EDITORIAL FOCUS
Vascular segmental permeabilities at high peak inflation
pressure in isolated rat lungs
J. C.
Parker and
S.
Yoshikawa
Department of Physiology, University of South Alabama,
Mobile, Alabama 36688
 |
ABSTRACT |
The response of segmental filtration
coefficients (Kf) to high peak inflation
pressure (PIP) injury was determined in isolated perfused rat lungs.
Total (Kf,t), arterial
(Kf,a), and venous (Kf,v)
filtration coefficients were measured under baseline conditions and
after ventilation with 40-45 cmH2O PIP.
Kf,a and Kf,v were measured under zone I conditions by increasing airway
pressure to 25-27 cmH2O. The microvascular segment
Kf (Kf,mv) was then calculated by: Kf,mv = Kf,t
Kf,a
Kf,v. The baseline Kf,t
was 0.090 ± 0.022 ml · min
1 · cmH2O
1 · 100 g
1 and segmentally distributed 18% arterial, 41%
venous, and 41% microvascular. After high PIP injury,
Kf,t increased by 680%, whereas
Kf,a, Kf,v, and
Kf,mv increased by 398, 589, and 975%, respectively. Pretreatment with 50 µM gadolinium chloride prevented the high PIP-induced increase in Kf in all
vascular segments. These data imply a lower hydraulic conductance for
microvascular endothelium due to its large surface area and a
gadolinium-sensitive high-PIP injury, produced in both alveolar and
extra-alveolar vessel segments.
barotrauma; mechanical ventilation; capillary permeability; gadolinium; filtration coefficient
 |
INTRODUCTION |
VENTILATOR-INDUCED
LUNG INJURY (VILI) is recognized as a significant contributing
factor in patient morbidity and mortality during ventilation for
critical lung failure due to enhanced transcapillary fluid leak and
induction of inflammatory cytokines (3, 8, 26). However,
the exact nature of leak sites, the relative contribution of alveolar
and extra-alveolar vessels, and the signaling pathways involved in
vascular injury induced by high peak inflation pressures (PIP) remain
elusive. These segmental differences could be significant because of
the different embryologic origin of microvascular and conduit
endothelial cell phenotypes (35). A lower baseline
permeability to fluid and solutes has been reported for cultured
pulmonary microvascular endothelial cell monolayers (30)
and a differential response of these endothelial phenotypes to
inflammatory mediators (16). In particular, a markedly
attenuated permeability increase in response to thapsigargin and
ionomycin in pulmonary microvascular endothelial monolayers suggests a
diminished response of this phenotype to increased calcium signaling
(16, 34).
In contrast, previous studies in isolated lungs suggest involvement of
calcium signaling in mechanical vascular injury. We observed that
infusion of gadolinium, an inhibitor of stretch-activated cation
channels, prevented the increase in filtration coefficient (Kf) after ventilation with periods of
increasing PIP up to 35 cmH2O (27). The
response to gadolinium suggests a role for mechanogated calcium entry
in mechanical injury, which could increase in permeability through
similar signal pathways as receptor ligand pathways. Static lung
inflation to collapse alveolar septal vessels and isolate alveolar
microvascular filtration from that of arterial and venous segments has
previously been used as a means of separating the contributions of
these vascular segments from the total Kf
(Kf,t) measurement (1). However,
the segmental vascular contribution to the vascular fluid and protein
leak induced by high PIP ventilation has not been previously described
(17, 23).
The purpose of the present study was to determine the contribution of
regional vascular segments to the overall Kf in
isolated perfused rat lungs under baseline conditions and after high
PIP-induced injury. In addition, we propose a relationship of the
segmental Kf measured in situ to the relative
permeabilities of the segmental endothelial phenotypes in culture and
also determined the effects of pretreatment with gadolinium on high
PIP-induced injury. The ability of gadolinium in preventing high PIP
injury suggests a calcium- or cation entry-dependent step in the
permeability response.
 |
METHODS |
Isolated Rat Lung Preparation
The isolated rat lung preparation has been previously described
(12, 27, 28, 33). Briefly, male Charles River CD
rats weighing between 306 and 476 g were anesthetized with an
intraperitoneal injection of pentobarbital sodium (65 mg/kg), the
trachea was cannulated, and the rats were ventilated with 20%
O2-5% CO2-75% N2 with a Harvard
rodent ventilator (model 683; South Natick, MA) with a tidal volume of
2.5 ml and a positive end expiratory pressure (PEEP) of 3 cmH2O at 40 breaths/min. This tidal volume resulted in a
nominal PIP of 7 cmH2O. The chest was opened, and 300 units
of sodium heparin were injected into the right ventricle. The pulmonary
artery and left atrium were then cannulated, and the heart and lungs
were excised en bloc and suspended from a force transducer.
Lungs were perfused with 5% bovine albumin in Krebs' bicarbonate
buffer (37°C) at a nominal flow of 6 ml · min
1 · g
predicted (initial) lung wt
1 by a Minipuls 2 roller pump
(Gilson, Middleton, WI). Homologous blood (10 ml) was obtained from a
donor rat and added to the perfusate to obtain a hematocrit of ~7%,
which was measured using a microcentrifuge. Pulmonary arterial (Ppa),
venous (Ppv), and airway (Paw) pressures were measured using Cobe
pressure transducers (Lakewood, CO), and the lung weight was
continuously recorded on a Grass model 7 polygraph (Grass, Quincy, MA).
Lungs were excised, and weight was measured at the end of each
experiment. A minimal blood flow was maintained during all states to
prevent ischemia and perfusate flows were reduced to 3 ml · min
1 · g
1
during high PIP ventilation to prevent alveolar edema accumulation, because adequate separation of arterial and venous segments could not
be obtained in the presence of significant alveolar edema. Blood flows
were returned to baseline values (6 ml · min
1 · g
1)
for all total Kf measurements. We also noted
that a Ppa of 5-8 cmH2O below Paw was necessary to
prevent flow in zone I conditions.
Total and Segmental Kf
After obtaining an isogravimetric state, we measured
Kf,t by raising the venous reservoir to obtain a
Ppv of ~15 cmH2O and maintained it for 20 min. Flow was
reduced to maintain a Ppa-Ppv pressure drop of ~2-3
cmH2O during the increase pressure state. Capillary
pressure (Ppc) was measured using the double occlusion pressure, and
the increase in capillary filtration pressure (
Ppc) was calculated
(36). The rate of weight gain in grams per minute was
averaged over the last 2 min of the lung weight gain curve (
Wt=20) at increased Ppv and used to calculate
Kf,t by
|
(1)
|
Segmental arterial (Kf,a) and venous
(Kf,v) filtration coefficients were obtained by
the method of Albert et al. (1). This method is based on
the use of a high static Paw to collapse alveolar septal vessels and
derecruit them from the filtration surface area. Separate
Kf,a and Kf,v
measurements were then obtained and subtracted from the
Kf,t to obtain the alveolar or microvascular segment Kf (Kf,mv). A
constant Paw of 20 cmH2O with Ppa maintained at
~14-15 cmH2O and Ppv at 5-7 cmH2O
was used for Kf,a followed by measurements at a
Ppv of 14-15 cmH2O with Ppa at ~5-7
cmH2O for determination of
Kf,v. Kf,mv was
calculated as the difference between the total and extra-alveolar
vessel Kf values by
|
(2)
|
All Kf values were normalized to 100 g predicted lung weight (PLW), which was based on body weight (BW)
according to
|
(3)
|
and calculated as
ml · min
1 · cmH2O
1 · 100 g
1 by assuming a specific gravity of 1.0 for filtered
fluid (27).
Pulmonary vascular resistance (Rt) was
calculated from Ppa, Ppv, and
using
|
(4)
|
Experimental Protocols
High PIP control group (n = 6).
After a baseline period of 30 min at a nominal PIP of ~7
cmH2O, baseline Kf,t,
Kf,a, Kf,v, and
Kf,mv were determined. The lungs were then
ventilated for 60 min at 45 cmH2O PIP with 3 cmH2O PEEP, after which the measurements of
Kf,t, Kf,a,
Kf,v, and Kf,mv were
repeated. The lungs were then weighed.
High PIP gadolinium group (n = 5).
After the baseline measurements of Kf,t,
Kf,a, Kf,v, and
Kf,mv, 50 µM of gadolinium chloride
(GdCl3) were added to the venous reservoir, and the same
protocol described above was performed.
Statistics
All values are expressed as means ± SE unless otherwise
stated. The Kf values were compared between
groups using an ANOVA with repeated measures and a Newman-Keuls
posttest with CRUNCH4 statistical software and a Gateway 2000 digital
computer. Where appropriate, an unpaired t-test was
used and a significant difference was determined at P < 0.05.
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RESULTS |
Hemodynamics and Lung Weights
Mean vascular and airway pressures and Rt
for the three groups before and after the ventilation periods are
summarized in Table 1. Vascular
pressures and total Rt in the table are those present at baseline PIP (9 cmH2O) after the
ventilation period and immediately before the Kf
measurements. The Rt are summarized in Table
2. There was a significant 97% increase
in Rt from baseline in the high PIP control
group after high PIP ventilation but no significant change occurred
after high PIP ventilation in the gadolinium group.
Rt during zone I conditions
used to measure Kf,a and
Kf,v was approximately twofold higher than
that measured at baseline pressures under zone III
conditions. The presence of blood flow when alveolar
pressure (Palv) exceeded arterial pressure by 5-6
cmH2O presumably indicates flow through alveolar corner vessels (21).
Respective terminal lung weights were 3.03 ± 0.18 g for the
high PIP control group and 2.77 ± 0.14 g for the high PIP
gadolinium group. These weights represented respective increases from
the predicted lung weights of 132 and 84%, and there was a
significantly greater increase in the high PIP control than in the high
PIP gadolinium group (Fig. 1). These lung
weight gains primarily represent filtration during the
Kf measurements because filtration during the
ventilation periods was reduced by reducing blood flow.

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Fig. 1.
Terminal lung weights as percent increase in lung weight
from predicted lung weight for the two groups. PIP, peak inflation
pressure. *P < 0.05 vs. control group.
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Capillary Kf
Previously published time controls indicate that
Kf does not increase over 1 h of low PIP
ventilation (12, 33, 40). Baseline
Kf,a, Kf,v, and
Kf,mv constituted 18, 41, and 41%,
respectively, of the Kf,t at baseline (Fig.
2). Ventilation for 1 h with
42-45 cmH2O PIP significantly increased
Kf,a, Kf,v, and
Kf,mv by 398, 589, and 975%, respectively, and
increased the Kf,t by 680% in untreated lungs
(Fig. 3). Infusion of 50 µM
GdCl3 after the baseline Kf
prevented the increases in segmental and total
Kf after high PIP ventilation relative to
baseline as shown in Fig. 4. None of the
segmental Kf in the GdCl3-treated
lungs ventilated at high PIP were different from comparable values
obtained in the untreated low PIP ventilation group. Figure
5 compares the effects of high PIP
ventilation on segmental and Kf,t values between
the untreated and GdCl3-treated lungs. All segmental and
total Kf were significantly lower
(P < 0.05) in lungs of the GdCl3-treated
group.

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Fig. 2.
Segmental filtration coefficients as a percentage of the
total filtration coefficient under baseline conditions in the high PIP
control group.
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Fig. 3.
Arterial, venous, microvascular segmental, and total
filtration coefficients (means ± SE) during the baseline period
(solid bars) and after high PIP ventilation (hatched bars) in the high
PIP control group. *P < 0.05 vs. baseline.
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Fig. 4.
Arterial, venous, microvascular segmental, and total
filtration coefficients (means ± SE) during the baseline period
(solid bars) and after high PIP ventilation (hatched bars) in the high
PIP gadolinium group.
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Fig. 5.
Comparison of arterial, venous, microvascular segmental,
and total filtration coefficients (means ± SE) after high PIP
ventilation in the high PIP control group (solid bars) and the high PIP
gadolinium group (hatched bars) after high PIP ventilation in both
groups. *P < 0.05 vs. control group.
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DISCUSSION |
We have previously reported that ventilation of isolated perfused
rat lungs with >35 cmH2O PIP for 1 h is sufficient to
increase the Kf,t (27, 29), whereas
low PIP ventilation (7-12 cmH2O) for up to 3 h
produces no significant increase in Kf or
Rt (12, 33, 40). The major new
findings of this study that have not previously been reported are that
ventilation with high PIP sufficient to cause VILI increased
Kf in all segments of the lung circulation, i.e., the arterial, venous, and alveolar capillary segments, and that
these increases were prevented by gadolinium treatment. Previous studies suggest that the extra-alveolar vessels in the lung can filter
significant amounts of fluid with increased hydrostatic pressure
(2), but the relative segmental contribution to edema formation varies with different types of injury (21). The
relative partitioning of segmental filtration coefficients was derived using the zone I condition to collapse and derecruit
alveolar septal vessels. A comparison of segmental
Kf obtained in the present study with those
previously published with this method is summarized in Table
3. We observed that the mean baseline
distribution of segmental Kf as a percentage of
Kf,t consisted of 18% arterial, 41% venous,
and 41% microvascular contributions. This distribution is similar to
most previous reports for isolated lung models except for those of
Khimenko and Taylor (18); these differences are doubtless
the result of differences in methodology because their studies were
also performed in isolated rat lungs. In our preparation, a minimal
flow was maintained during all pressure states to avoid ischemic injury, whereas Khimenko and Taylor prevented all flow during Kf,v, Kf,a, and
Kf,t measurements. Higher Ppv may have been
required in their baseline measurements to prevent flow because alveolar corner vessel flow can occur when Palv exceeds Ppa by 8-16 cmH2O (21). On the other hand, the
minimal flow maintained during Kf,a and
Kf,v measurements in our study could result in an overestimate of the extra-alveolar vessel Kf
to the extent that the perfused alveolar corner vessels were included
as filtration surface area. Using intravital microscopy, Lamm et al.
(21) observed complete cessation of flow in alveolar
septal vessels when Palv exceeded arterial inflow pressure, but a
graded reduction in flow through alveolar corner vessels as transmural
pressure was reduced from about
4 to
16 cmH2O. On the
basis of their observations, the septal alveolar vessels should have
been derecruited using our arterial-to-alveolar pressure gradient of
5 to
6 cmH2O, but alveolar corner vessels would be
minimally derecruited and likely distended. A resistance increase of
only twofold during the zone I measurements indicates that
alveolar pathways were maintained, but the possible contribution of
these pathways to filtering surface area is unknown.
In our study, segmental Kf increased in all
vascular segments after high PIP injury, but only the
Kf,mv increased as a proportion of
Kf,t (41-54% of
Kf,t) (Table 3). Relative to their baseline values, Kf,mv increased by the greatest amount
(975%). In fact, the percent contribution of the
Kf,mv to Kf,t increased
after all of the diverse types of injury shown in Table 2. Of these injuries, oleic acid produced the greatest relative increase in the
Kf,mv, possibly due to diffuse contact of oleic
acid with the capillary surface area (22). The effect of
hydrochloric acid injury on Kf,a and
Kf,v was attributed to contact of the acid with
small vessels adjacent to airways (22), whereas the relatively larger increase in Kf,v observed
after ischemia-reperfusion injury was attributed to activation
of residual neutrophils (18). The electron microscopy
studies of Chetham et al. (5) tend to support the concept
of an increased extra-alveolar leak in isolated rat lungs during
inflammation because there were gaps in the endothelium and
perivascular edema cuffs around the extra-alveolar vessels after
thapsigargin treatment. However, most microscopic studies of mechanical
injury tend to support a greater role of alveolar capillary vessels as
a source of the increased fluid and protein leak. Fu et al.
(11) observed a 10-fold increase in endothelial and
epithelial breaks in alveolar capillaries when vascular pressures were
increased a high lung volume (PIP = 20 cmH2O) compared
with low lung volume (PIP = 5 cmH2O) in rabbit lungs
perfused in situ. Microscopic features of the high vascular and airway
pressure injury include separation of the epithelium and endothelium
from their basement membranes, fragmentation of the epithelium, rupture
of basement membranes, and extravasation of red cells into the
interstitial and alveolar spaces. Dreyfuss et al. (7) also
reported endothelial gaps and matrix separation of alveolar capillary
endothelium and epithelium in high PIP-ventilated rat lungs. These
morphological changes observed in alveolar capillaries could be the
basis of the increased Kf,mv we observed after
high PIP ventilation in the present study, but the morphological basis of small arterial and venous vessel injury after mechanical ventilation has not been systematically studied.
Several investigators have used monolayers of endothelial cells
cultured from lung microvascular and extra-alveolar vessels segments to
compare the filtration and permeability properties of lung vascular
segments (16, 30, 32). Parker and Trenkle (30) recently reported a hydraulic conductance
(Lp) for monolayers of cultured rat pulmonary
macrovascular endothelial cells (RPMVEC) that was 12- to 97-fold lower
than that measured in monolayers of rat pulmonary artery endothelial
cells (RPAEC), depending on the hydrostatic pressure and time in
culture of the monolayers. In previous studies, Schnitzer et al.
(32) and Del Vecchio et al. (6) reported
diffusional permeabilities that were 15- to 16 -fold lower for sucrose
and twofold lower for albumin in bovine lung microvascular endothelial
monolayers compared with bovine arterial or venous endothelial
monolayers. Likewise, Kelly et al. (16) observed
diffusional permeabilities for 12- and 72-kDa dextrans that were 3.5- and 11.3-fold higher, respectively, for monolayers of RPAEC compared
with RPMVEC. Dextran permeabilities in the RPAEC monolayers increased
in response to increased intracellular calcium induced by both
thapsigargin and low-dose ionomycin, but permeability in the RPMVEC
monolayers was unchanged. Dextran permeability across both RPMVEC and
RPAEC monolayers was increased by a high dose of ionomycin and the
protein phosphatase inhibitor calyculin A. Thus the microvascular
endothelial phenotype appears to have a much lower baseline
permeability compared with the macrovascular endothelial phenotype and
to be relatively unresponsive to moderate increases in intracellular
calcium. The attenuated thapsigargin response of RPMVEC appears to
result from a decreased rate of Ca2+ entry, a higher basal
cAMP content, and a more rapid response of cAMP levels
(34), but an increased permeability may occur with
enhanced phosphorylation of intracellular proteins despite a blunted
calcium response. In contrast to the response of cultured microvascular
endothelial cells to thapsigargin, the alveolar capillary segment of
the intact lung exhibited a significant increase in permeability
(Kf) in response to mechanical stress. Although the relationship of mechanical stress to store-operated calcium release
remains to be elucidated, mechanical strain can cause calcium entry
through stretch-activated cation channels and direct breaks in the
plasma membrane of the endothelial cells (11, 37).
Strain-induced separation of endothelial and epithelial cells from
basement membranes may also result from shear forces or activation of
matrix metalloproteinases (7, 10). We have also observed
that the permeability response of isolated rat lungs to high PIP
ventilation was markedly increased in the presence of phenylarsine
oxide, a protein tyrosine phosphatase inhibitor (29). Such
studies suggest that pulmonary microvascular endothelial cells may lose
barrier integrity under mechanical strain due to phosphorylation of
focal adhesion and adherens junctional proteins, which then could lead
to separation of cell-matrix and cell-cell adhesions. Endothelial and
epithelial separation from basement membranes is a prominent feature of
high PIP lung injury (11).
To directly compare the segmental Kf measured in
isolated lungs to the Lp obtained in cultured
monolayers, it is necessary to estimate the relative filtration surface
areas of the alveolar and extra-alveolar segments measured in intact
lungs. Although systematic morphometric studies of the pulmonary
vascular tree are not available for the rat, detailed vascular cast
studies of human pulmonary arterial and venous vascular trees, as well as morphometric estimates of pulmonary capillary surface area, have
been published for human lung. Weibel (38) used
morphometric and statistical techniques to estimate a capillary surface
area for the human lung of 70 m2. The vascular cast data of
Horsfield et al. (13, 14) for human lung can be used to
calculate the conduit vessel surface area by summing the cylindrical
areas of the arterial and venous vascular tree branches likely to
filter fluid. Cumulative vascular surface areas (S) can be
calculated for arterial generations 1-6 (diameter
13-138 µm) and venous generations 1-7
(13-140 µm diameter) using
|
|
where S is total surface area,
g is the surface area sum of all generations,
N is the total number of branches in each generation,
D is branch diameter, and L is branch length. We
obtained respective cumulative arterial and venous surface areas for
these generations of 11,695 and 12,076 cm2. Thus there is a
capillary-to-conduit vessel surface area ratio of 60-fold for small
arteries and 58-fold for small veins. From our estimates of baseline
segmental Kf, the predicted in situ Lp for pulmonary arterial endothelial cells
would be ~26-fold higher than Lp of alveolar
capillary endothelium, whereas Lp for the
pulmonary venous endothelium would be 58-fold higher than the
Lp of alveolar capillary endothelium. Although
there are presently no in situ measurements for alveolar capillary
Lp, Qiao and Bhattacharya (31)
reported a 40% higher Lp for small veins
compared with small arteries measured in situ using the spit drop
technique. These estimates of the relative baseline
Lp of the segmental endothelial phenotypes in
situ are in substantial agreement with the relatively lower
permeabilities to fluid and solutes reported for cultured pulmonary
microvascular vs. macrovascular endothelial monolayers. However, the
large increase in Kf,mv observed in response to
high PIP mechanical injury and several other types of lung injury
(Table 2) indicates that the in situ microvascular endothelial
permeability was substantially increased in response to injury.
Although the pathways that affect barrier function of microvascular
endothelial cells in situ are uncertain, multiple cell signaling events
are undoubtedly involved.
One of the signaling events that may be involved in microvascular
injury is calcium entry through stretch-activated cation channels. We
have previously reported that pretreatment with GdCl3 prevented the 3.7-fold increase in Kf,t induced
by ventilation with an increased PIP up to 35 cmH2O
(27). In the present study, 50 µM GdCl3
prevented the 6.8-fold increase in Kf,t as well
as the Kf increase in all vascular segments
after ventilation with 44.4 ± 0.5 cmH2O PIP.
Gadolinium is a trivalent lanthanide used as the agent of choice for
blocking stretch-activated nonselective cation channels
(19). Gadolinium may act on multiple ion channel sites and
has been reported to block other types of calcium, potassium, or
nonselective cation channels depending on the dose (4). We
have proposed these stretch-activated cation channels as an important
signaling event for calcium entry during mechanical stress. This may
initiate many of the signaling cascades triggered by calcium entry
known to initiate permeability increases through ligand-gated channels
(27). These events could involve contraction of
actinomyosin fibrils in endothelial cells, rearrangement of cytoskeletal elements, and phosphorylation of intracellular proteins involved in intercellular and cell-matrix adhesion complexes
(23). Indeed, Bhattacharya and colleagues (20,
39) have observed an increased endothelial calcium in small
vessels in isolated lungs during vascular pressure increases as well as
epithelial calcium increases during lung hyperinflation. Significant
differences in the endothelial calcium responses were observed in the
same vessel between individual endothelial cells in situ, which
indicates marked phenotype differences in the calcium response
(20, 39). These pressure-induced calcium increases were
attenuated by gadolinium in all endothelial cells (20,
39). An alternative route for calcium entry into endothelial
calcium entry is through direct wounding or breaks in the plasma
membrane of endothelial cells (37). Although there is
ample evidence that gadolinium can block the mechanogated calcium entry
into endothelial cells both in vitro and in vivo, there are multiple
cell types present in the intact lung that could also have a role in
the increased Kf response to high PIP
ventilation. Recent studies suggest that alveolar macrophages may have
a significant role in VILI, since chemical ablation of macrophages
attenuated the injury in intact rats (9).
In summary, the baseline segmental distribution of
Kf was 18% arterial, 41% venous, and 41%
microvascular determined using zone I isolation of arterial
and venous vascular segments. Considering the large microvascular
surface area in the pulmonary circulation, these estimates imply a
lower fluid conductance per unit of surface area for microvascular
endothelium. Most cell culture studies of these endothelial phenotypes
support this concept. Although the specific leak sites, intracellular
signaling pathways for conduit vessel, and microvascular endothelial
phenotypes in situ have not been established for VILI, our studies
indicate that all vascular segments contributed to the increased fluid
conductance induced by high PIP ventilation with the
Kf,mv contributing the greatest portion of the
total increase in Kf. Whether the most predominant microvascular endothelial lesion involves intercellular gap
formation (25), transcellular "breaks"
(11), or cell-matrix separation (7, 11)
remains to be established.
 |
ACKNOWLEDGEMENTS |
This work was supported by National Heart, Lung, and Blood
Institute Grants HL-66347 and HL-66299 and American Heart Association Grant 981018SE.
 |
FOOTNOTES |
Address for reprint requests and other correspondence:
J. C. Parker, Dept. of Physiology, MSB 3024, College of
Medicine, Univ. of So. Alabama, Mobile, AL 36688 (E-mail:
Jparker{at}usouthal.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.
June 14, 2002;10.1152/ajplung.00488.2001
Received 20 December 2001; accepted in final form 7 June 2002.
 |
REFERENCES |
1.
Albert, RK,
Kirk W,
Pitts C,
and
Butler J.
Extra-alveolar vessel fluid filtration coefficients in excised and in situ canine lobes.
J Appl Physiol
59:
1555-1559,
1985[Abstract/Free Full Text].
2.
Albert, RK,
Lakshminarayan S,
Charan NB,
Kirk W,
and
Butler J.
Extra-alveolar vessel contribution to hydrostatic pulmonary edema in in situ dog lungs.
J Appl Physiol Respir Environ Exercise Physiol
54:
1010-1017,
1983[Abstract/Free Full Text].
3.
Brower, RG,
Matthay MA,
Morris A,
Schoenfeld D,
and
Thompson BT.
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and respiratory distress syndrome.
N Engl J Med
342:
1301-1308,
2000[Abstract/Free Full Text].
4.
Caldwell, RA,
Clemo HF,
and
Baumgarten CM.
Using gadolinium to identify stretch-activated channels: technical considerations.
Am J Physiol Cell Physiol
275:
C619-C621,
1998[Abstract/Free Full Text].
5.
Chetham, PM,
Babal P,
Bridges JP,
Moore TM,
and
Stevens T.
Segmental regulation of pulmonary vascular permeability by store operated Ca2+ entry.
Am J Physiol Lung Cell Mol Physiol
276:
L41-L50,
1999[Abstract/Free Full Text].
6.
Del Vecchio, PJ,
Siflinger Birnboim A,
Belloni PN,
Holleran LA,
Lum H,
and
Malik AB.
Culture and characterization of pulmonary microvascular endothelial cells.
In Vitro Cell Dev Biol
28A:
711-715,
1992.
7.
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].
8.
Dreyfuss, D,
and
Saumon G.
Ventilator induced lung injury: lessons from experimental studies.
Am J Respir Crit Care Med
157:
294-323,
1998[Free Full Text].
9.
Eyal, FG,
Hamm CR,
Coker-Flowers PJ,
Stober M,
and
Parker JC.
The neutralization of alveolar macrophages reduces barotrauma induced lung injury (Abstract).
FASEB J
16:
A410,
2002.
10.
Foda, HD,
Rollo EE,
Drews M,
Conner C,
Appelt K,
Shalinsky DR,
and
Zucker S.
Ventilator-induced lung injury upregulates and activates gelatinases and EMMPRIN: attenuation by the synthetic matrix metalloproteinase inhibitor, Prinomastat (AG3340).
Am J Respir Cell Mol Biol
25:
717-724,
2001[Abstract/Free Full Text].
11.
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].
12.
Fujimoto, K,
Parker JC,
and
Kayes SG.
Activated eosinophils increase vascular permeability and resistance in isolated perfused rat lungs.
Am Rev Respir Dis
142:
1414-1421,
1990[ISI][Medline].
13.
Horsfield, K.
Morphometry of the small pulmonary arteries in man.
Circ Res
42:
593-597,
1978[Abstract].
14.
Horsfield, K,
and
Gordon WI.
Morphometry of pulmonary veins in man.
Lung
159:
211-218,
1981[ISI][Medline].
15.
Iliff, LD.
Extra-alveolar vessels and edema development in excised dog lungs.
Circ Res
28:
524-532,
1971[ISI].
16.
Kelly, JJ,
Moore TM,
Babal P,
Diwan AH,
Stevens T,
and
Thompson WJ.
Pulmonary microvascular and macrovascular endothelial cells: differential regulation of Ca2+ and permeability.
Am J Physiol Lung Cell Mol Physiol
274:
L810-L819,
1998[Abstract/Free Full Text].
17.
Khimenko, PL,
Moore TM,
Wilson PS,
and
Taylor AE.
Role of calmodulin and myosin light-chain kinase in lung ischemia-reperfusion injury.
Am J Physiol Lung Cell Mol Physiol
271:
L121-L125,
1996[Abstract/Free Full Text].
18.
Khimenko, PL,
and
Taylor AE.
Segmental microvascular permeability in ischemia-reperfusion injury in rat lung.
Am J Physiol Lung Cell Mol Physiol
276:
L958-L960,
1999[Abstract/Free Full Text].
19.
Kohler, R,
Schonfelder G,
Hopp H,
Distler A,
and
Hoyer J.
Stretch-activated cation channel in human umbilical vein endothelium in normal pregnancy and in preeclampsia.
J Hypertens
16:
1149-1156,
1998[ISI][Medline].
20.
Kuebler, WM,
Ying X,
Singh B,
Issekutz AC,
and
Bhattacharya J.
Pressure is proinflammatory in lung venular capillaries.
J Clin Invest
104:
495-502,
1999[Abstract/Free Full Text].
21.
Lamm, WJ,
Kirk KR,
Hanson WL,
Wagner WW, Jr,
and
Albert RK.
Flow through zone 1 lungs utilizes alveolar corner vessels.
J Appl Physiol
70:
1518-1523,
1991[Abstract/Free Full Text].
22.
Lamm, WJ,
Luchtel D,
and
Albert RK.
Sites of leakage in three models of acute lung injury.
J Appl Physiol
64:
1079-1083,
1988[Abstract/Free Full Text].
23.
Michel, CC,
and
Curry FE.
Microvascular permeability.
Physiol Rev
79:
703-761,
1999[Abstract/Free Full Text].
24.
Mitzner, W,
and
Robotham JL.
Distribution of interstitial compliance and filtration coefficient in canine lung.
Lymphology
12:
140-148,
1979[ISI][Medline].
25.
Moore, TM,
Chetham PM,
Kelly JJ,
and
Stevens T.
Signal transduction and regulation of lung endothelial cell permeability. Interaction between calcium and cAMP.
Am J Physiol Lung Cell Mol Physiol
275:
L203-L222,
1998[Abstract/Free Full Text].
26.
Parker, JC,
Hernandez LA,
and
Peevy K.
Mechanisms of ventilator induced injury.
Crit Care Med
21:
131-143,
1993[ISI][Medline].
27.
Parker, JC,
Ivey C,
and
Tucker A.
Gadolinium prevents high airway pressure induced permeability increases in isolated rat lungs.
J Appl Physiol
84:
1113-1118,
1998[Abstract/Free Full Text].
28.
Parker, JC,
and
Ivey CL.
Isoproterenol attenuates high vascular pressure induced permeability increases in isolated rat lungs.
J Appl Physiol
83:
1962-1967,
1998[Abstract/Free Full Text].
29.
Parker, JC,
Ivey CL,
and
Tucker A.
Phosphotyrosine phosphatase and tyrosine inhibition modulate airway pressure induced lung injury.
J Appl Physiol
85:
1753-1761,
1998[Abstract/Free Full Text].
30.
Parker, JC,
and
Trenkle L.
Hydraulic conductance (Lp) in pulmonary artery and microvascular endothelial monolayers (Abstract).
FASEB J
15:
A158,
2001.
31.
Qiao, RL,
and
Bhattacharya J.
Segmental barrier properties of the pulmonary microvascular bed.
J Appl Physiol
71:
2152-2159,
1991[Abstract/Free Full Text].
32.
Schnitzer, JE,
Siflinger Birnboim A,
Del Vecchio PJ,
and
Malik AB.
Segmental differentiation of permeability, protein glycosylation, and morphology of cultured bovine lung vascular endothelium.
Biochem Biophys Res Commun
199:
11-19,
1994[ISI][Medline].
33.
Seibert, AF,
Thompson WJ,
Taylor AE,
Wilborn WH,
and
Barnard JW.
Reversal of increased microvascular permeability associated with ischemia reperfusion: role of cAMP.
J Appl Physiol
72:
389-395,
1992[Abstract/Free Full Text].
34.
Stevens, T,
Creighton J,
and
Thompson WJ.
Control of cAMP in lung endothelial cell phenotypes. Implications for control of barrier function.
Am J Physiol Lung Cell Mol Physiol
277:
L119-L126,
1999[Abstract/Free Full Text].
35.
Stevens, T,
Rosenberg RL,
Aird W,
Quertermous T,
Johnson FL,
Garcia JGN,
Hebbel RP,
Tuder RM,
and
Garfinkel S.
NHLBI workshop report: endothelial cell phenotypes in heart, lung and blood diseases.
Am J Physiol Cell Physiol
281:
C1422-C1433,
2001[Abstract/Free Full Text].
36.
Townsley, MI,
Korthuis RJ,
Rippe B,
Parker JC,
and
Taylor AE.
Validation of double vascular occlusion method for Pc,i in lung and skeletal muscle.
J Appl Physiol
61:
127-132,
1986[Abstract/Free Full Text].
37.
Vlahakis, NE,
and
Hubmayr RD.
Plasma membrane stress failure in alveolar epithelial cells.
J Appl Physiol
89:
2490-2496,
2000[Abstract/Free Full Text].
38.
Weibel, ER.
Morphometric estimation of pulmonary diffusion capacity.
Respir Physiol
14:
26-43,
1972[ISI][Medline].
39.
Ying, X,
and
Bhattacharya J.
High vascular pressure increases endothelial free Ca++ concentration [Ca++]i in venular capillaries of rat lung (Abstract).
FASEB J
11:
A134,
1997.
40.
Yoshikawa, S,
Kayes SG,
and
Parker JC.
Eosinophils increase lung microvascular permeability via the peroxidase-hydrogen peroxide-halide system. Bronchoconstriction and vasoconstriction unaffected by eosinophil peroxidase inhibition.
Am Rev Respir Dis
147:
914-920,
1993[ISI][Medline].
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