| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Department of Physiology, University of South Alabama, Mobile, Alabama 36688
 |
ABSTRACT |
|---|
 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
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 · cmH2O1 · 100 g1 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 |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
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 |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
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 · min1 · g
predicted (initial) lung wt1 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 · min1 · g1
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 · min1 · g1)
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) |
|
(2) |
|
(3) |
1 · cmH2O1 · 100 g1 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.| |
RESULTS |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
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.
|
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.
|
|
|
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
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
|
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 |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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
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
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
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
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
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[ISI][Medline].
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
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
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
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
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
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
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
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[ISI][Medline].
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
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
23.
Michel, CC,
and
Curry FE.
Microvascular permeability.
Physiol Rev
79:
703-761,
1999
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
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
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
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
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
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
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
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
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
37.
Vlahakis, NE,
and
Hubmayr RD.
Plasma membrane stress failure in alveolar epithelial cells.
J Appl Physiol
89:
2490-2496,
2000
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].
This article has been cited by other articles:
|
|
 |
|
  A. Boueiz, M. Damarla, and P. M. Hassoun Xanthine oxidoreductase in respiratory and cardiovascular disorders Am J Physiol Lung Cell Mol Physiol, May 1, 2008; 294(5): L830 - L840. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Miyahara, K. Hamanaka, D. S. Weber, M. Anghelescu, J. R. Frost, J. A. King, and J. C. Parker Cytosolic phospholipase A2 and arachidonic acid metabolites modulate ventilator-induced permeability increases in isolated mouse lungs J Appl Physiol, February 1, 2008; 104(2): 354 - 362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Troyanovsky, D. F. Alvarez, J. A. King, and K. L. Schaphorst Thrombin enhances the barrier function of rat microvascular endothelium in a PAR-1-dependent manner Am J Physiol Lung Cell Mol Physiol, February 1, 2008; 294(2): L266 - L275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Hamanaka, M.-Y. Jian, D. S. Weber, D. F. Alvarez, M. I. Townsley, A. B. Al-Mehdi, J. A. King, W. Liedtke, and J. C. Parker TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs Am J Physiol Lung Cell Mol Physiol, October 1, 2007; 293(4): L923 - L932. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Miyahara, K. Hamanaka, D. S. Weber, D. A. Drake, M. Anghelescu, and J. C. Parker Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs Am J Physiol Lung Cell Mol Physiol, July 1, 2007; 293(1): L11 - L21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Solodushko and B. Fouty Proproliferative phenotype of pulmonary microvascular endothelial cells Am J Physiol Lung Cell Mol Physiol, March 1, 2007; 292(3): L671 - L677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Parker Hydraulic conductance of lung endothelial phenotypes and Starling safety factors against edema Am J Physiol Lung Cell Mol Physiol, February 1, 2007; 292(2): L378 - L380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Parker, T. Stevens, J. Randall, D. S. Weber, and J. A. King Hydraulic conductance of pulmonary microvascular and macrovascular endothelial cell monolayers Am J Physiol Lung Cell Mol Physiol, July 1, 2006; 291(1): L30 - L37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Mehta and A. B. Malik Signaling Mechanisms Regulating Endothelial Permeability Physiol Rev, January 1, 2006; 86(1): 279 - 367. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Stevens Molecular and Cellular Determinants of Lung Endothelial Cell Heterogeneity Chest, December 1, 2005; 128(6_suppl): 558S - 564S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wu, E. A. Cioffi, D. Alvarez, S. L. Sayner, H. Chen, D. L. Cioffi, J. King, J. R. Creighton, M. Townsley, S. R. Goodman, et al. Essential Role of a Ca2+-Selective, Store-Operated Current (ISOC) in Endothelial Cell Permeability: Determinants of the Vascular Leak Site Circ. Res., April 29, 2005; 96(8): 856 - 863. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Bartsch, H. Mairbaurl, M. Maggiorini, and E. R. Swenson Physiological aspects of high-altitude pulmonary edema J Appl Physiol, March 1, 2005; 98(3): 1101 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Parker and M. I. Townsley Evaluation of lung injury in rats and mice Am J Physiol Lung Cell Mol Physiol, February 1, 2004; 286(2): L231 - L246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. L. Minnear Vascular endothelial cells actively participate in high inflation pressure-induced permeability and edema Am J Physiol Lung Cell Mol Physiol, December 1, 2002; 283(6): L1200 - L1202. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||
