Division of Developmental Lung Biology, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah 84132
PHYSIOLOGISTS HAVE KNOWN for
over a century that the lungs are filled with liquid during fetal life
(53), but the origin of this liquid was uncertain until
1948 when Jost and Policard (35) challenged the then
prevailing view that liquid in the lumen of the fetal lung came from
intrauterine aspiration of amniotic contents (2). In
studies designed to examine the ontogeny of the pituitary-adrenal axis,
these French scientists ligated the tracheae of fetal rabbits and
serendipitously discovered that over a period of 9 days, the lungs
became distended with fluid (35). This observation,
subsequently confirmed and expanded on by others (3, 32),
established that the lung itself rather than the amniotic sac is the
source of liquid that fills the lumen of the developing lung, thereby
serving as a well-regulated template for fetal lung growth. Subsequent
studies, most of them in sheep, showed that this liquid derives from
chloride secretion across the respiratory epithelium (1,
51), a process that can be inhibited by diuretics that block
Na-K-2Cl cotransport (18, 20, 56). In vitro studies using
cultured tissue explants and monolayers of epithelial cells harvested
from human fetal lung have provided convincing evidence that
cation-dependent chloride transport, driven by epithelial cell
Na-K-ATPase, is the mechanism by which liquid is secreted into the
lumen of the mammalian lung during development (5, 40).
Rapid removal of liquid from potential airspaces is a key step in
establishing the timely switch from placental to pulmonary gas exchange
at birth. A sudden gush of fluid from the mouth often punctuates a
baby's birth, signaling the start of extrauterine life. This
observation helped to promulgate what has come to be known as the
"vaginal squeeze," a notion that was introduced almost half a
century ago by Karlberg et al. (36) to explain how liquid is removed from the lungs as air breathing begins. This concept was
derived from intrathoracic pressure measurements that a group of
Swedish investigators made during delivery of normal-term infants (36). They reported that "Once the head is delivered a
pressure difference between the mouth and the thorax is created which
would serve to express the amniotic fluid from the airways. This
reasoning seems in agreement with the clinical observation that fluid
flows out of the nose and mouth, sometimes as a jet, at this stage of delivery." The report went on to say that "because the
intrathoracic pressure variations during vaginal delivery appear to
play a role in facilitating the subsequent aeration of the lung
parenchyma, it may be speculated upon whether the absence of `the
squeeze' in infants delivered by Cesarean section may, at least in
part, be responsible for the higher incidence of neonatal
respiratory complications occurring in this group"
(36). Although several reports have documented the
importance of labor in facilitating lung liquid removal during birth
(12-15, 23) and the adverse effects of a cesarean
section without prior labor on the incidence and severity of neonatal
respiratory distress (16, 17, 26, 49), it has taken the
better part of four decades for scientists to clarify how liquid drains
from the lungs around the time of birth. Although the vaginal
squeeze is undeniably crucial in expelling the fetus from the
introitus, mechanical compression of the thorax per se appears to have
little, if any, impact on liquid drainage from the lungs during birth
(12, 15). Indeed, the normal transition from liquid to air
inflation of the lungs during parturition is considerably more complex
than the characteristic oral gush at delivery would imply.
As birth approaches near term gestation, the rate of liquid formation
and the volume of liquid within the lumen of the fetal lung decrease
(30, 39). These changes occur at a stage of lung
development in which there is increased pulmonary expression of
epithelial sodium channels and Na-K-ATPase (28, 34, 43, 48,
55) as well as increased activity of Na-K-ATPase in distal lung
epithelial cells (11, 24, 34). Several investigators (8, 47, 54) have examined the bioelectric properties of monolayers of cultured lung epithelial cells obtained from near-term fetal rats, showing that these cells have the capacity to absorb sodium. Thus developmental changes in lung epithelial cell ion transport late in gestation, switching from predominantly chloride secretion to predominantly sodium absorption near birth, appear to have
an important role in preparing the lung for its pivotal postnatal adaptation.
What regulates the balance between secretion and absorption of lung
liquid near birth? Several studies have demonstrated that hormonal
changes occurring in the fetus just before and during labor, notably
increased release of epinephrine from the adrenal medulla, may have an
important role in triggering the switch from liquid secretion to
absorption. In studies done with fetal lambs late in gestation, Walters
and Olver (58) found that intravenous infusion of
epinephrine or isoproterenol, but not of norepinephrine, led to the
absorption of liquid from potential airspaces, an effect that
The decrease in lung liquid production that occurs in fetal sheep
before birth may be related to a rise in plasma concentration of
epinephrine late in labor (15). In fetal sheep, however, lung liquid production and lung water content often decrease before there is any detectable release of catecholamines (13,
23). Several reports have shown, however, that the concentration
of During the past decade, the guinea pig has eclipsed the sheep as the
experimental model of choice for studying developmental changes in lung
fluid balance, confirming and, in some instances, expanding on
observations that had been made previously on fetal and newborn sheep,
goats, rabbits, and rats. Studies using excised lungs of fetal guinea
pigs showed that Na-K-2Cl cotransport in the respiratory epithelium is
the mechanism by which liquid secretion occurs in the fetal lung
(56). Further studies using the same experimental model
showed that the net production of lung liquid tends to decrease late in
gestation (52) and that epinephrine, cAMP, cortisol, and
aldosterone each can cause an abrupt decrease in fetal lung liquid
formation (37, 38, 62). Studies using fetal and newborn
guinea pigs have also shown that plasma epinephrine concentrations are
elevated during labor and after birth (31, 42) and that
inhibition of sodium transport across the respiratory epithelium slows
the rate at which liquid is removed from the lungs postnatally
(44, 45). The finding that propranolol inhibits lung
liquid clearance in newborn guinea pigs (31) provides
further evidence that epinephrine may play a critical role in perinatal clearance of lung liquid in this species. A recent study
(4) indicated that the stimulatory effect of epinephrine
on lung liquid clearance is coupled to increased postnatal pulmonary
expression of amiloride-sensitive sodium channels, which is mediated,
at least in part, by a perinatal increase in plasma cortisol
concentrations (4). Thus the interaction of multiple
hormones of adrenal origin appears to have a major regulatory role in
converting the respiratory epithelium from a predominantly
chloride-secreting membrane during fetal development to a predominantly
sodium-absorbing membrane after birth.
This issue of the American Journal of Physiology-Lung Cellular
and Molecular Physiology includes a paper describing experiments related to the mechanisms and regulation of lung liquid clearance in
late-gestation guinea pigs after labor was induced by maternal injection of oxytocin (42). The results confirm the
previous observations (15, 23, 45) made on near-term
fetuses and newborn animals after the spontaneous onset of labor that
events associated with parturition trigger absorption of liquid from the lung lumen across the respiratory epithelium into the pulmonary interstitium by a process that involves amiloride-sensitive sodium channels. This paper also shows that plasma epinephrine concentrations were significantly elevated in guinea pigs that had received oxytocin compared with those in control pups and that Early death from respiratory failure occurs in the absence of
functional epithelial sodium channels (33), whereas the
essential role of epinephrine in this cascade of events is less
clear-cut. At least two reports have indicated that absorption of lung
liquid near birth does not depend on epinephrine. McDonald et al.
(41) showed that irreversible blockade of What is the clinical relevance of the aforementioned
observations? First, there can be little doubt that delivery by
cesarean section without prior labor greatly increases the risk of
respiratory distress in human neonates. It remains to be determined
whether induction of labor by oxytocin has the same effect on lung
liquid clearance and associated respiratory function in newborn infants as it apparently has on near-term fetal guinea pigs. Although enormous
progress has been made in recent years to help clarify how liquid is
produced in the fetal lung and how it is removed during and after
birth, there has been relatively little attention paid as to how this
information relates to the human lung during development and how it
might be applied therapeutically to alter lung growth before birth or
to prevent respiratory distress after birth. Knowledge of how
epithelial chloride secretion might be enhanced pharmacologically could
prove useful in promoting expansion and growth of the fetal lung in
situations that are known to be associated with pulmonary hypoplasia
(congenital diaphragmatic hernia, prolonged oligohydramnios).
ARTICLE
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ARTICLE
REFERENCES
-adrenergic blockade with propranolol prevented. The same group of
investigators subsequently showed that intraluminal administration of
amiloride, a sodium transport inhibitor, blocked the effect of
epinephrine on lung liquid absorption in fetal sheep (50). This finding suggests that
-adrenergic agonists stimulate sodium uptake by the lung epithelium, which, in turn, drives liquid from the
lung lumen into the interstitium where it can be absorbed into the
pulmonary circulation or drain through lung lymphatics into the
systemic circulation (13). Tracheal instillation of dibutyryl cAMP (an analog of cAMP) also leads to the absorption of lung
liquid in fetal lambs late in gestation (6, 59). The
inhibitory effects of both dibutyryl cAMP and epinephrine on the net
production of lung liquid increase with advancing gestational age, and
both responses are attenuated by prior removal of the thyroid gland
(6). Barker et al. (10) showed that
replacement therapy with triiodothyronine after thyroidectomy restored
the inhibitory effect of epinephrine on lung liquid production in fetal
sheep. These investigators subsequently found that treatment of preterm
fetal sheep with a combination of triiodothyronine and hydrocortisone
may stimulate early maturation of epinephrine-induced absorption of
lung liquid (7, 9). Another study (22) showed a synergistic effect of terbutaline, a
-adrenergic agonist, and aminophylline, a phosphodiesterase inhibitor, in switching lung liquid
secretion to absorption in fetal lambs. In these studies, addition of
amiloride to the lung liquid prevented its absorption. These
observations support the view that as birth approaches, conditions that
stimulate release of cAMP in the lung may trigger absorption of liquid
from the lung lumen in response to transepithelial sodium efflux.
-adrenergic receptors in lung tissue increases late in gestation (25, 60, 61), which may make the lungs more responsive to the effects of epinephrine during labor (15).
-adrenergic blockade with propranolol markedly inhibited the rate of removal of lung liquid
with and without prior treatment with oxytocin. These observations add
to the growing body of evidence that the stress of labor, whether it
occurs spontaneously or after oxytocin induction, stimulates release of
epinephrine into the circulation, presumably increasing pulmonary cAMP
and thereby increasing sodium absorption through amiloride-sensitive
sodium channels on the luminal surface of the respiratory epithelium.
-adrenergic
receptors in fetal rabbits did not prevent the normal reduction in lung
water that occurs during parturition, and Chapman et al.
(23) found that inhibition of
-adrenergic activity with
propranolol did not prevent lung liquid absorption in fetal lambs late
in labor. Both of these studies were done on living animals, whereas
the studies reported by Norlin and Folkesson (42) in this
issue of the Journal were conducted in lungs of fetuses after death. Thus, under in vivo physiological conditions, other hormones such as
vasopressin (21, 57), cortisol, and aldosterone (7, 9, 37), all of which have been shown to reduce lung liquid production in fetal animals late in gestation, may substitute for
epinephrine in stimulating sodium absorption in the respiratory epithelium. It is also possible that the mechanisms and regulation of
lung liquid absorption may differ between species. For example, the
bicarbonate concentration of lung luminal liquid is low (~2 meq/l) in
fetal sheep and guinea pigs, whereas the bicarbonate concentration of
lung liquid in fetal dogs and monkeys is similar to that of plasma
(~25 meq/l) (27, 46). Thus one needs to be cautious in
extrapolating results of studies done under specific experimental
conditions in one species to the normal physiology of other species.
Nevertheless, evidence is mounting to support the notion that the
interaction of several hormones that are released late in gestation and
during labor, including epinephrine, have an important role in
regulating sodium-dependent lung liquid absorption near birth.
-Adrenergic agonists are often used to treat apparent
bronchoconstriction in infants with chronic lung injury, and yet there
has been little, if any, interest in determining the potential benefit
of such therapy on lung liquid clearance in infants with acute
respiratory distress. Recent reports (19, 29) indicate
that intrapulmonary delivery of nitric oxide or surfactant may reduce
the net production of liquid within the lungs of fetal sheep. It
remains to be seen if these biologically active substances, which are
so important in neonatal adaptation of the pulmonary circulation and
terminal respiratory units, respectively, can be applied
therapeutically to hasten liquid removal from the lungs in neonatal
respiratory distress that is associated with alveolar edema. Lessons
learned from the lung in labor need not be left to linger in the laboratory.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. D. Bland, Division of Developmental Lung Biology, Dept. of Pediatrics, Univ. of Utah School of Medicine, 50 North Medical Dr., Salt Lake City, UT 84132 (E-mail: dick.bland{at}hsc.utah.edu).
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REFERENCES |
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