Lung Biology Laboratory, College of Physicians and Surgeons, St. Luke's-Roosevelt Hospital Center, Columbia University, New York, New York 10019
PRESSURE ELEVATION in the pulmonary
circulation, a bed that physiologically downregulates pressure, has
long been recognized as a cause of lung pathology. In the 1980s, the
classic studies of N. C. Staub established a model in
which high pressure induces fluid accumulation in the lung rather than
causing direct injury to the vascular wall (2, 9). This
benign, injury-sparing view of high vascular pressure has been
challenged in recent studies. In several reports, West and
colleagues have shown that if elevated sufficiently, pressure
causes "stress failure" in lung capillaries and alveoli, as evident
in the formation of breaks and discontinuities in endothelial and
epithelial membranes of the blood-gas barrier (BGB) (10).
These new findings center attention on high pressure as a direct agency
for vascular injury and on stress failure as a critical mechanism
underlying some forms of hydrostatic pulmonary edema.
The proneness of the lung to pressure-induced pathology is attributable
to the fine BGB structure that comprises basolateral juxtapositions of
alveolar epithelial and capillary endothelial cells. The BGB at its
so-called "thick" part includes a sliver of extracellular matrix
(ECM) between the basement membranes of these cells, although at the
"thin" part, the basement membranes are directly apposed and fused.
In a theoretical analysis, West and Mathieu-Costello (12)
point out that the circumferential stress in the capillary wall (hoop
stress) relates inversely to wall thickness and must, therefore, be
greater in the thin than in the thick part. Consequently, the thin part
is rendered more vulnerable to stress-induced disruption.
Estimates of the threshold pressure for inducing capillary breaks
support the notion that a major determinant of stress failure in
capillaries is BGB thickness. Thus threshold pressures vary among
horse, dog, and rabbit because of differences in BGB thickness. In the
adult dog lung, the breaks appear at an estimated capillary pressure of
~100 cmH2O and increase in number with further pressure increases (5). The threshold pressure is ~45
cmH2O higher in the horse, which has a thicker BGB
(1), and ~45 cmH2O lower in the rabbit that
has a thinner BGB (10). In a paper by Fu et al., the
current article in focus (Ref 2a, see p. L703 in this issue),
the group has further tested the hypothesis in the newborn rabbit,
which has the least BGB thickness among species studied. Interestingly,
the threshold pressure was also the least recorded, namely a mere 15 cmH2O. This low threshold pressure is particularly
significant in the context of neonatal lung disease because it presages
stress failure conditions in the range of clinically encountered
pressures in newborns.
However, the question we may ask is: In addition to BGB thickness, what
other factors should we take into account in trying to understand
stress failure? Consider the following features of stress failure. The
capillary breaks may occur with basement membranes intact
(5), suggesting that disrupted segments of the cell
membrane slide apart on the basement membrane. This was especially
evident in the newborn study in which no capillary breaks associated
with breaks in the basement membrane. An intriguing possibility is that
increase in endothelial membrane fluidity, a feature characteristic of
interstitial pulmonary edema (8) and one that may decrease
tensile strength in the membrane, contributes to endothelial stress
failure. The breaks spare endothelial junctions and appear to localize
to the alveolus-facing plasma membrane of the capillary. In fact,
electron micrographs of capillaries subjected to stress failure
frequently depict red blood cells impacted at endothelial breaks
(5, 10), possibly to block the leak sites. Staub
considered this possibility to explain the beneficial effect of red
blood cells in reducing abnormally high filtration rates in dog lungs
(7). These features suggest that in addition to BGB
thickness, specific responses of the endothelial cell may determine the
biology of capillary stress failure.
In response to mechanical stress, cells develop focal adhesions at
sites of cell-ECM contact. Although focal adhesions have not been
reported in pressure-stressed capillaries, capillary stretch
attributable to high tidal volume ventilation increases focal adhesion
formation in lung endothelial cells (1a). Evidently, focal
adhesions act as rivets that bind the endothelial plasma membrane to
the ECM, thereby distributing the wall stress of the capillary to the
ECM. Interestingly, the stress failure data indicate that despite the
global application of high pressure, capillary breaks tend to occur at
a relatively low rate along the capillary length. Thus for the dog,
breaks occurred at a frequency of ~5/mm (5). Assuming
that an endothelial cell in situ has a length of ~50 µm, a
millimeter length of capillary may contain 20 cells. Hence, the
reported break frequency indicates that only a few cells, 25% by this
approximate calculation, are affected by stress failure. The question
is, What makes the injury selective? Although the answers are unclear,
the extent to which poor focal adhesion formation at break sites
accounts for the data needs consideration.
The ability of capillary breaks to undergo repair is yet another
fascinating aspect of the stress failure story. Thus no breaks are
evident if pressure is first increased to stress failure levels and
then returned to noninjurious levels (11). How are the
breaks repaired? In disrupted cell membranes, membrane repair occurs by
Ca2+-induced exocytosis of multiple vesicles that
accumulate at the rupture site and that locally add membrane to the
cell surface (5). Accordingly, inhibition of exocytosis
inhibits membrane repair (11). Membrane wounding also
induces the small GTPases Rho and Cdc42 that drive actin cable
formation to secure the wound while filopodia close the gap
(13). The extent to which these mechanisms operate in the
recovery phase of stress failure is not known. Because pressure induces
endothelial Ca2+ increases in lung capillaries
(4), it is possible that vesicular exocytosis, a
Ca2+-dependent process, is brought into play rapidly to
repair stress-injured cell membranes.
In conclusion, the studies by West and colleagues (10,
12) have established pressure-induced stress failure as
a quantifiable phenomenon in the lung. Clearly, the challenge for
future research is to understand the cell biology underlying stress
failure, both in terms of cellular signaling responses as well as of
constituent cell proteins that might contribute to membrane integrity
(3).
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. Bhattacharya, College of Physicians and Surgeons, Columbia Univ., New York, NY (E-mail: jb39{at}columbia.edu).
10.1152/ajplung.00425.2002
Received 12 December 2002; accepted in final form 17 December 2002.
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