1 Department of Physiology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272-0095; 2 Cardiovascular Research Institute, and 3 Department of Pediatrics, University of California, San Francisco, California 94143-0130
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ABSTRACT |
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Knowledge
about the conversion of the epithelium in the distal air spaces of the
lung from secretion to absorption is imperative to the understanding of
postnatal lung development; little such information is available in
rats. Distal air space fluid clearance was therefore measured in 21- to
22-day gestation rat fetuses and newborn (40 h) rats. Distal air space
fluid clearance was measured from the increase in
131I-albumin concentration in an isosmolar, physiological
solution instilled into the developing lungs. There was no net fluid
movement across the distal air space epithelium in the lungs of 21-day gestation fetuses. Twenty-four hours later, distal air space fluid was
cleared at a rapid rate in the 22-day gestation fetuses. Within the
first 40 h after birth, the rate rapidly declined to adult levels.
The high distal air space fluid clearance at 22 days gestation and at
40 h after birth was mediated by -adrenergic receptors as
demonstrated by elevated plasma epinephrine levels and inhibition by
propranolol. Interestingly, the elevated distal air space fluid clearance in the 22-day gestation fetuses was only minimally amiloride sensitive; however, amiloride sensitivity increased over the first 40 h after birth. In conclusion, these studies demonstrate that 1) rapid rates of net alveolar fluid clearance occur late in
gestation in the rat and 2) this clearance is driven by
elevations of endogenous epinephrine.
amiloride sensitivity; development; distal air space epithelium; epinephrine; Na+ transport; pulmonary edema; neonatal respiratory distress syndrome
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INTRODUCTION |
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CONVERSION OF THE EPITHELIUM in the distal air spaces of the lung from secretion to absorption is critical for survival of the newborn near term when the fetus has to switch from placental to pulmonary gas exchange. Recent as well as older data have identified a significant role for endogenous epinephrine in stimulating Na+ and fluid absorption near term (35, 49) and in newborn and adult lungs (14, 34), although some studies have suggested that it might not be the only factor of importance (1, 3, 40). It is known that active Na+ transport drives alveolar fluid across the normal healthy adult alveolar epithelium into the lung interstitium and vasculature (17, 30, 32, 34). Amiloride-sensitive epithelial Na+ channels, localized to alveolar epithelial type II cells, and a basolaterally located Na+-K+-ATPase constitute one molecular mechanism involved in apical Na+ uptake (20, 30, 31, 37, 48).
Although some investigators have studied epithelial fluid transport
during the later periods of gestation in larger animals such as sheep
and guinea pigs (6, 10, 14, 38), there have been no
studies of distal air space fluid clearance in developing rat fetuses.
Data on expression and regulation of the transporters implied in
transepithelial Na+ transport, the sodium channel, and
the Na+-K+-ATPase are available (21, 22,
47), although functional studies are lacking. Because the mature
rat lung has fluid transport properties similar to the human lung in
terms of both the rate of transport and the fractional sensitivity to
amiloride (18, 41, 42), studies in rat fetuses may provide
insights regarding fetal fluid transport that could be germane to the
human lung. Therefore, the first objective of the current study was to
study distal air space fluid clearance at different developmental
stages near term in rats. The age groups studied were 20- to 22-day
gestation rat fetuses and newborn (40 h) rats. We also measured
extravascular lung water in the developing rat fetuses. Our goal was to
determine the efficiency of distal air space fluid clearance
immediately before and after birth. Because it has been shown that
catecholamines may be important for regulating distal air space fluid
clearance at birth (14, 49), our second aim was to
investigate the contribution of endogenous -adrenergic stimulation
on clearance of fetal lung fluid in late-gestation rat fetuses and at
birth. We used the
-adrenergic antagonist propranolol to investigate
whether endogenous catecholamines were responsible for clearing the
distal air spaces from fluid. Plasma samples were obtained from each
developmental stage for measurements of endogenous epinephrine levels.
Because epithelial Na+ transport via amiloride-sensitive
Na+ channels provides much of the driving force for
alveolar fluid reabsorption in adult and newborn lungs (14, 30,
38), the third aim was to determine whether the
amiloride-sensitive fraction of distal air space fluid clearance in the
fetal and newborn lungs.
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METHODS |
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Animals
Rats of the Sprague-Dawley strain (n = 138, divided in 16 litters, Charles River, Wilmington, MA) were used in the study. Both male and female rat fetuses were used in the study. The timed-pregnant rats were housed in separate cages in temperature- and humidity-controlled units (20 ± 2°C and 55 ± 10% relative humidity). Adult rats (n = 6) were used for determination of the normal dry lung extravascular lung water. All studies were approved by the University of California at San Francisco Committee on Animal Research.Surgery
Timed-pregnant rats and their fetuses were anesthetized by maternal intramuscular injections of ketamine (50 mg/kg body wt; Ketalar, Parke-Davis, Warner-Lambert, Morris Plains, NJ) mixed with xylazine (5 mg/kg body wt; Rompun, Bayer, Pittsburgh, PA). After all fetuses had been delivered, the female rats were euthanized with an overdose intracardiac pentobarbital sodium (100 mg/kg body wt; Nembutal, Abbott Laboratories, Chicago, IL) and bilateral pneumothoraces.The anesthetized timed-pregnant female rats were placed on a temperature-controlled pad heated to 38°C to maintain their body temperature. An abdominal hysterotomy was carried out by a midline laparotomy, and the fetuses were delivered one by one. Between deliveries of the fetuses, the uterus was kept closed by a noninjurious hemostat. Once the fetus was delivered, pithing the spinal cord with a needle immediately killed it. The fetus was fixed to a surgical board after death. The lower jaw was dislocated by bilateral cuts. The larynx was visualized, and a tracheal cannula (Angiocath no. 24, Becton-Dickinson, Sandy, UT), connected to a 1-ml syringe containing the fluid instillate, was inserted through the larynx into the trachea. The syringe was fixed to the surgical board with modeling clay. The rat fetuses were placed under a heating lamp to maintain normal body temperature during the experimental time period, and the heating lamp was cycled on and off to maintain an incubating temperature of 38-40°C in the incubation area. Temperature in the incubation area was measured by the use of a calibrated temperature probe.
General Experimental Protocol
The 5% albumin instillate solution with the 131I-labeled albumin as a distal air space protein tracer was instilled into both lungs over 2-3 s through the tracheal cannula. The fetuses were given 10 ml/kg body wt of fluid as instillate. The volume of instilled fluid does not affect the rate of alveolar fluid clearance (24, 32). After fluid instillation, the fetuses remained in the incubator area for the 30-min experiment. At the end of the experiment, remaining distal air space fluid was aspirated through the tracheal cannula. Radioactivities in instillates and air space samples of the 131I-labeled albumin were measured. Both lungs were excised and placed in a sample tube and counted for radioactivity as a confirmation of the location of the fluid instillate. Lungs that lacked significant radioactivity, i.e., when the radioactivity left in the lungs was below 70% of the instilled radioactivity, were discarded with their corresponding distal air space fluid samples because of uncertainty of location of the fluid instillate in those fetuses. Plasma epinephrine levels were measured in plasma samples from littermates to the ones used for the distal air space fluid clearance studies in all age groups by a commercially available ELISA method (IBL, Hamburg, Germany). The interassay and intra-assay coefficients of variation for the epinephrine ELISA were 6.2 and 15.2%, respectively.Preparation of Instillates
The 131I-labeled 5% albumin instillate solution was prepared by dissolving 50 mg/ml bovine serum albumin (Sigma Biochemical, St. Louis, MO) in an isosmolar aqueous solution of 0.9% NaCl with 0.1 µCi 131I-labeled human serum albumin (Frosst Laboratories, Montreal, Canada). For studies of endogenous epinephrine dependence of distal air space fluid clearance, we added the generalSpecific Experimental Protocols
The following experimental groups and specific experimental protocols were used. All rat fetuses used for distal air space fluid clearance studies were studied for 30 min and processed as described above in General Experimental Protocol. All experimental groups contained fetuses from at least two different dams. The n values of the groups represent individual fetuses. To verify that our method provided values of alveolar fluid clearance that did not differ between anesthetized rats and our in situ continuous positive airway pressure oxygenated fetuses, we compared the alveolar fluid clearance in the 40-h postnatal rats with the adult ventilated rat. In the 40-h-old rats, alveolar fluid clearance was not different from that in the adult rat when extrapolated to 1 h (16 ± 2%) in the 40-h-old rats and compared with that in adult rats (17 ± 2%, data from Ref. 16).Group 1. Determination of preexisting distal air space fluid
volume [21-day gestation, n = 6; 22-day gestation, n = 6;
newborn (40 h), n = 6].
Because the lung is filled with a protein-free fluid in utero
(6), we needed a method to account for the fraction of
this fluid that would still be present in the air spaces of the lungs. The presence of fetal lung fluid in the air spaces would dilute the
131I-labeled albumin concentration in the instilled
solution and, therefore, confound calculations of distal air space
fluid clearance, depending on volume of fluid present in different age
groups. Therefore, the volume of the preexisting fluid was used to
correct the instilled 131I-labeled albumin concentrations
for the dilution of the instillate that would occur if there were
already fluid in the lung before instillation of the
131I-labeled 5% albumin solution in corresponding
experimental groups. Littermates to rat fetuses used for distal air
space fluid clearance experiments were instilled with 10 ml/kg body wt
of the 131I-labeled 5% albumin instillate into the lungs.
The fluid was immediately retrieved and reinstilled four times to
ensure adequate mixing with preexisting lung fluid, as we have done
before (14). After the last mixing, the fluid was
retrieved and radioactivity counted. The whole procedure required ~1
min; during this time, it is unlikely that significant amounts of
131I-labeled albumin left or entered the air spaces or that
significant volumes of fluid were reabsorbed from or secreted into the
air spaces. Because protein would not cross the distal air space
epithelium during this short time, any change in
131I-labeled albumin concentration would represent a
dilution by preexisting protein-free fluid. We calculated preexisting
fluid volume by the relationship
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(1) |
Group 2. Control studies [21-day gestation, n = 8; 22-day gestation, n = 8; newborn (40 h), n = 6]. Rat fetuses were instilled with 10 ml/kg body wt of the 131I-labeled 5% albumin instillate into the lungs. In preliminary experiments, we also attempted to use 20-day gestation rat fetuses, but these fetuses were too small and fragile to carry out successful studies of distal air space fluid clearance.
Group 3. Endogenous epinephrine studies [21-day gestation,
n = 6; 22-day gestation, n = 6; newborn (40 h), n = 6].
Rat fetuses were instilled with 10 ml/kg body wt of the
131I-labeled 5% albumin instillate containing
104 M propranolol into the lungs. Endogenous epinephrine
levels were measured in plasma from littermates to the rat fetuses used
for the distal air space fluid clearance studies in each group
(n = 6-9 in each group, 21- to 22-day gestation
and newborn, i.e., 40 h) and in 20-day gestation fetuses.
Group 4. Amiloride studies [21-day gestation, n = 6; 22-day
gestation, n = 8; newborn (40 h), n = 6].
Rat fetuses were instilled with 10 ml/kg body wt of the
131I-labeled 5% albumin instillate containing
103 M amiloride into the lungs.
Group 5. Extravascular lung water determination [20-day
gestation, n = 6; 21-day gestation, n = 5; 22-day gestation,
n = 7; newborn (40 h), n = 6; adult, n = 6].
We measured extravascular lung water in 20-day gestation rat fetuses in
addition to littermates of rat fetuses that were used for the studies
of distal air space fluid clearance. In these groups, blood for
hemoglobin measurement was obtained by decapitation of the rat fetuses.
Then, the lungs were rapidly excised, the heart was removed, and the
lungs were placed in preweighed sample tubes and immediately weighed.
Distilled water (200 µl) was added to the tubes, the lungs were
reweighed and then kept frozen at 20°C until they were homogenized
and processed as described below. We used adult rats as a reference
point for these studies. The adult rats were killed with 100 mg/kg body
wt pentobarbital sodium intraperitoneally. A blood sample was obtained
for hemoglobin measurement before the heart stopped beating. In adult
rats, the lungs were excised through a midline sternotomy; the heart
was removed, and the lungs were placed in tubes. Distilled water (4 ml)
was added, and the lungs were homogenized and further processed as
described below. This method for determination of excess lung water has
been described previously in detail (4). In brief, extravascular lung water was determined by measuring extravascular water-to-dry weight ratio (g water/g dry lung) (43) and
was calculated as
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(2) |
Distal Air Space Fluid Clearance Calculation
Clearance of fluid from the lung distal air spaces was measured by the increase in distal air space protein concentration of the instilled solution over 30 min. The increase in protein concentration due to removal of water from the air spaces is a direct reflection of distal air space fluid clearance, as demonstrated before (4, 17, 32, 34). Data are presented as a ratio between final and instilled protein concentration or as distal air space fluid clearance in percent instilled volume. This method is accurate for measuring distal air space fluid clearance, since protein leaks due to a change in epithelial and endothelial permeability were likely to be negligible. The term distal air space fluid clearance does not imply that all fluid is reabsorbed at the alveolar level, since certainly some of the fluid may be reabsorbed by the distal airways. For example, Ballard and colleagues (2) have demonstrated that distal airways can transport sodium and thereby potentially absorb luminal fluid. Distal air space fluid clearance (AFC) was calculated from the equation
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(3) |
Statistics
All data are presented as means ± SD. Data were analyzed with one-way analysis of variance (ANOVA) with Tukey's test as post hoc. Two groups were compared with unpaired Student's t-test. Differences were considered significant when a P value of <0.05 was reached. The n for the different groups represents individual fetuses. ![]() |
RESULTS |
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Distal Air Space Fluid Volume in Developing Fetal and Newborn Lungs
Because lungs are fluid filled in utero, the presence of preexisting lung fluid was assessed. As expected, the most premature lungs contained the highest volume of preexisting lung fluid (Fig. 1). The volume of preexisting distal air space fluid corresponded to a 38% dilution of the instilled fluid's 131I-labeled albumin concentration in the 21-day gestation rat fetuses, a dilution that decreased to 14% dilution in the 22-day gestation rat fetuses and declined to only 2% at 40 h after birth. This volume was used to correct the distal air space fluid clearance calculations.
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Distal Air Space Fluid Clearance During Development
The results are presented as the ratio between final to instilled 131I-labeled albumin concentrations and as the distal air space fluid clearance in percent instilled volume (Figs. 2, 4, and 5). There was no net distal air space fluid clearance in 21-day rat fetuses (Fig. 2). The final to instilled 131I-labeled albumin concentration was highest in 22-day gestation rat fetuses, showing that 18 ± 8% of the instilled volume was removed from the distal air spaces (Fig. 2). In the 40-h-old rats, alveolar fluid clearance was 8 ± 2%, a level not different from that in the adult rat when extrapolated to 1 h (Fig. 2) (16 ± 2%) in the 40-h-old rats and compared with that in adult rats (17 ± 2%, data from Ref. 16).
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Sensitivity to Endogenous -Adrenergic Stimulation During
Development
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Because endogenous plasma epinephrine levels in near-term rat fetuses
(22-day gestation) and newborn rats (40 h old) were high (Fig. 3) and
alveolar fluid clearance in adult rats can be stimulated by exogenous
administration of -adrenergic agonists (24), we studied
whether distal air space fluid clearance is sensitive to inhibition by
the
-adrenergic antagonist propranolol and whether such a
sensitivity varies with development and plasma epinephrine levels.
Addition of propranolol significantly decreased the elevated distal air
space fluid clearance in 22-day gestation rat fetuses and completely
abolished fluid clearance in rat lungs at 40 h after birth (Fig.
4). Propranolol blocked distal air space fluid clearance only when plasma epinephrine levels were elevated.
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Involvement Of Amiloride-Sensitive Na+ Channels During Development
We used amiloride to determine the contribution of the amiloride-sensitive Na+ channels for distal air space fluid clearance during late gestation and early postnatal development. There was no inhibition by amiloride (10
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Extravascular Lung Water
Extravascular lung water was highest in the most premature rat fetuses and steadily decreased as term approached (Fig. 6). A further decrease in extravascular lung water was observed after birth in 40-h rats. However, extravascular lung water was still significantly higher in 40-h rats than in adult rats.
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DISCUSSION |
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Because the majority of infants make the transition from intrauterine life to postnatal life without complications, it is easy to forget that, only hours before birth, the lungs are filled with an essentially protein-free saltwater solution that is actively secreted by the lung's epithelium. Were this fluid not removed rapidly and effectively at birth, adequate oxygenation would be difficult to achieve. We therefore determined the rate of distal air space fluid clearance in developing rat fetuses and whether it varied with development near term. There were significant differences in the ability of the distal air space epithelium to clear excess fluid from the air spaces during late fetal and early postnatal life in the rat. One day before birth, at 21 days gestation, the fetal lung still secreted fluid into the air spaces. Distal air space fluid clearance then increased significantly over the next 12-24 h to reach a very high rate in 22-day gestation rat fetuses, a rate that rapidly decreased after birth and already reached adult levels 40 h after delivery. High endogenous plasma epinephrine levels seemed to mediate the high distal air space fluid clearance in 22-day gestation rat fetuses. Even though the rate of distal air space fluid clearance decreased over the first 40 h after birth, plasma epinephrine levels remained elevated. We measured extravascular lung water in littermates to rat fetuses that were used for the distal air space fluid clearance experiments. Extravascular lung water decreased toward the end of gestation and birth but remained significantly elevated in newborn rats compared with adult levels, suggesting that significant volumes of fetal lung fluid still were present in the developing postnatal rat lungs. Furthermore, distal air space fluid clearance became amiloride sensitive first at birth, although it reached a higher sensitivity at 40 h after birth.
What regulates distal air space fluid clearance at birth? In adult
animals, it has been demonstrated that addition of exogenous -adrenergic agonists can stimulate reabsorption of fluid from the
air spaces (4, 5, 24, 34). Also, endogenous epinephrine can stimulate reabsorption of fetal lung fluid near term (6, 7,
13, 14, 49). Endogenous epinephrine, levels of which increase in
the blood circulation during labor and delivery (7), may
play an important role in lung fluid clearance at birth
(14). However, even though some data exist to support this
hypothesis, there is little functional evidence linking endogenous
epinephrine levels and fluid absorption rates in fetal rats. Therefore,
the involvement of endogenous epinephrine in regulating distal air space fluid clearance at birth was determined by two methods. First,
endogenous epinephrine plasma levels were measured in the developing
rat fetuses, and we correlated these levels to the ability to clear
excess distal air space fluid. Second, functional inhibition of
-adrenergic receptor stimulation by addition of propranolol to the
instilled fluid determined the extent of receptor stimulation.
Endogenous plasma epinephrine levels were partly correlated with an
increased ability of the lung to clear excess distal air space fluid as
term approached. Endogenous epinephrine levels were significantly
elevated in 22-day gestation rat fetuses, at the time when distal air
space fluid clearance was the highest (Figs. 3 and 4). However, distal
air space fluid clearance decreased rapidly during the first 40 h
after birth, whereas epinephrine levels remained elevated, suggesting
that other factors may be involved or that there is another reason why
epinephrine levels remained high. As confirmation of the importance of
epinephrine and
-adrenergic receptors for clearance of fetal lung
fluid at birth, distal air space fluid absorption in 22-day gestation
fetal rat lungs and in 40-h postnatal rats was highly sensitive to
propranolol-inhibition (Fig. 4). Thus propranolol inhibited distal air
space fluid clearance only when endogenous plasma epinephrine levels
were elevated, indicating that
-adrenergic receptor stimulation was
a major mechanism for clearing the fetal lung fluid from the distal air spaces of the lung.
Why would epinephrine levels in fetal plasma remain elevated 40 h
after birth in rats? In guinea pigs, we found a decrease in plasma
epinephrine concentrations immediately after birth that paralleled the
decline in alveolar fluid clearance (14). In contrast, in
rats the distal air space fluid clearance decreased immediately after
birth, whereas no apparent decrease in plasma epinephrine levels was
observed. Why? Guinea pigs are born with mature, fully alveolarized
lungs (27), whereas rats are born with saccular lungs, and
alveolarization primarily occurs postnatally (8). Less
mature lungs may be expected to contain more extravascular lung water.
As such, newborn rats may experience transient periods of hypoxia,
situations known to release epinephrine (25, 44). In fact,
our data show that extravascular lung water in the 40-h postnatal rats
was significantly elevated compared with that in adult animals (Fig.
6). Extravascular lung water of 5.8 ± 0.6 g water/g dry lung
in newborn 40-h rats is comparable with excess water present in the
lungs. Although not measured in this study, this could result in a
hypoxic situation for newborn 40-h rats, which in turn may result in
increased plasma epinephrine levels and propranolol sensitivity even
though these animals are fully air breathing. Another possibility may
relate to postnatal development of rat lungs and differences in
response to -adrenergic stimulation between airways and alveoli. The
rat is born with a saccular lung, which likely would have a larger
proportion of airway surface area compared with alveolar surface area
(8). In adult animals, it has been shown that
-adrenergic stimulation results in fluid secretion in airways
(23) and increased fluid absorption in distal alveolar
regions of the lung (31). If the surface area of
the airways constitutes a proportionally larger fraction of the
transporting surface area in newborn rats, it is plausible that
secretory forces may counteract the otherwise expected elevation of
distal air space fluid clearance at birth from the increased plasma
epinephrine levels. Our data suggest, however, that in rats,
epinephrine may not be the only factor responsible for stimulation of
distal air space fluid clearance at birth. In fact, other studies have
suggested that epinephrine is not the only factor in, or even necessary
for, the clearance of fluid from the lungs at birth (11,
33). Although not studied here, plasma cortisol, thyroid hormone, and change in postnatal O2 levels may contribute
to development of distal air space fluid clearance at birth in addition
to the apparent role of epinephrine as has been implied in other
studies (1, 3, 40).
What is the mechanism for clearing fetal lung fluid near term and at
birth? In adult lungs, active Na+ transport through
amiloride-sensitive epithelial Na+ channels (ENaC) is a key
mechanism for creating a driving force for alveolar epithelial water
reabsorption (for review see Refs. 29 and 31). Amiloride
has been demonstrated to impair reabsorption of fetal lung fluid in
several species (14, 38, 39). Little if any functional
data are available on possible differences in sensitivity to amiloride
inhibition during late gestation and postnatal lung development in
rats. Therefore, we investigated whether inhibition of distal air space
fluid clearance by amiloride differed at different developmental
stages. Interestingly, the results showed that a significantly larger
fraction of distal air space fluid clearance was inhibited by amiloride
in newborn 40-h rats than in 21-day gestation and 22-day gestation
fetal rats (Fig. 5). The -ENaC subunit is found earliest at
gestational day 19, whereas neither the
- nor
-subunit
is significantly expressed until or after birth in isolated distal lung
epithelial cells and in whole lung preparations
(47). The fact that ENaC requires all three
subunits to become fully functional as a Na+ channel may
explain the low amiloride sensitivity on the day of birth (22-day
gestation rat fetuses) seen in our study and the greatly increased
amiloride sensitivity after birth in 40-h-old rats. However, it is also
possible that amiloride affects other sodium transporting pathways,
even the basolateral Na+-K+-ATPase. If a
significant amiloride inhibition of the
Na+-K+-ATPase occurs here, an inhibition of the
alveolar fluid clearance as early as fetal day 21 would be
expected because Na+-K+-ATPase is expressed
then (21). In summary, the rat data largely confirm the
conclusion that ENaC may be responsible for a large fraction of distal
air space fluid clearance at birth, becoming fully active in rats
just after birth, and being already active before birth in guinea pigs
(14) and perhaps also in human lungs (19,
45).
Our results also indicate that amiloride-insensitive pathways may
mediate a fraction of the alveolar fluid clearance at birth in the rat.
It was recently demonstrated that amiloride-insensitive Na+
transport was responsible for a large fraction of the alveolar fluid
clearance observed after -adrenergic stimulation in the adult rat
(36). This fluid clearance was likely to be mediated by
the amiloride-insensitive cyclic nucleotide-gated (CNG) sodium channels, which have been shown to be present in the rat lung (12). However, the role for these channels at birth is
unknown. In fetal sheep, it has been demonstrated that CNG channels
lacked significance when the lungs were to be cleared of fetal lung
fluid at birth (26). It is, however, possible that there
exist species differences and that such channels may be active at birth
in the rat.
A role for the water-only pathways, the aquaporins, in clearing the alveolar spaces from fluid at birth has been postulated, and experiments have been carried out to test this. A developmental expression pattern exists that might suggest a role for the aquaporins at birth (9, 50). However, more recent studies using transgenic mice suggest that aquaporins are of limited importance for the absorption of the fetal lung fluid at birth because genetically modified animals lacking these channels survive birth without respiratory complications (28, 46).
In conclusion, we found functional evidence in late-gestation fetal rat lungs for a stimulated distal air space fluid clearance that rapidly decreased toward adult levels within hours after birth. The elevated distal air space fluid clearance depended on elevations in plasma levels of epinephrine near term.
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ACKNOWLEDGEMENTS |
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This study was supported by National Heart, Lung, and Blood Institute Grant RO#1 HL-51854 and Program Project Grant HL-24075, the Swedish Natural Science Research Council, the Crafoord Foundation, and the Magnus Bergwall Foundation.
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FOOTNOTES |
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Address for reprint requests and other correspondence: H. G. Folkesson, Dept. of Physiology, Northeastern Ohio Univs. College of Medicine, 4209 State Rte. 44, P.O. Box 95, Rootstown, OH 44272-0095 (E-mail: hgfolkes{at}neoucom.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.
10.1152/ajplung.00183.2001
Received 25 May 2001; accepted in final form 3 October 2001.
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