Departments of Medicine and Physiology, Cardiovascular Research Institute, University of California, San Francisco, California 94143-0521
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ABSTRACT |
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Continuous movement of fluid into and out of the pleural compartment
occurs in normal chest physiology and in pathophysiological conditions
associated with pleural effusions. RT-PCR screening and immunostaining
revealed expression of water channel aquaporin-1 (AQP1) in
microvascular endothelia near the visceral and parietal pleura and in
mesothelial cells in visceral pleura. Comparative physiological
measurements were done on wild-type vs. AQP1 null mice. Osmotically
driven water transport was measured in anesthetized, mechanically
ventilated mice from the kinetics of pleural fluid osmolality after
instillation of 0.25 ml of hypertonic or hypotonic fluid into the
pleural space. Osmotic equilibration of pleural fluid was rapid in
wild-type mice (50% equilibration in <2 min) and remarkably slowed by
greater than fourfold in AQP1 null mice. Small amounts of AQP3
transcript were also detected in pleura by RT-PCR, but osmotic water
transport was not decreased in AQP3 null mice. In spontaneously
breathing mice, the clearance of isosmolar saline instilled in the
pleural space (~4
ml · kg1 · h
1) was not
affected by AQP1 deletion. In a fluid overload model produced by
intraperitoneal saline administration and renal artery ligation, the
accumulation of pleural fluid (~0.035 ml/h) and was not affected by
AQP1 deletion. Finally, in a thiourea toxicity model of acute
endothelial injury causing pleural effusions and lung interstitial
edema, pleural fluid accumulation in the first 3 h (~4
ml · kg
1 · h
1) was not
affected by AQP1 deletion. These results indicate rapid osmotic
equilibration across the pleural surface that is facilitated by AQP1
water channels. However, AQP1 does not appear to play a role in
clinically relevant mechanisms of pleural fluid accumulation or clearance.
lung; pleura; water transport; aquaporin-1; pleural effusion
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INTRODUCTION |
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FLUID IS
CONTINUOUSLY SECRETED into and cleared from the pleural space in
mammals. In humans, the balanced rates of fluid secretion and
absorption in the steady state are ~0.01
ml · kg1 · h
1
(33). The normal amount of fluid in the pleural space is
very small (0.1-0.2 ml/kg) (27), with only 6-12
ml in humans and 3-6 µl in mice, despite the large pleural
surfaces areas of 4,000 and 10 cm2, respectively
(1). Substantial increases in pleural fluid volume
(pleural effusions) occur in a variety of clinical conditions such as
congestive heart failure, lung infections, tumors, and acute
respiratory distress syndrome. Fluid entry into the pleural space
involves filtration across microvascular endothelia near the pleural
surface and movement across a mesothelial barrier lining the pleural
space (4, 32). Fluid clearance from the pleural space is
thought to occur primarily by lymphatic drainage (18).
Under normal conditions Starling forces provide the driving force for
fluid accumulation in the pleural space (8, 18).
In this study we investigated the role of aquaporin-type water channels in pleural fluid dynamics. Aquaporins are integral membrane proteins that function as bidirectional transporters of water and, in some cases, small solutes such as glycerol (reviewed in Refs. 10 and 28). Water movement across aquaporins can be driven by osmotic, oncotic, or hydrostatic forces. Recent studies in mice lacking specific aquaporins have indicated an important role for aquaporins in several organs (30). For example, mice lacking aquaporin-1 (AQP1) or AQP3 have nephrogenic diabetes insipidus with marked polyuria (13, 24), mice lacking AQP4 manifest reduced cerebral edema in response to brain injury (17), and mice lacking AQP5 have defective saliva secretion (14). Humans lacking AQP2, the vasopressin-regulated water channel, have a rare autosomal form of hereditary nephrogenic diabetes insipidus (6).
The rationale for investigation of the role of aquaporins in pleural fluid transport is the observation that AQP1 is present in most microvascular beds including those in lung (21) and that AQP1 deletion in mice produces marked alterations in the water permeability of microvasculature in lung (2), renal vasa recta (22), and the peritoneal barrier (36). Immunostaining revealed strong AQP1 protein expression in microvascular endothelia near the pleural surface. To investigate the role of AQP1 in pleural fluid dynamics, we developed mouse models to measure osmotically induced water transport, isosmolar pleural fluid clearance, hydrostatically driven pleural fluid accumulation, and endothelial injury-induced pleural effusions. Physiological data in matched wild-type and AQP1 null mice provided direct information about the role of AQP1 in pleural fluid transport.
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METHODS |
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Transgenic mice. Transgenic knockout mice deficient in AQP1 or AQP3 were generated by targeted gene disruption as described previously (13, 16). Measurements were done in litter-matched mice (8-10 wk of age) produced by intercrossing of heterozygous mice in a CD1 genetic background. The investigators were blinded to genotype information for all physiological measurements. Protocols were approved by University of California, San Francisco, Committee on Animal Research.
Osmotic water permeability measurements. Mice were anesthetized with pentobarbital sodium (50 mg/kg ip) and mechanically ventilated through a tracheostomy (Harvard Instruments, tidal volume 7-10 ml/kg, respiratory rate 70-90/min, room air). After 5 min, 0.25 ml of fluid [either saline containing 200 mM sucrose and 1% BSA (500 mosmol/kgH2O) or saline diluted with water containing 1% BSA (200 mosmol/kgH2O)] was infused into the pleural cavity bilaterally (0.15 ml right side, 0.1 ml left side) using a 1-ml syringe and 27-gauge needle. The chest wall was punctured laterally between the 5th and 6th ribs, with the tip of needle parallel to the lung surface to avoid lung puncture. If needed, small amounts of pentobarbital were given to maintain anesthesia. At specified times (0.5-20 min), the abdominal cavity was rapidly exposed and the descending aorta was transected. The chest was opened by a midline incision, and pleural fluid was withdrawn using a micropipette. After low-speed centrifugation (1,000 rpm, 5 min), supernatant osmolality was measured in duplicate using a freezing-point depression osmometer (Precision System, Natick, MA).
Determination of osmotic water permeability.
Assuming that the pleural barrier is effectively a single barrier
separating the pleural cavity and the blood compartment, then the
volume flux out of the pleural cavity (Jv) is
given by Jv = PfvwS[Co Ci(t)], where vw is the partial
molar volume of water (18 cm3/mol), S is
pleural surface area (10 cm2 in mouse, from Ref.
1), Co is plasma osmolality (320 mosmol/kgH2O), Ci(t) is pleural
fluid osmolality, and Pf is the osmotic water permeability. For impermeant osmotic solutes in the pleural cavity, Jv = [VoCi(0)/Ci(t)2][dCi(t)/dt],
where Vo is initial volume of instilled pleural fluid (0.25 ml) of osmolality Ci(0) (200 or 500 mosmol/kgH2O). Solving the differential equation subject to
the initial condition Ci(t) = Ci(0) at t = 0,
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(1) |
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Isosmolar pleural fluid clearance. Mice were briefly anesthetized by halothane inhalation. Isosmolar fluid (0.25 ml) consisting of saline containing 1% albumin and added NaCl (320 mosmol/kgH2O) was infused into the right pleural cavity. After discontinuation of anesthesia, mice resumed normal activity without signs of distress. Mice were given free access to water. After 0.5, 30, 60, or 90 min, mice were reanesthetized, and pleural fluid was withdrawn as described above. Care was taken to withdraw as much fluid as possible. After centrifugation, the weight of the supernatant fluid was determined.
Hydrostatically driven pleural effusions. A fluid overload model of pleural effusion consisted of bilateral renal vessel ligation followed by intraperitoneal saline infusion. Renal vessel ligation was required because the polyuria in AQP1 null mice is not responsive to the V2 agonist 1-desamino-8-D-arginine vasopressin (DDAVP) (13). Mice were anesthetized with pentobarbital (50 mg/kg ip). The lateral abdomen skin was exposed, and a 2- to 3-cm incision was made in the back just lateral to the midline. The renal vessels were isolated and exposed by blunt dissection without damaging the peritoneum. The renal vessels were ligated bilaterally with 3-0 silk suture, and the skin was sutured closed. Isosmolar saline (40% body wt) was infused into the peritoneal cavity, and body weight was determined. After 3 h, body weight was measured to confirm anuria. After anesthesia with pentobarbital (150 mg/kg ip), pleural fluid was collected as described above, and lungs were harvested for determination of wet-to-dry weight ratio.
Thiourea-induced endothelial injury. Thiourea (10 mg/kg) in isosmolar saline (5 mg/ml concentration) was infused into the peritoneal cavity. At 2, 3, or 5 h, the mice were anesthetized with pentobarbital (150 mg/kg ip), pleural fluid was collected as described above, and lungs were harvested for determination of wet-to-dry weight ratio as described previously (26).
RT-PCR and immunocytochemistry. Pleural membranes were carefully microdissected from three wild-type and three AQP1 knockout mice and one AQP3 knockout mouse after euthanasia by pentobarbital overdose. Perfusion of the pulmonary artery with saline at high pressure facilitated detachment of the visceral pleura from lung parenchyma. Tissues were immediately homogenized in Trizol reagent (GIBCO BRL) for mRNA isolation using Oligotex mRNA mini kit. After reverse transcription, PCR was carried out using gene-specific primers designed to amplify portions of the coding sequences of each of the nine mouse aquaporins as described previously (37). Control PCR reactions were done in parallel using as template a cDNA mixture prepared from brain, lung, kidney, and liver. Immunofluorescence localization of AQP1 and AQP3 protein in cryostat sections of paraformaldehyde-fixed pleural membranes was done using specific rabbit polyclonal antibodies.
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RESULTS |
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RT-PCR was carried out to identify transcripts encoding mammalian
aquaporins in pleura. Reverse-transcribed cDNA from microdissected pleural membranes was PCR amplified using specific primers for the nine
mammalian aquaporins cloned in mice. Figure
1A shows a strongly amplified
AQP1 fragment and weakly amplified bands for AQPs 3, 7, and 9. The
weakly amplified transcripts encoding AQPs 3, 7, and 9 may represent
contamination of the pleural membranes by fat and blood/immune cells.
In the control lanes in which the template consisted of cDNA derived
from a tissue mixture containing all aquaporins, all nine aquaporins
were amplified. Based on these results, immunolocalization was done for
AQP1 and AQP3 (good antibodies not available for AQP7 and AQP9).
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AQP1 protein was strongly expressed in microvessels near diaphragmatic (Fig. 1B-a), visceral (b), and parietal (c) pleura of wild-type mice. AQP1 was found at endothelial cell plasma membranes in small and medium-sized vessels. These results are consistent with previous data showing AQP1 expression in the microvasculature of many organs (21). AQP1 was also expressed in surface mesothelial cells of visceral pleura (Fig. 1B-b, arrowheads) and to a lesser extent in parietal and diaphragmatic pleura. No specific immunostaining was found in pleura from AQP1 null mice (Fig. 1B, bottom). No immunostaining of AQP3 was seen in wild-type or AQP1 null mice (not shown).
Osmotically driven water transport across the pleural surface was
measured in anesthetized, mechanically ventilated mice in which 0.25 ml
of hyperosmolar (500 mosmol/kgH2O) or hyposmolar (200 mosmol/kgH2O) fluid was instilled into the pleural space. Mice were killed at specified times, and pleural fluid was collected from the chest cavity for measurement of osmolality. After instillation of 500 mosmol/kgH2O fluid into the pleural space, wild-type
mice had consistently more fluid in the pleural space than AQP1 null mice killed at the same time, indicating more osmotic water entry and
hence higher osmotic water permeability. Figure
2 shows that pleural fluid osmolality
equilibrated rapidly with the 50% equilibration time
(t1/2) after instillation of hyperosmolar fluid
(time at which osmolality was 410 mosmol/kgH2O,
representing average of instilled 500 mosmol/kgH2O and
plasma 320 mosmol/kgH2O) in wild-type mice at 1.7 min. The
t1/2 was 7.5 min in AQP1 null mice, indicating that AQP1 deletion produced a greater than fourfold decrease in apparent pleural barrier osmotic water permeability. As measured at a
single time point of 5 min, AQP3 deletion did not reduce water
permeability. Rates of osmotic equilibration were even faster in
response to instillation of the hyposmolar fluid, with
t1/2 values of 0.7 min (wild type) and 1.8 min
(AQP1 null).
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Apparent osmotic water permeability coefficients (Pf) were computed from t1/2 values as described in METHODS, assuming a smooth pleural surface of area 10 cm2. In response to infusion of hyperosmolar (500 mosmol/kgH2O) fluid, water moved into the pleural space with a Pf of 0.024 cm/s in wild-type mice. Pf was reduced to 0.006 cm/s in AQP1 null mice. In response to infusion of hyposmolar fluid (200 mosmol/kgH2O), Pf values were 0.086 cm/s (wild type) and 0.033 cm/s (AQP1 null). These values are subject to more uncertainty than those for the hyperosmolar study because of the rapid equilibration times. The interesting asymmetry in pleural fluid transport is discussed in DISCUSSION.
The high pleural fluid osmolality at the 30-s time point in the AQP1 null mice infused with 500 mosmol/kgH2O solution suggests that the pleural space contains little fluid at the time of infusion, which is consistent with reported volumes of 0.1-0.2 ml/kg in many species (27). Indeed, very little pleural fluid could be collected from control wild-type or AQP1 null mice that were killed without fluid infusion (26). To estimate the amount of pleural fluid directly, the pleural spaces of wild-type and AQP1 null mice were instilled with 0.25 ml of isosmolar fluid containing 125I-albumin as a volume marker. Mice were killed immediately for collection of pleural fluid and assay of 125I-labeled albumin concentration. The measured ratios of instilled-to-collected 125I-albumin concentrations [1.09 ± 0.02, wild type; 1.11 ± 0.01, AQP1 null (± SE); n = 3] confirmed that initial pleural space fluid volume was under ~25 µl in the mice studied here.
To determine whether the decreased pleural osmotic water permeability
results in impaired clearance (absorption) of pleural fluid, the
pleural space was instilled with isosmolar fluid, and the pleural fluid
volumes remaining at specified time points were measured. Figure
3 shows an approximately linear decrease
in collected pleural fluid volume with averaged volume absorption rates
of 3.8 (wild type) and 4.0 ml · kg1 · h
1 (AQP1 null).
It is concluded that AQP1 deletion does not affect isosmolar pleural
fluid clearance. Since measurements are comparative, the validity of
this conclusion is unlikely to be affected by the imperfect recovery of
pleural fluid by the micropipette collection method (0.23 ml recovered
at time 0 of 0.25 ml instilled).
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To determine whether AQP1 deletion affects pleural fluid accumulation
in response to a hydrostatic driving force, a model of fluid overload
with renal artery ligation was used. An excess of isosmolar fluid was
infused into the peritoneal cavity, where it was absorbed to produce
intravascular volume overload and pleural effusions. Although the
classic model of acute volume expansion in rodents utilizes fluid
overload (39), urinary losses were a concern here. Because
DDAVP is ineffective in AQP1 null mice (13), bilateral
renal artery occlusion was required to eliminate the kidney as a
significant route of fluid clearance. The acute volume overload
produced a marked accumulation of pleural fluid (Fig.
4A) but no significant
elevation in lung water (Fig. 4B). AQP1 deletion did not
affect the accumulation of pleural fluid.
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Last, an established model of endothelial lung injury was used to
create transient pleural effusions. In mice, intraperitoneal administration of thiourea (10 mg/kg) produces rapid accumulation of
pleural fluid with peak volumes at 3 h in wild-type mice, followed by slow spontaneous clearance of the pleural effusion (23,
35). We tested whether the kinetics of thiourea-induced pleural
fluid accumulation or clearance was affected by AQP1 deletion. Mice were killed at specified times after thiourea administration for assay
of pleural fluid volume and lung water. AQP1 deletion did not
significantly affect the kinetics of pleural fluid volume after 2, 3, and 5 h (Fig. 5A), nor
did it affect lung water accumulation (Fig. 5B).
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DISCUSSION |
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The principal finding of this study was that, whereas AQP1 provides a major pathway for osmotically driven water transport across the pleural barrier, AQP1 did not appear to play a role in physiologically and clinically important pleural fluid balance. Mouse models were developed for measurement of pleural osmotic water permeability, isosmolar fluid clearance, and hydrostatic fluid accumulation. Thiourea toxicity was used as an established experimental model of endothelial cell injury producing pleural effusions. The AQP1 null mouse provided a useful model with which to examine the role of AQP1 in the various processes associated with pleural fluid balance.
Osmotic water permeability across the pleural barrier was reduced by greater than fourfold by AQP1 deletion, while the anatomy of the pleural surface and microvasculature was not affected at the light microscopic level. Since AQP1 is expressed primarily in microvascular endothelial cells near the pleural surface, the reduced osmotic water permeability in AQP1 null mice suggests that the microvascular endothelium is a principal barrier for osmosis. Similar conclusions were reported for osmosis across the microvascular barriers in kidney (22) and lung (2). Indeed, 50% osmotic equilibration across the pleural surface in wild-type mice occurred in <1.7 min, much less than that of >10 min for osmotic equilibration in the peritoneal cavity (36). The apparent osmotic permeability coefficient, Pf, of the pleural barrier (~0.02 cm/s) in wild-type mice was quite high, probably because of the excellent microvascular supply and the relatively leaky mesothelial barrier. The pleural surface thus provides an exceptionally efficient route for rapid water addition to or removal from the vascular compartment.
The asymmetry in pleural osmotic water permeability was an unanticipated observation. In general, water permeability is symmetric for simple membrane and epithelial barriers. However, osmotic water transport across the complex pleural barrier may be asymmetric for a number of reasons that cannot be distinguished from the data here, including changes in microvascular blood flow in response to hypo- vs. hyperosmolar pleural instillates, changes in pleural morphology in response to water exit vs. entry, and changes in effective pleural surface area. The computation of a single apparent osmotic water permeability coefficient for the complex pleural barrier may thus not be valid. In any case, the results here indicate that pleural osmotic water permeability is high and significantly reduced by AQP1 deletion.
Whereas osmotically induced water transport across the pleural surface was reduced 10-fold by AQP1 deletion, hydrostatically driven accumulation of pleural and lung fluid was not affected. To compare results from wild-type and AQP1 null mice, it was necessary to ligate the renal artery because of the polyuria and nephrogenic diabetes insipidus in AQP1 null mice. The insensitivity of pleural fluid accumulation to AQP1 deletion indicates that AQP1-independent pathways such as paracellular transport provide the major route for fluid movement. Also, because AQP1 is a water-specific transporter that does not transport salts, pleural fluid accumulation would require a route for salt movement, which probably involves transient breakdown of the pleural barrier (34). Any accumulation of solute-free water in the pleural space would promptly be reabsorbed by osmotic forces. Our results thus provide evidence against a role for AQP1 in pleural fluid accumulation. In a perfused lung model, we reported previously that AQP1 deletion caused a small decrease in lung water in response to large increases in pulmonary artery pressures (25). Although this observation is unlikely to be explained by accumulation of solute-free water in the lung interstitial compartment, we believe that AQP1 deletion is associated with differences in the integrity of the pulmonary microvasculature. Another difference between the pleural and lung interstitial compartments is that the pleural space is open and expandable, whereas the lung interstitium is filled with an extracellular matrix that mechanically restricts volume changes.
The spontaneous clearance of isosmolar fluid instilled into the pleural
space was ~4
ml · kg1 · h
1 in the mice
studied here. This value is substantially greater than measured
clearance rates of 0.017 ml · kg
1 · h
1 in rabbits
(5) and 0.32 ml · kg
1 · h
1 in sheep
(34). The reduced thickness of the pleural barrier in
rodents compared with larger animals (27) may account for the more rapid fluid clearance, as well as the high capacity of the
mouse lymphatic system to clear fluid. AQP1 deletion did not affect
clearance of isosmolar fluid instilled into the pleural space. Because
Starling forces favor fluid accumulation, it is likely that the
majority of fluid exiting the pleural space passes through lymphatics
located throughout the parietal pleura (3, 9, 18). Thus
the expression of AQP1 in pleural microvasculature does not facilitate
pleural fluid clearance.
Thiourea toxicity was studied as an experimental model of endothelial lung injury associated with transient pleural effusions (12, 23). After injection of thiourea, lung fluid accumulation and pleural effusions were maximal at 3 h (12). AQP1 deletion did not alter the time course or magnitude of pleural effusions formed in the first 3 h after thiourea administration. After 5 h, both pleural fluid volume and wet-dry weight ratio of lung were decreased, but there was no significant difference. We conclude that AQP1 does not affect pleural fluid dynamics in response to endothelial injury.
In summary, although AQP1 provides a major pathway for osmotically induced water transport across the pleural barrier, it does not play an important role in pleural fluid dynamics in normal physiology and disease. The question arises as to why AQP1 is expressed in a number of microvascular beds where its deletion is not associated with physiological defects, including lung (2, 25), salivary gland (14), and lacrimal gland (19). Although we think that it is unlikely, AQP1 may be important in pleural fluid dynamics in stresses not tested here. AQP1 may play a non-water-transporting role in the microvasculature, possibly in endothelial growth and proliferation based on its identification as an early response gene (11) and its expression in tumor microvasculature (7). AQP1 has been proposed to play a role in carbon dioxide transport in oocyte studies (20), but does not appear to be important in erythrocytes and lung in vivo (38). As found recently for AQP4 expression in skeletal muscle (37) and gastric parietal cells (31), the data here support the conclusion that the tissue-specific expression of an aquaporin does not ensure a physiological function.
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ACKNOWLEDGEMENTS |
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We thank Liman Qian for breeding and genotyping of transgenic mice.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants HL-59198, HL-51854, DK-35124, HL-60288, and DK-43840 and by a grant from the National Cystic Fibrosis Foundation.
Address for reprint requests and other correspondence: A. S. Verkman, Cardiovascular Research Institute, 1246 Health Sciences East Tower, Box 0521, Univ. of California, San Francisco, San Francisco, CA 94143-0521 (E-mail: verkman{at}itsa.ucsf.edu; web site: http://www.ucsf.edu/verklab).
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.
Received 6 April 2000; accepted in final form 5 July 2000.
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