of alveolar configurations. Specifically, changes in
alveolar surface densities would not be expected if alveolar interstitial edema or alveolar
flooding did not occur.
Our earlier studies also identified an association between increases in alveolar surface
densities and depletion of type I1 cell lamellar
bodies in isolated perfused lungs. The present
results, in which cardiodynamic changes in the
pulmonary microcirculation, in vivo, occurred
without associated changes in alveolar configurations or depletion of type I1 cell lamellar
bodies, are consistent with the interpretation
that alterations in alveolar configurationscould
represent one of several possible stimuli which
trigger a diminution of lamellar bodies in the
alveolar type I1 cells. Since the rate of surfactant secretion was not measured in our present
or previous studies, further assessment of surfactant synthesis and secretion under normal
and edematous conditions is required to test
this interpretation. As pointed out by Mason
and Williams (1977),cellular mechanisms regulating surfactant release from type I1 cell lamellar bodies are uncertain.
The authors thank Drs. Parimal Chowdury
and William Cua for their participation in the
experimental aspects of these studies and Mrs.
Perlita Hill and Ms. Gail Smith for their technical assistance. The late Mr. Gary Schroller
also participated in these studies.
This investigation was supported in part by
Public Health Service grants HL 19571 and
HL 12879 and by grant-in-Aid from the American Heart Association with funds contributed
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