Thoughts on the pulmonary blood-gas barrier
John B. West
Department of Medicine, University of California San Diego, La Jolla,
California 92093-0623
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ABSTRACT
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The pulmonary blood-gas barrier is an extraordinary structure because of
its extreme thinness, immense strength, and enormous area. The essential
components of the barrier were determined early in evolution and have been
highly conserved. For example, the barriers of the African, Australian, and
South American lungfish that date from as much as 400 million years ago have
essentially the same structure as in the modern mammal or bird. In the
evolution of vertebrates from bony fishes through amphibia, reptiles, and
ultimately mammals and birds, changes in the pulmonary circulation occurred to
limit the stresses in the blood-gas barrier. Only in mammals and birds is
there a complete separation of the pulmonary and systemic circulations, which
is essential to protect the extremely thin barrier from the necessary
high-vascular pressures. To provide the blood-gas barrier with its required
strength, evolution has exploited the high ultimate tensile strength of type
IV collagen in basement membrane. Nevertheless, stress failure of the barrier
occurs under physiological conditions in galloping Thoroughbred racehorses and
also apparently in elite human athletes at maximal exercise. The human
blood-gas barrier maintains its integrity during all but the most extreme
physiological conditions. However, many pathological conditions cause stress
failure. The structure of the blood-gas barrier is apparently continually
regulated in response to wall stress, and this regulation is essential to
maintain the extreme thinness but adequate strength. The mechanisms of this
regulation remain to be elucidated and constitute one of the fundamental
problems in lung biology.
vertebrate evolution; stress failure; type IV collagen; exercise-induced pulmonary hemorrhage; lung overinflation; pulmonary circulation
IT IS CERTAINLY AN HONOR to give this lecture in memory of Dr.
Julius Comroe. I was fortunate enough to know him fairly well. I visited my
many friends at the Cardiovascular Research Unit at University of California
San Francisco on several occasions while he was there and gave a couple of
lectures. But Dr. Comroe's influence on my career started long before this.
Back in 1955, when I was newly graduated in medicine and working in London,
Charles Fletcher recommended that I spend a year at the Medical Research
Council Pneumoconiosis Research Unit (PRU) in South Wales to learn respiratory
physiology so that I could join a new program that was planned for the
Postgraduate Medical School, Hammersmith Hospital, in London. While I was at
the PRU, the first edition of Dr. Comroe's The Lung
(9) came out, and I still have
my copy dated August 1955. That book made an enormous impression on me and was
one of the main reasons why I chose a career in respiratory physiology. When I
joined the Postgraduate Medical School a year later, we worked on alveolar gas
analysis using the newly invented respiratory mass spectrometer
(55). This introduced me to
pulmonary gas exchange and, particularly, the fascinating world of
ventilation-perfusion inequality. The second most-influential book of that
time for me was A Graphical Analysis of the Respiratory Gas Exchange
by Rahn and Fenn (41). I still
have my copy, dated May 1956. Parenthetically, I wish the name of Hermann Rahn
was better known to younger respiratory physiologists because he was also a
giant in the field, with seminal contributions to both pulmonary gas exchange
and mechanics.
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DISCOVERY OF THE BLOOD-GAS BARRIER
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The first intimation of the blood-gas barrier (BGB) was by Marcello
Malpighi (1628-1694) in 1661 when he wrote two letters to his friend Giovanni
Borelli (1608-1679) about his first microscopic observations of frog lung. He
wrote "... by careful investigation I have discovered that the whole
mass of the lung... is an aggregate of very fine thin membranes..."
(levissimis et tenuissimis membranis)
(37). However, further
progress on the structure of the BGB was stymied by the fact that it is so
thin that it is beyond the resolution of the light microscope. In fact, the
French physician Albert Policard
(40) wrote that "The
respiratory surface is like the flesh of an open wound" (La surface
respiratoire est assimable à une plaie à vif), by which he
meant that the pulmonary capillaries with their endothelium were directly
exposed to the alveolar gas. It was not until Frank Low
(32) prepared the first
electron micrographs of the BGB that it became clear that on the thin side,
the barrier consisted only of a single layer of alveolar epithelium, the
capillary endothelium, and the intervening extracellular matrix (ECM), which
contained the basement membranes (BM) of the two cell layers. Modern electron
micrographs show the ultrastructure of the BGB with dramatic clarity
(19,
53).
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DESIGN CHALLENGE OF THE BGB
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The BGB has a basic dilemma. On one hand, it must be extremely thin for
adequate gas exchange because this occurs through passive diffusion, and the
diffusion resistance is directly proportional to the thickness of the barrier.
Moreover, the BGB needs to have a very large area because the diffusion
conductance of the barrier is directly proportional to its area. Evolution has
been enormously successful in providing for the human lung. As an example, the
BGB is of the order of 0.2 µm in thickness over much of its area of 50-100
m2 (19).
But this is only part of the challenge. In spite of its extreme thinness,
the barrier also needs to be immensely strong because, as discussed later, the
tensile stresses in the barrier become extremely high under certain
conditions. These include intense exercise when the hydrostatic pressure in
the pulmonary capillaries rises and also high states of lung inflation when
the capillary wall is under tension because of the longitudinal stresses in
the alveolar walls. Thus the dilemma of the BGB is to combine extreme thinness
with immense strength, and this has to be done over a very large area.
It is interesting to consider the necessary components of the BGB. First,
since developmentally all blood vessels are basically endothelial derivatives,
the blood capillaries themselves are lined by an endothelium. Next, because
the respiratory surface develops by invagination from the epithelial lining of
the primitive pharynx, an epithelial covering exists. However, these two
cellular layers by themselves cannot provide the necessary tensile strength.
Fortunately, the type IV collagen of the BM of the cellular layers is
extremely strong, so this is exploited to confer the required tensile strength
for the BGB. As electron micrographs show
(Fig. 1), the two BM of the
endothelial and epithelial cell layers fuse in the thinnest parts of the BGB,
forming a central band of type IV collagen, perhaps only 50 nm thick. The net
result of this ingenious design is that the BGB may be only 0.2 µm thick in
the human lung but it is also able to withstand high tensile stresses.

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Fig. 1. A: diagram of the thin part of the blood-gas barrier (BGB). Most
of the type IV collagen responsible for the strength of the BGB is located in
the lamina densa (LD). This is only 50 nm thick and is sandwiched in the
middle of the extracellular matrix (ECM). [From West and Mathieu-Costello
(56).] B:
ultrastructure of the thin part of the BGB in rat with portions of alveolar
epithelial cell and capillary endothelial cell. Note that the ECM has a
central LD flanked by a lamina rara externa (LRE) and lamina rara interna
(LRI). The LD is formed by fusion of the basement membranes of the 2 cellular
layers. Bar, 0.1 µm. [Modified from Vaccaro and Brody
(51).]
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STRENGTH OF THE BGB
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What is the evidence that the strength of the BGB comes from its BM and, in
particular, the type IV collagen that is an important component of these? The
evidence can be summarized as follows. 1) In animal preparations with
high capillary transmural pressures, disruptions often occur in the epithelial
and endothelial layers, but the BM remains intact
(59). 2) Experiments
on isolated rabbit renal tubules show that the elastic properties of the
tubules are determined by the BM
(54). 3) The
distensibility of frog mesentery capillaries is attributable to the mechanical
properties of the BM (45).
4) Renal glomerular capillaries routinely withstand a high transmural
pressure and have a correspondingly thick BM. 5) Measurements show
that the thickness of the BM of systemic capillaries increases down the body
as their transmural pressure rises, notably in the giraffe
(62).
Type IV collagen itself has a triple helix structure like that of other
matrix collagens, but it is distinctive in that the COOH-terminal end has an
NC1 globular domain that allows two of the
400-nm-long molecules to join
to form a doublet (Fig. 2). The
other NH2 terminus contains the 7S domain, which allows four
doublet molecules to form a matrix configuration similar to chicken wire. This
configuration apparently combines great strength with porosity. The 7S domain
allows the collagen to link with integrins
1
1 and
2
1
(30).

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Fig. 2. Some features of type IV collagen. Each molecule is 400 nm long. Two
join at the COOH-terminal region (C) and 4 at the NH2-terminal
region (N) to give a matrix that has a very high ultimate tensile strength.
[Modified from Timpl et al.
(48).]
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It is well known that collagens are some of the strongest soft tissues in
the body, although there have been few studies of the ultimate tensile
strength of BM. However, studies of BM from cat lens capsule
(15) and measurements of
mechanical properties of BM from isolated rabbit renal tubules
(54) suggest that the ultimate
tensile strength of type IV collagen is
1 x 106 N
· m-2, a very high value. As discussed below, calculated
stresses in the type IV collagen layer of the BGB can approach these values
under some extreme physiological conditions.
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PHYLOGENESIS OF THE BGB
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A fascinating aspect of the BGB is how evolution fixed on the basic
tripartite structure shown in Fig.
1 very early after vertebrate transition to land and the adoption
of air breathing, and how this has apparently altered very little over the
ensuing 400 million years or so. Figure
3 shows the BGB of the lungs of the lungfishes (Dipnoi), one of
the earliest air-breathing taxa. Figure
3A is from the South American lungfish Lepidosiren
paradoxa, and it can be seen that the structure is similar to that shown
in Fig. 1 and that the
capillary endothelial cell, prominent ECM, and epithelial cell are very
evident. There is also an obvious surface lining layer in this perfusion-fixed
preparation. Figure 3B
shows the BGB of the Australian lungfish Neoceratodus forsteri, and
again the epithelial, endothelial, and ECM layers are clearly seen.
Interestingly, the epithelial cell body has prominent microvilli and also
osmophilic bodies, features that show uncompleted differentiation of pulmonary
pneumocytes in primitive lungs, and resemble the type II alveolar epithelial
cell of mammals. Figure
3C shows the BGB of the African lungfish Protopterus
aethiopicus, and again the three layers are obvious. Thus all three
extant genera of lungfishes, which are some of the earliest air-breathing
vertebrates and are taxa that have been separated for about 300 million years,
show the same basic structure of the BGB as in
Fig. 1.

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Fig. 3. A: BGB from the lung of the South American lungfish
Lepidosiren paradoxa. Note that the BGB of this animal that appeared
400 million years ago shows the 3 layers consisting of air space
epithelium, capillary endothelium (en), and ECM. A surface lining layer is
also seen. a, air space; en, endothelium; i, interstitium; e, epithelium; c,
capillary. [Modified from Hughes
(25).] B: BGB of the
Australian lungfish Neoceratodus forsteri showing the same 3 layers.
Note that the epithelial cell body has microvilli and osmophilic bodies as in
the mammalian type II alveolar epithelial cell. Courtesy of John H. T. Power.
C: BGB of the African lungfish Protopterus aethiopicus
showing the same basic structure. e, erythrocyte; p, plasma; en, endothelium;
b.l., basal lamina; a, air space; ep, epithelium; in, interstitium. [Modified
from Maina and Maloiy
(36).]
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The same BGB structure is also seen in amphibia, and
Fig. 4 shows the BGB of the
tree frog Chiromantis petersi where the electron-dense band in the
center of the ECM is prominent and very much like the appearance shown in
Fig. 1. A similar structure
occurs in reptiles, and Fig. 5
shows the BGB of the black mamba snake Dendroaspis polylepis. Here
the endothelial layer is unusually thick, partly because of the overlapping
junction of two endothelial cells. However, the electron-dense band in the
center of the ECM is remarkably prominent.

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Fig. 4. BGB of the tree frog Chiromantis petersi. This amphibian shows the
3 layers of the BGB very clearly with a central LD in the ECM. ep, epithelium;
bl, basal lamina; en, endothelium; p, plasma; e, erythrocyte. [Modified from
Maina (33).]
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Fig. 5. BGB of the black mamba snake Dendroaspis polylepis. This reptile
shows the tripartite structure very clearly, and the electron-dense layer in
the center of the ECM is prominent. e, erythrocyte; p, plasma; en,
endothelium; bl, basal lamina; ep, epithelium. [Modified from Maina
(35).]
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A particularly informative structure is seen in the avian lung (for
example, that of the domestic chicken Gallus gallus variant
domesticus) (Fig. 6).
Note that the stress-bearing ECM forms an unbroken ring around the blood
capillary to counter the stresses caused by the capillary transmural pressure
(Fig. 7). However, where two
air capillaries adjoin, the ECM with its type IV collagen component is
conspicuously lacking because the avian lung is virtually rigid and has a
negligibly small change in volume during ventilation
(27). This is additional
evidence confirming the critical importance of type IV collagen in the ECM in
maintaining the integrity of the BGB.

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Fig. 6. Lung of the domestic chicken Gallus gallus variant
domesticus showing the 3 layers of the BGB and, in particular, the
ECM, which forms a "cable" around the blood capillaries (arrow).
However, this band of type IV collagen is not seen in the tissue separating
adjacent air capillaries (arrowhead). a, air capillary; c, blood capillary; e,
erythrocyte. [Modified from Maina
(34).]
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Fig. 7. Diagram showing 2 mechanisms that can cause an increased stress in the BGB.
Circled 1, the hoop or circumferential stress caused by the capillary
transmural pressure; circled 2, results from linear tension in the alveolar
wall, which increases as the lung is inflated. P, capillary hydrostatic
pressure. [From West et al.
(59).]
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It is remarkable that evolution has conserved the basic structure of the
BGB over such a long period of time in spite of the fact that the gross
anatomy of the lung has changed out of all recognition
(35). As an example, the lung
of the South American lungfish is long and spindly and completely different
from a morphological point of view compared with the chicken parabronchial
lung (Fig. 6), which is itself
very different from the mammalian bronchoalveolar lung. Nevertheless, the
basic structure of the BGB is almost unchanged.
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STRESSES IN THE BGB
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Figure 7 shows the two
mechanisms by which stresses can be generated in the BGB. The first is the
hoop or circumferential stress that develops as a result of the transmural
pressure across the curved capillary wall according to the Laplace
relationship. If we regard the capillary as part of a thin-walled cylindrical
tube, the stress S is given by Pr/t where P is the transmural pressure, r is
the radius of the capillary, and t is the thickness of the load-bearing
structure.
The transmural pressure of the capillaries of the human lung during
exercise is not known with any accuracy, but pulmonary arterial wedge
pressures as high as 21.1 mmHg have been measured
(52). Consistent with this,
mean pulmonary artery pressures have been shown to increase from 13.2 mmHg at
rest to 37.2 mmHg during exercise
(12,
20,
52). Micropuncture studies of
the pressures in small pulmonary blood vessels in anesthetized cats have shown
that capillary pressure is about halfway between arterial and venous pressure,
and much of the pressure drop in the pulmonary circulation occurs in the
capillary bed (3). This means
that at midlung during heavy exercise, the capillary pressure is about halfway
between 37 and 21 mmHg, that is 29 mmHg. Because the capillaries at the bottom
of the upright lung are
10 cm lower, adding the hydrostatic gradient
gives a capillary pressure there of
36 mmHg
(59).
We do not have good data on the radius of human pulmonary capillaries at
high capillary pressures, but using the average for rabbits and dogs gives a
value of 3.5 µm (4). As
indicated earlier, there is evidence that the stress-bearing structure is the
thin band of type IV collagen in the electron-dense region of the ECM as shown
in Fig. 1. The thickness of
this is of the order of 50 nm. With the use of these numbers, which are
admittedly approximate, the tensile stress in the type IV collagen layer is
calculated to be
3 x 105 N · m-2. This
is approaching the ultimate tensile strength of type IV collagen of
1
x 106 N · m-2 as discussed above.
Therefore, it appears that the normal lung does not have a great deal of
reserve in terms of the strength of the BGB, and this fits with the apparent
changes in the integrity of the BGB that are seen in elite athletes at very
high levels of exercise, as discussed later.
The second mechanism responsible for increasing stress in the BGB is
increased tension in the alveolar wall as occurs at high states of lung
inflation. In this context, we can think of the alveolar wall as a string of
capillaries with at least part of the longitudinal tension of the wall being
transmitted to the capillary wall. As discussed later, there is evidence that
when the lung is inflated to very high volumes, for example, as a result of
high levels of positive end-expiratory pressure (PEEP) in the intensive care
unit, the integrity of the BGB is impaired.
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STRESS FAILURE OF THE BGB
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To determine the ultrastructural changes that occur in the walls of
pulmonary capillaries when the stresses are greatly increased, measurements
were made in anesthetized rabbits where the pulmonary artery and left atrium
were cannulated so that the capillary transmural pressure could be accurately
measured. The lungs were then fixed for electron microscopy using buffered
glutaraldehyde. An example of the ultrastructural changes is shown in
Fig. 8, top. Note that
there is disruption of the capillary endothelial cell, although its intact BM
can be clearly seen. Close inspection of the two ends of the endothelial layer
shows that the structures are smoothly rounded, suggesting that the
plasmalemmal layer is intact. The alveolar epithelial layer is also intact as
is its BM. Another example of stress failure is shown in
Fig. 8, bottom. In
this case there is disruption of the alveolar epithelial layer
(Fig. 8, top). In
addition, close inspection reveals disruption of the capillary endothelial
layer (Fig. 8, bottom), and a blood platelet appears to be adhering to the exposed
BM. This is not surprising because the BM is electrically charged and highly
reactive.

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Fig. 8. A: the effects of raising the capillary transmural pressure in the
rabbit. Note that there is a disruption in the capillary endothelial layer
(Cap), but the alveolar epithelium (Alv) and 2 basement membranes are intact.
B: disruptions of both the alveolar epithelial layer (top)
and capillary endothelial layer (bottom). A blood platelet is
adhering to the exposed basement membrane below. [From West et al.
(59).]
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An interesting question is whether the disruptions occur at intercellular
junctions. We do not have good information on this point for the capillary
endothelium, but scanning electron micrographs show that for the alveolar
epithelium, almost no breaks occurred at intercellular junctions, but within
the cells themselves breaks did occur
(10). This suggests that the
junctions themselves have considerable mechanical strength consistent with the
highly organized intercellular junctions of type I alveolar epithelial cells.
This finding that the disruptions are within instead of between cells is
consistent with reports that when the capillary transmural pressure of frog
mesentery is raised, >80% of the breaks in the endothelium are
transcellular rather than intercellular
(38).
In our rabbit preparation, the first indications of stress failure were
seen at a capillary transmural pressure of 24 mmHg, but the number of breaks
was much increased at a pressure of 39 mmHg, and the frequency was even
greater at 53 mmHg (50). The
fact that some disruptions were seen at a pressure as low as 24 mmHg is
remarkable in view of the evidence presented above that some of the
capillaries of the human lung during severe exercise have a transmural
pressure as high as 36 mmHg. However, of course, we cannot assume that stress
failure occurs at the same pressures in rabbit and human lung, and indeed we
have shown that different pressures are required in rabbit, dog, and horse
lung (4).
A remarkable feature of these disruptions is that many are rapidly
reversible when the capillary transmural pressure is reduced. This was shown
in our rabbit preparation by first raising the pressure to a high level and
then reducing it to a low level, followed by intravascular fixation at the low
pressure. The results showed that
70% of both the endothelial and
epithelial breaks closed within a few minutes
(13). The breaks that closed
were predominantly those that were initially small and also associated with an
intact BM.
The micromechanics underlying the mechanism of stress failure are poorly
understood, but one possibility is that the high hoop stress in the type IV
collagen layer causes this to stretch, thus distorting the matrix arrangement
shown in Fig. 2. It is known
that type IV collagen molecules have sites that allow bending to occur. For
example, in human
1(IV) and
2(IV)
polypeptide chains,
25 irregularly spaced sites have been described that
impart flexibility to the whole molecule
(47), and a 90-nm-long segment
of high flexibility near the 7S domain also exists
(22). Thus it may be that the
BM elongates with the result that the overlying cell disrupts. If the BM
regains its original configuration when the capillary transmural pressure is
reduced, this could explain the rapid reversibility of many of the breaks.
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PHYLOGENETIC STRATEGIES TO AVOID STRESS FAILURE
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It is instructive to look at the evolution of vertebrates to understand how
they avoid stress failure of lung or gill capillaries.
Figure 9 shows that in fishes,
the heart consists of only a single atrium and single ventricle in series, and
blood is pumped to the gills and then distributed to the tissues via the
dorsal aorta. This arrangement means that the hydrostatic pressure in the gill
capillaries must exceed that in the dorsal aorta. It is known that in some
athletic fish, such as the albacore tuna Thunnus alalunga, the mean
dorsal aortic pressure is as high as 79 mmHg
(6). Therefore, the capillary
transmural pressure in the gill of this animal greatly exceeds that which is
necessary to cause stress failure in some mammals. However, the wall of the
gill capillary can afford to be much thicker and, therefore, stronger than in
the mammal because the maximal oxygen consumption of the fish is considerably
less than in a mammal of the same size. In other words, the diffusion
requirements of the barrier are less, and, therefore, it can afford to be
thicker.

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Fig. 9. Stages in the evolution of the pulmonary circulation. In fishes, the gill
capillaries are exposed to the full dorsal aorta pressure. In amphibia and
noncrocodilian reptiles, the pulmonary circulation is functionally partly
separated by streaming of blood within the heart for more efficient gas
exchange. However, only the fully endothermic mammals and birds have achieved
total separation, thus protecting the vulnerable pulmonary capillaries from
the high vascular pressure. [From West and Mathieu-Costello
(57).]
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With gradual evolution through the amphibia and reptiles to the highly
aerobic mammals and birds, the pulmonary circulation is gradually separated
from the systemic circulation so that the pulmonary capillaries are eventually
exposed to much lower pressures. In the modern amphibian, such as the frog,
the beginning of a separation of the two circulations is seen because the
atria are completely separate, although there is only one undivided ventricle.
It is known that streaming of blood within the heart results in much of the
oxygenated blood from the lungs finding its way into the aorta, but since the
ventricle is undivided, the lung capillaries presumably see a high pressure.
Again, however, the low maximal oxygen consumption of these exothermic animals
and the fact that some respiration occurs through the skin means that the BGB
can afford to be thicker.
In the noncrocodilian reptile, the ventricle is now partially divided, and
streaming of oxygenated and poorly oxygenated blood results in a functionally
well-developed double circulation. However, the fact that the ventricles do
communicate means that the pulmonary capillaries are potentially exposed to a
high pressure. A remarkable exception is the monitor lizard Varanus
exanthematicus, which has an unusually high aerobic scope and in which
there is a ridge in the ventricle that separates the two outflow tracts during
systole. The result is that the pressure in the pulmonary artery is much lower
than in the aorta (8).
Only in the fully endothermic vertebrates, such as mammals and birds, is it
essential that the pressures in the pulmonary circulation be much lower than
in the systemic circulation. This is because the high levels of maximal oxygen
consumption are only possible when the pulmonary capillary walls are extremely
thin, to allow rapid diffusion of oxygen. Thus full endothermy requires
complete separation of the two ventricles, and this explains why this is
mandatory in mammals and birds.
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ONTOGENY RECAPITULATES PHYLOGENY
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It is interesting that the changes that occur in the pulmonary and systemic
circulations of the mammal at birth reflect those seen in vertebrate
evolution. In the fetus, the outflow tracts of the left and right ventricles
are connected by the large patent ductus arteriosus. As in amphibians and
reptiles, streaming of blood occurs in the heart, with the result that the
best oxygenated blood from the placenta via the inferior vena cava tends to be
directed to the brain. However, the pressure in the pulmonary artery is high,
being the same as that in the aorta. At first sight, this suggests that the
pulmonary capillaries would be prone to stress failure. However, the blood
flow through the lung is only
15% of the cardiac output, and this
restricted flow is accomplished by having considerable tone in the highly
muscularized pulmonary arteries. The result is that the pulmonary capillaries
are protected from the high pressure.
At birth, the blood flow through the lung has to increase to 100% of the
cardiac output. This is brought about by a striking fall in pulmonary vascular
resistance, partly caused by release of hypoxic pulmonary vasoconstriction,
and also by expansion of the lung. The pulmonary capillaries would, therefore,
be at risk if it was not for the fact that the pulmonary artery pressure
simultaneously falls as a result of constriction of the ductus arteriosus. It
is extraordinary that these two events, opening of the pulmonary arterial
throttle and closure of the ductus arteriosus, are so well synchronized in the
majority of births. It is also interesting that recent work in our laboratory
has shown that the capillaries in the newborn rabbit lung are much more
fragile and vulnerable to stress failure than in the adult animal
(17,
18).
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PHYSIOLOGICAL CONDITIONS CAUSING STRESS FAILURE
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The most remarkable physiological example of stress failure of the BGB is
seen in galloping Thoroughbred racehorses. It is now known that all
Thoroughbreds in training bleed into their alveolar spaces based on the
finding of hemosiderin-laden macrophages in their tracheal washings
(60). This so-called
exercise-induced pulmonary hemorrhage has been known for hundreds of years but
the mechanism has been obscure until recently. It is now known that galloping
Thoroughbreds have extremely high pulmonary vascular pressures. For example,
measurements with animals galloping on a treadmill show that the left atrial
pressure measured directly with a catheter can be as high as 70 mmHg, and this
is associated with a mean pulmonary artery pressure as high as 120 mmHg
(14,
28). Other vascular pressures
are equally astonishing, with a mean systemic arterial pressure as high as 240
mmHg and a mean right atrial pressure of 40 mmHg.
The basic reason for these extraordinarily high pressures is that the
animals have been selectively bred for hundreds of years for extremely high
aerobic performances. For example, they have maximal oxygen consumptions of up
to 180 ml · min-1 ·
kg-1 and cardiac outputs as high as 750 ml ·
min-1 · kg-1. These
enormous cardiac outputs demand very high filling pressures in the left
ventricle and, therefore, very high left atrial pressures, and the pulmonary
artery pressure is passively raised in response. There is no evidence of
increased pulmonary vascular resistance. However, it is clear that the
transmural pressure of the pulmonary capillaries must be of the order of 100
mmHg. Under these conditions, it is not at all surprising that stress failure
of the BGB occurs; indeed, it would be astonishing if it did not. Of course,
with these enormous maximal oxygen consumptions, the BGB has to be very thin
to allow rapid diffusion. Direct observations of the ultrastructure of the
lung in Thoroughbreds after galloping on the treadmill show unequivocal
evidence of breaks in the BGB
(58).
These remarkable findings in Thoroughbred racehorses prompt the question of
whether elite human athletes during maximal exercise ever have ultrastructural
changes in their BGB. There is now strong evidence for this. We studied six
elite cyclists who sprinted uphill at maximal effort sufficient to give a mean
heart rate of 177 beats · min-1. Within an hour
of finishing the exercise, the volunteers underwent bronchoalveolar lavage
(BAL), and the results were compared with normal sedentary subjects who did
not exercise before BAL. It was found that the athletes had significantly
higher concentrations of red blood cells, total protein, albumin, and
leukotriene B4 (LTB4) in their BAL fluid than control
subjects (24). In other words,
brief but very intense exercise in elite human athletes causes changes in the
integrity of the BGB.
Do the same changes occur if similar athletes exercise for a longer period
of time at submaximal exercise levels? We tested this by carrying out a
further study on a similar group of six elite cyclists who exercised at 77% of
their maximal oxygen consumption for 1 h and then underwent BAL. The controls
were eight normal nonathletes who did not exercise before BAL. In contrast to
the results in the previous study, the concentrations of red blood cells,
total protein, and LTB4 in the BAL fluid of the exercising athletes
were not different from those of the control subjects
(23). There were higher
concentrations of surfactant apoprotein A in the athletes, but this is known
to occur with exercise. The overall conclusion of these two studies in elite
human athletes is that the integrity of the BGB is altered only at extreme
levels of exercise, and indeed, this is what might be expected on general
evolutionary lines. It is reasonable that the structure of the organism
evolves to cope with all but the most extreme stresses to which it is
subjected.
 |
PATHOLOGICAL CONDITIONS CAUSING STRESS FAILURE
|
---|
Stress failure of the BGB occurs under many pathological conditions, and
these are summarized in Table
1. As we saw in the previous section, the normal human BGB retains
its integrity up to virtually the highest stresses that occur under
physiological conditions. However, if the capillary transmural pressure rises
to unphysiologically high levels, stress failure is inevitable. This occurs in
high-altitude pulmonary edema (HAPE), which is discussed in more detail later,
and also heart diseases, such as mitral stenosis, and left ventricular failure
that raise pulmonary capillary pressure.
Another cause of stress failure of the BGB is abnormally high states of
lung inflation, as predicted in Fig.
7. This is frequently seen in the intensive care unit if high
levels of PEEP are used (11).
We have shown, in animal preparations, that increasing lung volume from normal
to high levels while keeping the capillary transmural pressure constant
results in a great increase in the number of disruptions in both the capillary
endothelial and alveolar epithelial layers
(16). Consistent with this, a
controlled trial of low vs. traditional high tidal volumes during mechanical
ventilation in intensive care units showed reduced mortalities with the low
tidal volumes (7).
Stress failure also occurs if the type IV collagen of the ECM, which is
responsible for the strength of the BGB
(Fig. 1), is weakened by
disease. This is the case with Goodpasture's syndrome
(61) in which bleeding occurs
into the alveolar spaces.
The mechanism of HAPE is interesting because it was disputed for many
years. In fact, it was this condition that initially sparked our interest in
the possibility of stress failure of the BGB. It is well known that HAPE is
strongly associated with a high pulmonary artery pressure, but the pulmonary
venous pressure is normal. A crucial finding was that the alveolar edema in
HAPE is of the high-permeability type, with a large concentration of
high-molecular-weight proteins and red blood cells
(43). Therefore, it seemed
likely that in some way, the high pulmonary artery pressure was damaging the
walls of the capillaries. One perplexing feature was how an increase in
pulmonary artery pressure could be transmitted to some of the capillaries
since the site of hypoxic vasoconstriction is believed to be upstream of the
capillaries. However, a reasonable explanation was given by Hultgren
(26) more than 30 years ago
when he suggested that if the hypoxic pulmonary vasoconstriction is uneven,
some of the capillaries would be exposed to a high pressure. Consistent with
this, it is known that there is a meager amount of vascular smooth muscle in
small pulmonary arteries in the adult lung after the involution that occurs
after birth, and the muscle that remains is unevenly distributed
(42). Convincing evidence that
HAPE is caused by stress failure of pulmonary capillaries was obtained by
Swenson et al. (46) when they
showed that in very early HAPE, BAL fluid showed increased red blood cell and
protein concentrations with no evidence of inflammatory markers.
 |
REGULATION OF THE BGB
|
---|
As pointed out earlier, the pulmonary BGB needs to satisfy two conflicting
requirements. It must be extremely thin for efficient gas exchange but also
immensely strong to withstand the high stresses in the capillary wall when
capillary pressure rises during exercise. The human BGB maintains its
integrity except under conditions of extreme exercise in elite athletes.
However, pathological conditions associated with an abnormally high capillary
pressure cause stress failure.
How is the structure of the BGB optimized so that it is just strong enough
to withstand almost all the normal mechanical stresses but at the same time
remain extremely thin? Our hypothesis is that the capillary wall senses the
wall stress in some way and then regulates its structure, especially the ECM,
which appears to be primarily responsible for its strength.
Pulmonary vascular remodeling is well known to occur in larger pulmonary
blood vessels and has been extensively reviewed, for example, by Stenmark and
Mecham (44). A particularly
interesting study was carried out by Tozzi et al.
(49), who applied mechanical
tension to explants of rings of rat main pulmonary artery and showed increases
in collagen synthesis (incorporation of [14C]proline), elastin
synthesis (incorporation of [14C]valine), mRNA for
pro-
1(I) collagen, and mRNA for protooncogene v-sis within 4
h. These changes were endothelium dependent because they did not occur when
the endothelium was removed from the arterial rings.
However, in contrast to the extensive literature on vascular remodeling in
pulmonary arteries and veins, remodeling of pulmonary capillaries has been
almost completely ignored. We know that it occurs because, as
Fig. 10 shows, marked
thickening of the BM of the capillary endothelial cells and alveolar
epithelial cells is seen in the pulmonary capillaries of patients with mitral
stenosis (21) and pulmonary
veno-occlusive disease (29).
In both conditions, pulmonary capillary pressure is raised, and it is
reasonable to infer that the thickening occurs in response to the increased
capillary wall stress. Careful inspection of
Fig. 10 suggests that most of
the thickening of the BM is associated with the capillary endothelial cell
instead of the alveolar epithelial cell, implicating the endothelium as the
main source. As noted earlier, Tozzi et al.
(49) showed that some aspects
of vascular remodeling in pulmonary artery were endothelium dependent. Of
course, the fact that the increase in BM thickness apparently comes from the
endothelial cell does not necessarily mean that this cell is the primary
sensor of the increased wall stress. It is possible that some other cell in
the parenchyma, such as an epithelial cell, fibroblast, or some other pericyte
responds to the increased tension and sends a signal to the endothelial cell.
It is known that cultures of type II alveolar epithelial cells are responsive
to stretch (63), and cultures
of pulmonary fibroblasts respond to stretch with an increase in proliferation
through an autocrine growth factor mechanism
(5) that involves
platelet-derived growth factor-B (PDGF-B)
(31).

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|
Fig. 10. Electron micrograph of a pulmonary capillary from a young patient with
mitral stenosis. Note thickening of the basement membranes of the capillary
endothelial and alveolar epithelial cells, particularly the former (arrow).
Courtesy of S. G. Haworth.
|
|
We have designed experiments in which the pulmonary capillary wall stress
was raised, and gene expression for ECM proteins and the concentrations of the
proteins themselves were measured in peripheral lung tissue, where most of the
blood vessels are pulmonary capillaries.
Table 2 summarizes some of the
results from three separate experiments. In the first experiment, the volume
of one lung of an anesthetized open-chest rabbit was raised while the other
lung was ventilated at a normal volume
(2). Additional control animals
had both lungs ventilated at normal states of lung inflation. It was found
that high states of lung inflation over 4 h resulted in increased gene
expression for
1(III) and
2(IV)
procollagens, fibronectin, basic fibroblast growth factor, and transforming
growth factor-
1 (TGF-
1). By contrast, mRNA levels for
1(I) procollagen and vascular endothelial growth factor were
unchanged. An unexpected finding was that the changes in mRNA listed above
were identical in both the overinflated lung (9 cmH2O PEEP) and
normally inflated lung (1 cmH2O PEEP) in the rabbit preparation in
which one lung was overinflated and the other lung was normally inflated. This
observation suggests that a generalized organ-specific response occurred after
the localized, unilateral application of mechanical force. The mechanism for
this was not identified, but one possibility was that information was
transferred via the circulation from the overinflated lung to the normally
inflated lung.
In a second experiment carried out by Parker and colleagues
(39), capillary transmural
pressure was increased by raising the venous pressure in isolated perfused rat
lungs. To avoid producing pulmonary edema, the venous pressure was increased
cyclically to 28 cmH2O for 15 s every minute for 4 h. Controls were
similar lungs perfused at low pressure and also unperfused lungs. As
Table 2 summarizes, this study
showed significant increases in gene expression for
1(I) and
1(III) procollagens, fibronectin, laminin, and
TGF-
1.
In a third experiment, alveolar hypoxia was used to raise the pressure in
some of the capillaries (1).
The rationale for this was described in the earlier section on high-altitude
pulmonary edema, and an assumption was that the hypoxic pulmonary
vasoconstriction was uneven so that some of the capillaries were exposed to an
increased hydrostatic pressure. Rats were exposed to 10% oxygen for 6 h or 3
days (short-term group) and 3 or 10 days (long-term group). The results showed
that in peripheral lung tissue, levels of mRNA for
2(IV)
procollagen increased sixfold after 6 h of hypoxia and sevenfold after 3 days.
The levels then decreased after 10 days of exposure. mRNA levels for PDGF-B
doubled after 6 h of hypoxia but returned to control values after 3 days. mRNA
levels for
1(I) and
1(III) procollagens
and fibronectin were increased after 3 days of hypoxia and then decreased
toward control values after 3 days. The results are consistent with capillary
remodeling in response to increased wall stress.
As shown in Table 2, the
results of these three different experiments were somewhat variable, and a
clear picture has not yet emerged. One of the practicable problems is the
difficulty of raising the wall stress in the capillaries without increasing
the pressures and, therefore, the wall stresses in larger pulmonary blood
vessels. An attempt to obviate this problem was made by only collecting tissue
from the outer few millimeters of lung. However, more studies are clearly
needed.
In conclusion, the structure of the BGB presents a fascinating challenge
because of the basic dilemma of combining extreme thinness with immense
strength. How the barrier is regulated to satisfy these conflicting demands so
that, for example, stress failure only occurs under the most extreme
conditions in the human lung remains a central issue for lung biology
research.
 |
DISCLOSURES
|
---|
This work was supported by National Heart, Lung, and Blood Institute Grant
RO1-HL-60698.
 |
ACKNOWLEDGMENTS
|
---|
I am indebted to numerous colleagues, especially Zhenxing Fu, Odile
Mathieu-Costello, and John Maina.
 |
FOOTNOTES
|
---|
Address for reprint requests and other correspondence: J. B. West, UCSD Dept.
of Medicine 0623A, 9500 Gilman Dr., La Jolla, CA 92093-0623 (E-mail:
jwest{at}ucsd.edu).
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.
 |
REFERENCES
|
---|
- Berg JT, Breen
EC, Fu Z, Mathieu-Costello O, and West JB. Alveolar hypoxia causes
increased gene expression of extracellular matrix proteins and PDGF-B in lung
parenchyma. Am J Respir Crit Care Med
158: 1920-1928,
1998.[Abstract/Free Full Text]
- Berg JT, Fu Z,
Breen EC, Tran HC, Mathieu-Costello O, and West JB. High lung inflation
increases mRNA levels of ECM components and growth factors in lung parenchyma.
J Appl Physiol 83:
120-128, 1997.[Abstract/Free Full Text]
- Bhattacharya J and Staub NC. Direct measurement of microvascular pressures in the
isolated perfused dog lung. Science
210: 327-328,
1980.[ISI][Medline]
- Birks EK,
Mathieu-Costello O, Fu Z, Tyler WS, and West JB. Comparative aspects of
the strength of pulmonary capillaries in rabbit, dog and horse.
Respir Physiol 97:
235-246, 1994.[ISI][Medline]
- Bishop JE,
Mitchell JJ, Absher PM, Baldor L, Geller HA, Woodcock-Mitchell J, Hamblin MJ,
Vacek P, and Low RB. Cyclic mechanical deformation stimulates human lung
fibroblast proliferation and autocrine growth factor activity. Am J
Respir Cell Mol Biol 9:
126-133, 1993.[ISI][Medline]
- Breisch EA,
White F, Jones HM, and Laurs RM. Ultrastructural morphometry of the
myocardium of Thunnus alalunga. Cell Tissue Res
233: 427-438,
1983.
- Brower RG,
Matthay MA, Morris A, Schoenfeld D, Thompson BT, and Wheeler A.
Ventilation with lower tidal volumes as compared with traditional tidal
volumes for acute lung injury and the acute respiratory distress syndrome.
N Engl J Med 342:
1301-1308, 2000.[Abstract/Free Full Text]
- Burggren W and
Johansen K. Ventricular haemodynamics in the monitor lizard Varanus
exanthematicus: pulmonary and systemic pressure separation. J
Exp Biol 96:
343-354, 1982.[ISI]
- Comroe JH.
The Lung: Clinical Physiology and Pulmonary Function
Tests. Chicago, IL: Year Book Publishers,
1955.
- Costello ML,
Mathieu-Costello O, and West JB. Stress failure of alveolar epithelial
cells studied by scanning electron microscopy. Am Rev Respir
Dis 145:
1446-1455, 1992.[ISI][Medline]
- Dreyfuss D,
Basset G, Soler P, and Saumon G. Intermittent positive-pressure
hyperventilation with high inflation pressures produces pulmonary
microvascular injury in rats. Am Rev Respir Dis
132: 880-884,
1985.[ISI][Medline]
- Ekelund LG and
Holmgren A. Central hemodynamics during exercise. Circ
Res 30: I33-I43,
1967.
- Elliott AR, Fu
Z, Tsukimoto K, Prediletto R, Mathieu-Costello O, and West JB. Short-term
reversibility of ultrastructural changes in pulmonary capillaries caused by
stress failure. J Appl Physiol
73: 1150-1158,
1992.[Abstract/Free Full Text]
- Erickson BK,
Erickson HH, and Coffman JR. Pulmonary artery and aortic pressure changes
during high intensity treadmill exercise in the horse: effect of frusemide and
phentolamine. Equine Vet J 24:
215-219, 1992.[ISI][Medline]
- Fisher RF and
Wakely J. The elastic constants and ultrastructural organization of a
basement membrane (lens capsule). Proc R Soc Lond B Biol
Sci 193: 335-358,
1976.[ISI][Medline]
- Fu Z, Costello
ML, Tsukimoto K, Prediletto R, Elliott AR, Mathieu-Costello O, and West
JB. High lung volume increases stress failure in pulmonary capillaries.
J Appl Physiol 73:
123-133, 1992.[Abstract/Free Full Text]
- Fu Z, Heldt G,
and West JB. Increased fragility of pulmonary capillaries in newborn
rabbit. Am J Physiol Lung Cell Mol Physiol
284: L703-L709,
2003.[Abstract/Free Full Text]
- Fu Z, Heldt GP,
and West JB. Thickness of the blood-gas barrier in premature and 1-day-old
newborn rabbit lungs. Am J Physiol Lung Cell Mol
Physiol 285:
L130-L136, 2003.[Abstract/Free Full Text]
- Gehr P,
Bachofen M, and Weibel ER. The normal human lung: ultrastructure and
morphometric estimation of diffusion capacity. Respir
Physiol 32:
121-140, 1978.[ISI][Medline]
- Groves BM,
Reeves JT, Sutton JR, Wagner PD, Cymerman A, Malconian MK, Rock PB, Young PM,
and Houston CS. Operation Everest II: elevated high-altitude pulmonary
resistance unresponsive to oxygen. J Appl Physiol
63: 521-530,
1987.[Abstract/Free Full Text]
- Haworth SG,
Hall SM, and Patel M. Peripheral pulmonary vascular and airway
abnormalities in adolescents with rheumatic mitral stenosis. Int J
Cardiol 18:
405-416, 1988.[ISI][Medline]
- Hofmann H, Voss
T, Kuhn K, and Engel J. Localization of flexible sites in thread-like
molecules from electron micrographs. Comparison of interstitial, basement
membrane and intima collagens. J Mol Biol
172: 325-343,
1984.[ISI][Medline]
- Hopkins SR,
Schoene RB, Henderson WR, Spragg RG, and West JB. Sustained submaximal
exercise does not alter the integrity of the lung blood-gas barrier in elite
athletes. J Appl Physiol 84:
1185-1189, 1998.[Abstract/Free Full Text]
- Hopkins SR,
Schoene RB, Martin TR, Henderson WR, Spragg RG, and West JB. Intense
exercise impairs the integrity of the pulmonary blood-gas barrier in elite
athletes. Am J Respir Crit Care Med
155: 1090-1094,
1997.[Abstract]
- Hughes G.
The Vertebrate Lung. Burlington, NC: Oxford/Carolina
Biological Supply Company, 1979.
- Hultgren HN. High altitude pulmonary edema. In:
Biomedicine of High Terrestrial Elevations, edited by
Hegnauer AH. New York: Springer-Verlag, 1969, p.
131-141.
- Jones JH,
Effmann EL, and Schmidt-Nielsen K. Lung volume changes during respiration
in ducks. Respir Physiol 59:
15-25, 1985.[ISI][Medline]
- Jones JH, Smith
BL, Birks EK, Pascoe JR, and Hughes TR. Left atrial and pulmonary arterial
pressures in exercising horses. FASEB J
6: A20201992.
(Abstract).
- Kay JM, De Sa
DJ, and Mancer JF. Ultrastructure of lung in pulmonary veno-occlusive
disease. Hum Pathol 14:
451-456, 1983.[ISI][Medline]
- Kern A, Eble J,
Golbik R, and Kühn K. Interaction of type IV collagen with the
isolated integrins a1b1 and a2b1. Eur J Biochem
215: 151-159,
1993.[Abstract]
- Liu M, Liu J,
Buch S, Tanswell AK, and Post M. Antisense oligonucleotides for PDGF-B and
its receptor inhibit mechanical strain-induced fetal lung cell growth.
Am J Physiol Lung Cell Mol Physiol
269: L178-L184,
1995.[Abstract/Free Full Text]
- Low FN.
Electron microscopy of the rat lung. Anat Rec
113: 437-443,
1952.[ISI]
- Maina JN.
The morphology of the lung of the black mamba Dendroaspis polylepis
(Reptilia: Ophidia: Elapidae). A scanning and transmission electron
microscopic study. J Anat 167:
31-46, 1989.[ISI][Medline]
- Maina JN.
Functional Morphology of the Vertebrate Respiratory
Systems. Enfield, UK: Science Publishers,
2002.
- Maina JN.
Fundamental structural aspects and features in the bioengineering of the gas
exchangers: comparative perspectives. Adv Anat Embryol Cell
Biol 163: 1-112,
2002.[ISI]
- Maina JN and
Maloiy GMO. The morphometry of the lung of the African lungfish
Protopterus-Aethiopicus and its structural-functional correlations.
Proc R Soc Lond B Biol Sci 224:
399-420, 1985.[ISI]
- Malpighi M.
Duae epistolae de pulmonibus. Florence, Italy:
1661.
- Neal CR and
Michel CC. Openings in frog microvascular endothelium induced by high
intravascular pressures. J Physiol
492: 39-52,
1996.[Abstract]
- Parker JC,
Breen EC, and West JB. High vascular and airway pressures increase
interstitial protein mRNA expression in isolated rat lungs. J Appl
Physiol 83:
1697-1705, 1997.[Abstract/Free Full Text]
- Policard A.
Les nouvelles idées sur la disposition de la surface respiratoire
pulmonaire. Presse Med 37:
1293-1295, 1929.
- Rahn H and Fenn
WO. A Graphical Analysis of the Respiratory Gas
Exchange. Washington, DC: American Physiological Society,
1955.
- Reid LM.
The pulmonary circulation: remodeling in growth and disease. Am Rev
Respir Dis 119:
531-546, 1979.[ISI][Medline]
- Schoene RB,
Swenson ER, Pizzo CJ, Hackett PH, Roach RC, Millis WJ Jr, Henderson WR Jr, and
Martin TR. The lung at high altitude: bronchoalveolar lavage in acute
mountain sickness and pulmonary edema. J Appl Physiol
64: 2605-2613,
1988.[Abstract/Free Full Text]
- Stenmark KR and
Mecham RP. Cellular and molecular mechanisms of pulmonary vascular
remodeling. Annu Rev Physiol
59: 89-144,
1997.[ISI][Medline]
- Swayne GT,
Smaje LH, and Bergel DH. Distensibility of single capillaries and venules
in the rat and frog mesentery. Int J Microcirc Clin
Exp 8: 25-42,
1989.[ISI][Medline]
- Swenson ER,
Maggiorini M, Mongovin S, Gibbs JS, Greve I, Mairbaurl H, and Bartsch P.
Pathogenesis of high-altitude pulmonary edema: inflammation is not an
etiologic factor. JAMA 287:
2228-2235, 2002.[Abstract/Free Full Text]
- Takami H,
Burbelo PD, Fukuda K, Chang HS, Phillips SL, and Yamada Y. Molecular
organization and gene regulation of type IV collagen. Contrib
Nephrol 107:
36-46, 1994.[Medline]
- Timpl R,
Wiedemann H, van Delden V, Furthmayr H, and Kühn K. A network model
for the organization of type IV collagen molecules in basement membranes.
Eur J Biochem 120:
203-211, 1981.[Abstract]
- Tozzi CA,
Poiani GJ, Harangozo AM, Boyd CD, and Riley DJ. Pressure-induced
connective tissue synthesis in pulmonary artery segments is dependent on
intact endothelium. J Clin Invest
84: 1005-1012,
1989.[ISI][Medline]
- Tsukimoto K,
Mathieu-Costello O, Prediletto R, Elliott AR, and West JB. Ultrastructural
appearances of pulmonary capillaries at high transmural pressures.
J Appl Physiol 71:
573-582, 1991.[Abstract/Free Full Text]
- Vaccaro CA and
Brody JS. Structural features of alveolar wall basement membrane in the
adult rat lung. J Cell Biol 91:
427-437, 1981.[Abstract]
- Wagner PD, Gale
GE, Moon RE, Torre-Bueno JR, Stolp BW, and Saltzman HA. Pulmonary gas
exchange in humans exercising at sea level and simulated altitude.
J Appl Physiol 61:
260-270, 1986.[Abstract/Free Full Text]
- Weibel ER.
Morphological basis of alveolar-capillary gas exchange. Physiol
Rev 53: 419-495,
1973.[Free Full Text]
- Welling LW and
Grantham JJ. Physical properties of isolated perfused renal tubules and
tubular basement membranes. J Clin Invest
51: 1063-1075,
1972.[ISI][Medline]
- West JB, Fowler
KT, Hugh-Jones P, and O'Donnell TV. Measurement of the
ventilation-perfusion ratio inequality in the lung by the analysis of a single
expirate. Clin Sci 16:
529-547, 1957.[ISI]
- West JB and
Mathieu-Costello O. Strength of the pulmonary blood-gas barrier.
Respir Physiol 88:
141-148, 1992.[ISI][Medline]
- West JB and
Mathieu-Costello O. Pulmonary circulation. In: Exercise and
Circulation in Health and Disease, edited by Saltin B, Boushel R,
Secher NH, and Mitchell J. Champaign, IL: Human Kinetics, 2000,
p. 79-91.
- West JB,
Mathieu-Costello O, Jones JH, Birks EK, Logemann RB, Pascoe JR, and Tyler
WS. Stress failure of pulmonary capillaries in racehorses with
exercise-induced pulmonary hemorrhage. J Appl Physiol
75: 1097-1109,
1993.[Abstract]
- West JB,
Tsukimoto K, Mathieu-Costello O, and Prediletto R. Stress failure in
pulmonary capillaries. J Appl Physiol
70: 1731-1742,
1991.[Abstract/Free Full Text]
- Whitwell KE and
Greet TR. Collection and evaluation of tracheobronchial washes in the
horse. Equine Vet J 16:
499-508, 1984.[ISI][Medline]
- Wieslander J and Heinegard D. The involvement of type IV collagen in Goodpasture's
Syndrome. Ann NY Acad Sci 460:
363-374, 1985.[Abstract]
- Williamson JR,
Vogler NJ, and Kilo C. Regional variations in the width of the basement
membrane of muscle capillaries in man and giraffe. Am J
Pathol 63:
359-370, 1971.[ISI][Medline]
- Wirtz HR and
Dobbs LG. Calcium mobilization and exocytosis after one mechanical stretch
of lung epithelial cells. Science
250: 1266-1269,
1990.[ISI][Medline]