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NeoReviews Vol.7 No.2 2006 e88
© 2006 American Academy of Pediatrics

Clearance of Fluid From Airspaces of Newborns and Infants

Nael Elias, MD^*
Hugh O’Brodovich, MD, FRCP(C)^*,

^* Programme in Lung Biology, Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
Department of Paediatrics, Hospital for Sick Children; Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada

Abbreviations: ARDS: acute respiratory distress syndrome • CHF: congestive heart failure • EF: edema fluid • ENaC: epithelial Na⁺ channel • FDLE: fetal distal lung epithelia • HMD: hyaline membrane disease • nRDS: neonatal respiratory distress syndrome • PD: potential difference • TTN: transient tachypnea of the newborn

	Objectives

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
After completing this article, readers should be able to:

1. Describe fetal lung fluid secretion, its application on lung development, and its reabsorption immediately after birth.
   
2. List the primary cellular mechanism responsible for lung fluid absorption.
   
3. Describe clinical conditions in newborns and infants associated with impaired sodium transport.
   
4. Describe how sodium transport can be influenced by fetal lung maturity.
   

	Introduction

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
When the airspaces of the lungs are filled with fluid, normal gas exchange cannot take place, and there is marked respiratory distress and the need for intensive care. This occurs in only two situations: failure to clear fetal lung liquid at birth and leakage of fluid from the vasculature filling the alveoli (alveolar pulmonary edema). Fluid that is secreted into the fetal airspaces to enable normal lung development must be absorbed at the time of birth for a normal transition from fetal to postnatal life. Failure to do so can lead to two well-known clinical syndromes: transient tachypnea of the newborn (TTN) and when there is coexistent relative surfactant deficiency, neonatal respiratory distress syndrome (nRDS). Pulmonary edema can be caused postnatally by many disorders; those that occur frequently during the neonatal period are patent ductus arteriosus or structural congenital heart disease with marked left-to-right shunting. It is not only biologically reasonable to assume that clearance of such airspace fluid would be beneficial to the patient, but studies in adults suffering from pulmonary edema have shown that the lung’s ability to clear such fluid correlates with survival.

In this article, we review how the epithelium of the lung uses the active transport of sodium (Na⁺), followed by chloride (Cl^–) and water, from the apical to basolateral side of the alveolar lining cells to clear fluid and how the underlying mechanisms for active Na⁺ transport are influenced by the degree of fetal lung maturity or the presence of factors within pulmonary edema fluid.

	Fetal Lung Liquid and the Lungs of the Mature Newborn

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
Fetal lung fluid is essential for normal lung development. It was shown many years ago that the fluid within the fetal or newborn lung arises from the lung and does not merely represent aspirated amniotic fluid. (1) When the volume of fetal lung fluid is abnormally small, lung hypoplasia occurs, as in conditions such as oligohydramnios, (2) pulmonary arterial occlusion, (3)(4) and chronic drainage of fluid from the lungs of fetal sheep. (5)(6) In contrast, excess fetal lung fluid results in lung overgrowth (hyperplasia), (6)(7) which has been demonstrated in both animal studies and in an experiment of nature in which an infant suffered from congenital laryngeal atresia yet had hyperplastic lungs that were overdistended with fluid. (8) Fetal lung fluid secretion arises from active Cl^– secretion by the fetal distal lung epithelia (FDLE) (Fig. 1). (9) (10)(11)

View larger version (25K): [in this window] [in a new window]   Figure 1. Model of fetal lung fluid secretion by epithelial cell. Basolaterally located ATPase extrudes Na+ in exchange for K+ (3 Na+ ions for 2 K+ ions) and generates an approximate 10-fold chemical gradient between the intracellular and extracellular fluid (approximately 10 versus 135 mM, respectively). This action, combined with basolateral K+ channels, which create an intracellular electrical potential of approximately -40 mV, creates a marked electrochemical gradient for Na+ to enter the cell. The Na+ electrochemical gradient "drags Na+" into the cell along with CI– and K+ across the basolateral membrane via a Na+/K+/2 CI– cotransporter. The negatively charged CI– "finds itself" within the cell that has a negative intracellular potential, and this electrical force enables CI– to be "pushed upstream" against its concentration gradient out of the apical anion-selective channels. Na+ follows CI– through paracellular pathways, with water flowing between or through cells via aquaporins.

	Cellular Mechanisms That Result in Epithelial Na+ Transport

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
To transport Na⁺ actively, the epithelia must possess intercellular tight junctions and be polarized, the phenomenon whereby some membrane proteins are localized at the apical membrane and others are localized at the basolateral membrane. As illustrated in Fig. 2, the Na⁺/K⁺ ATPase located at the epithelial basolateral side pumps Na⁺ out of the cell to generate an approximately 10-fold chemical gradient between the intracellular and extracellular fluid (approximately 10 versus 135 mM, respectively). This action, combined with basolateral K⁺ channels, which create an intracellular electrical potential of approximately –40 mV, creates a marked electrochemical gradient for Na⁺ to enter the cell. When there are apical membrane entry pathways, such as Na⁺-permeant ion channels, which allow the ion to traverse the lipid cytoplasmic membrane, Na⁺ flows down its electrochemical gradient into the cell and is extruded across the basolateral membrane via the Na⁺/K⁺ ATPase. The vectorial transport of Na⁺ results in Cl^– and water passively following through paracellular or intracellular pathways. (14)

View larger version (25K): [in this window] [in a new window]   Figure 2. Model of fetal lung fluid absorption by epithelial cell. Fluid absorption results from vectorial transport of Na+, driven by Na+/K+ ATPase. The resultant electrochemically increased gradient leads to passive Na+ absorption via apical Na+-permeant channels that is extruded by Na+/K+ ATPase out of the cell. CI– and water passively follow the Na+ ions although paracellular or intracellular pathways. (See text for details.)

	Conversion of the Perinatal Lung from Fluid Secretion to Fluid Absorption

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
The ability of the mature fetal lung to shift rapidly and dramatically from fluid secretion to fluid absorption has been demonstrated in animal studies. (18) These studies, confirmed by later investigators, showed that the infusion of beta- or beta₂-receptor agonists can convert the in utero fetal ovine lung within minutes from a fluid-secreting to a fluid-absorbing organ. Adding to the biologic importance of these studies is the observation that the concentrations of epinephrine that are required to produce such rapid changes are comparable to those seen in spontaneous labor. However, the increased concentrations of catecholamines are only present for a brief period of time; once the infusion stops, the fetal lung rapidly reverts to fluid secretion. Clearly, there must be a more permanent "on switch" for Na⁺ absorption. One potential candidate is the sevenfold increase in ambient oxygen concentration that the respiratory epithelium "sees" at birth. Experiments have shown that a switch from 3% to 21% oxygen induces Na⁺ transport capacity and ENaC mRNA levels in FDLE (19) and converts distal lung explants from fluid secretion to absorption. (20)

The biologic importance of active Na⁺ transport in the transition from fetal to postnatal life was suggested by fetal experiments, (18)(21) although pharmacologic studies using amiloride, an inhibitor of Na⁺ transport, provided the first direct evidence that defective Na⁺ transport was clinically relevant. (22) Otherwise normal newborn animals in which amiloride was instilled into the airspace prior to the first breath had markedly impaired postnatal lung liquid clearance and associated respiratory distress and hypoxemia. (22) After the amiloride-sensitive ENaC was cloned, (15) it was demonstrated that alpha-ENaC knockout mice, although having apparently normal fetal lung development, died shortly after birth of defective ability to clear their lung fluid. (23) It is also known that ENaC mRNA levels increase in fetal rat lung as it matures. (24) Interestingly, patients who have pseudohypoaldosteronism, the "human alpha-ENaC subunit knockout," (25) do not have a comparable marked impairment in clearance of lung liquid at birth, as evidenced by a lack of nRDS at birth. (26) There are several potential explanations for this variation between species, including the possibility that low levels of alpha-ENaC subunits rescue the pseudohypoaldosteronism lung, (27) that the beta-ENaC subunit may be the rate-limiting subunit in human respiratory epithelium as it is for murine lung airway epithelial Na⁺ transport, (17) or that other Na⁺-permeant ion channels compensate for deficient ENaC activity.

	Clinical Significance of Inadequate Lung Epithelial Na+ Transport in the Term Newborn

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
TTN is a result of too much fetal lung liquid remaining in the distal units after birth. Infants who have TTN most frequently are term, have mature surfactant pathways, and more frequently are delivered by cesarean section. Clinically, infants suffering from TTN have hyperinflated chests, and their chest radiographs demonstrate marked overinflation, with evidence of peribronchial interstitial and some air space edema. In general, these infants do well with minimal or modest respiratory support; full recovery usually is seen within 48 to 72 hours after birth. (28)

The observations that infants who had TTN had significantly lower nasal epithelium amiloride-sensitive potential difference (PD) compared with control infants who did not have TTN and that this amiloride-sensitive PD increased as the infants recovered from their disease (29) suggested that TTN results from immature amiloride-sensitive epithelial Na⁺ transport capacity. Fortunately, these infants have the "usual normal term newborn" 10-fold greater amount of surfactant compared with adults. (30) This helps prevent acute lung injury by keeping the alveolar capillary membrane fully intact, which eventually enables slow absorption of the excess fluid and a relatively benign clinical course.

Cesarean section, relative to vaginal delivery, results in clearance of a greater amount of lung liquid at the time of birth (12) due to at least two factors. First, the infants have not benefited from both the labor process during which fluid could be absorbed following the release of catecholamines and other stimuli that can promote liquid absorption. Second, they would not have had a component of their lung liquid squeezed out the lungs as they passed through the birth canal.

	Clinical Significance of Inadequate Lung Epithelial Na+ Transport in the Preterm Infant

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
Preterm infants frequently suffer from a severe form of respiratory distress that has been referred to as idiopathic respiratory distress syndrome, nRDS, or hyaline membrane disease (HMD). (31)(32) It is characterized by diffuse microatelectasis with accompanying acute lung injury, airspace fluid, hyaline membranes that are composed of fibrin and desquamated epithelium, and proteinaceous exudate that arises from the increase in alveolar capillary membrane permeability. (33) Advances in ventilation modalities, along with exogenous surfactant replacement, have led to improved morbidity and mortality of infants who have nRDS. (34)

It is important to note that preterm infants suffering from nRDS also have less amiloride-sensitive transepithelial PD in their nasal respiratory epithelium, (35) presumably reflecting deficient ENaC expression in their respiratory epithelium. This speculation is supported by animal studies that alpha-, beta-, and gamma-ENaC subunit mRNAs are significantly less abundant in the pseudoglandular and canalicular fetal lung development stages than they are in the postnatal lung. (24) Recent studies have shown that preterm human infants who have nRDS have low levels of alpha-, beta-, and gamma-ENaC mRNA. (36)

Ongoing research is attempting to identify strategies whereby ENaC expression and function can be increased and, hence, augment the clearance of airspace fluid in the preterm and already injured lung.

	Proposed Model of nRDS

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
Because all newborns have significant amounts of salt water within their lung airspaces at the time of birth, preterm infants often have a relative surfactant deficiency, and the new understanding that some infants are born with immature and inadequate respiratory epithelial Na⁺ transport systems has prompted the proposal of a new model to explain the pathogenesis of noninfective RDS in the newborn. Mature newborns who have normal transitions from fetal to postnatal life have mature surfactant and epithelial Na⁺ transport systems. On the other hand, TTN occurs when mature newborns have mature surfactant pathways but have not yet developed adequate respiratory epithelial Na⁺ transport. (37) If an infant is born preterm and has both immature surfactant and epithelial Na⁺ transport, he or she will develop severe nRDS or HMD.

	Pulmonary Edema Clearance in the Postnatal and Adult Lung

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
As described previously, the leakage of protein-rich pulmonary edema fluid occurs in nRDS when lungs are damaged by the respiratory efforts required to overcome the combination of surfactant deficiency and airspace fluid filling from the inability to clear fetal lung liquid. (38) Also, infants who have bronchopulmonary dysplasia likely have pulmonary edema, (39)(40) although pulmonary edema may occur in an infant who has mature lungs or in an older child or adult. Such pulmonary edema can be produced by one of two mechanisms or their combination. The most common mechanism causing increased fluid movement out of the microvasculature is an increase in the transvascular pressure gradients, as clinically occurs in congestive heart failure (CHF). The second mechanism is an abnormally high permeability of lung blood vessels, such as occurs in the acute respiratory distress syndrome (ARDS), which allows water and solutes to move more easily out of intravascular space toward interstitium and airspaces. This raises the question of how the mature lung, whether an infant or adult lung, clears the edema from its airspaces.

Matthay and colleagues (41) first showed that passive classic Starling forces could not explain how fluid was reabsorbed from the alveolar space of the adult lung. Shortly thereafter, it was shown that, in a manner similar to fetal lamb studies, clearance could be increased in the adult lung by beta-receptor stimulation. (42) These studies, along with experiments performed with nonprimate mammalian and human distal lung epithelia, (14)(43)(44) demonstrated that edema fluid is cleared from airspaces of the adult lung through the active transport of Na⁺, with Cl^– and water following (Fig. 2). Alveolar liquid fluid in humans is cleared at a rate of approximately 25% per hour. (14)(43)(44)

	Clinical Importance of Pulmonary Edema Clearance

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
An obvious question is whether this active transport-dependent clearance of fluid from airspaces is clinically important. First, it is biologically reasonable because these spaces should be maintained in a fluid-free state to enable the lungs to perform the physiologic role of gas exchange. Second, defective Na⁺ transport in the newborn is associated with respiratory distress. Third, reabsorption of fluid from airspaces is related to clinical outcome (amount of mechanical ventilation and death rate) in adults suffering from CHF or ARDS. It has been shown that approximately 60% of those who have CHF and 90% of those who have ARDS exhibit impaired airspace fluid clearance, and this correlates with clinical outcomes. (45)(46)

	The Ability of the Lung to "Upregulate" Pulmonary Edema Fluid Clearance

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
Recently it was shown that exposure of distal lung epithelia to cardiogenic pulmonary edema fluid (EF) increases its ability to transport salt and water. (47) However, it was surprising that this occurred via amiloride-insensitive pathways; was not associated with increases in the mRNA encoding the alpha-, beta-, or gamma-ENaC subunits; and did not require the alpha-ENaC subunit. The effect was both time- and dose-dependent and was abrogated by heated or trypsin-treated EF, suggesting that protein(s) were involved in the phenomena. Our laboratory has identified one of the compounds responsible for this effect (unpublished data). We are hopeful that this compound and others that we are attempting to identify will permit us to develop a novel approach to the treatment of pulmonary edema regardless of whether it occurs in the newborn, child, or adult patient.

	Summary

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
As previously described, the fetal lungs require fluid for normal development, which should be cleared immediately after birth to enable normal gas exchange. Lung fluid is absorbed via cellular Na⁺ vertical transport. In newborns, impaired Na⁺ transport leads to fluid-flooded airspaces, as occurs clinically in TTN and nRDS. On the other hand, infants who have flooded airspaces resulting from increased transvascular pressure or high-permeability pulmonary edema benefit from efficient clearance of fluids from the airspaces. Based on these findings, the observation that EF increases clearance of airspace fluid is clinically important.

	Footnotes

 
Author Disclosure

Drs Elias and O’Brodovich did not disclose any financial relationships relevant to this article.

	References

Top Objectives Introduction Fetal Lung Liquid and... Cellular Mechanisms That Result... Conversion of the Perinatal... Clinical Significance of... Clinical Significance of... Proposed Model of nRDS Pulmonary Edema Clearance in... Clinical Importance of Pulmonary... The Ability of the... Summary References

 
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This Article Extract Full Text (PDF) Take the CME quiz: Vol. 7 No. 2, February 2006 E-Letters: Submit a response Alert me when this article is cited Alert me when E-Letters are posted Alert me if a correction is posted Citation Map Services E-mail this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Elias, N. Articles by O’Brodovich, H. Search for Related Content PubMed Articles by Elias, N. Articles by O’Brodovich, H.