Published online November 30, 2007
PEDIATRICS Vol. 120 No. 6 December 2007, pp. 1311-1316 (doi:10.1542/peds.2007-0100)
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ARTICLE

Expression of the Epithelial Sodium Channel in Airway Epithelium of Newborn Infants Depends on Gestational Age

Otto Helve, MD, Cecilia Janér, MD, Olli Pitkänen, MD, PhD and Sture Andersson, MD, PhD

Department of Pediatrics, Hospital for Children and Adolescents, Helsinki, Finland


   ABSTRACT
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 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. In the newborn infant, removal of fetal lung liquid from the airways depends on ion transport through the airway epithelium. The epithelial sodium channel is considered rate limiting for the postnatal clearance of lung liquid, but it is unknown whether during the early postnatal period the expression of epithelial sodium channel is associated with maturity. Our objective was to study the relationship between gestational age and epithelial sodium channel expression in airway epithelium.

METHODS. In 90 newborn infants (preterm [gestational age < 37]: n = 29; term [gestational age ≥ 37]: n = 61), we measured the expression of epithelial sodium channel (reported as attomoles of subunit expression normalized to femtomoles of expression of cytokeratin 18) in nasal epithelium at 1 to 5 and 22 to 28 hours after birth.

RESULTS. At 1 to 5 hours postnatally, airway expression of {alpha}-, β-, and {gamma}-subunits of epithelial sodium channel was lower in preterm than in term infants. At this time point, significant correlations existed between gestational age and airway expression of {alpha}- and β-epithelial sodium channel. By 22 to 28 hours after birth, only the expression of β-epithelial sodium channel had decreased significantly in the preterm infants, whereas the expression of all epithelial sodium channel subunits had decreased significantly in the term infants. At this time point, no difference in expression of any of the subunits was found between preterm and term infants.

CONCLUSIONS. Airway expression of epithelial sodium channel at 1 to 5 hours of age is significantly lower in preterm than in term infants. Low postnatal expression of {alpha}-, β-, and {gamma}-epithelial sodium channel subunits in the airway epithelium may contribute to the development of respiratory distress in the preterm infant.

Key Words: ENaC • epithelium • ion transport • lung development • newborn infant

Abbreviations: ENaC—epithelial sodium channel • BPD—bronchopulmonary dysplasia • N-PD—nasal potential difference • RDS—respiratory distress syndrome • PCR—polymerase chain reaction • GA—gestational age

The fetal lung secretes chloride, and through this active transport, water is secreted into the lung lumen. Lung liquid is required for normal lung development.1,2 A switch from secretion to net absorption takes place perinatally, allowing for rapid lung liquid removal at birth.3 The apically located epithelial sodium channel (ENaC) is considered the rate-limiting factor in the process of liquid removal; {alpha}-ENaC–knockout mice die shortly after birth as a result of respiratory distress characterized by an excess of lung liquid.4,5 The β- and {gamma}-subunits of ENaC were previously considered to possess a regulatory role, and recent observation of increased β-ENaC expression leading to cystic fibrosis–like symptoms in rodents has further increased interest in this subunit.6 In the mammalian lung, the role of ENaC in lung liquid clearance has been shown to be critical in postnatal pulmonary adaptation, whereas, in the more mature lung, amiloride-insensitive channels account for a substantial part of epithelial sodium transport.7–9

The regulation of ENaC expression and activity before birth may be important in preparation for postnatal lung liquid removal. This is affected by several factors, such as aldosterone, catecholamines, thyroxin, estradiol, progesterone, intracellular pH, and intra-alveolar oxygen tension.10–14 Also, glucocorticoids have been shown to increase ENaC expression in vitro, in animal models, and in preterm infants who were treated with dexamethasone for severe bronchopulmonary dysplasia (BPD).15–18

In developing mouse lung, {alpha}-ENaC is not apparent before fetal day 16,19 whereas in fetal human lung, expression of all 3 ENaC subunits has been found at early gestation.20–22 It is unknown whether ENaC expression in the human fetal lung changes during gestation; however, a significantly lower airway epithelial ENaC activity, as measured by nasal potential difference (N-PD), has been demonstrated in preterm infants with respiratory distress syndrome (RDS) and in term infants with transient tachypnea of the newborn.23–25 In addition, we previously reported15,26 that the expression of ENaC is significantly lower in newborn preterm infants with RDS than in healthy term infants. Our aim was to study how the airway epithelial expression of the 3 ENaC subunits relates to gestational age (GA) and whether it changes in the early postnatal period in the newborn infant.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
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Ninety newborn infants were studied at 1 to 5 and 22 to 28 hours after birth (Table 1). Of them, 29 were preterm (GA < 37 weeks). Term infants were sampled at 128 ± 62 and 1503 ± 76 minutes and preterm infants at 146 ± 78 and 1534 ± 204 minutes after birth (not significant for difference between the 2 groups). Of the mothers of preterm infants, 24 had received antenatal betamethasone, 4 had from preeclampsia, and 1 had chorioamnionitis. In 4 cases, delivery was preceded by premature rupture of the membranes for >24 hours (Table 1). One of the preterm infants developed sepsis. RDS was diagnosed by an attending clinician and BPD according to requirement of additional oxygen at 36 weeks' GA.27


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  		TABLE 1 Clinical Characteristics of the Newborn Infants

 
The samples were prepared and quantified as described previously.26 Total RNA quantification of the epithelial specimens was performed using a commercially available kit including a standard RNA preparation (RiboGreen RNA Quantitation Kit; Molecular Probes, Eugene, OR). The emission at 520 nm of the adducts was measured after excitation at 480 nm using a spectrofluorometer (LS50B; Perkin Elmer, Shelton, CT), and the sample RNA content was deduced from the standard plot.

Reverse transcription of RNA to cDNA was performed with TaqMan Reverse Transcription Reagents (Applied Biosystems, Foster City, CA) according to the manufacturer's instructions. Samples were analyzed by real-time polymerase chain reaction (PCR), which was performed with specific TaqMan predeveloped primers and probes ({alpha}-ENaC, β-ENaC, and {gamma}-ENaC; Applied Biosystems) using an Applied Biosystems Prism 7700 Sequence Detection System. Primers and probes for cytokeratin 18 were designed with Primer Express software (Applied Biosystems). The PCRs were run as singleplex in duplicate wells. The ENaC expression of each sample was normalized against that of cytokeratin 18, which was used as an epithelial marker (ENaC: cytokeratin 18, attomole per femtomole [amol/fmol]). Tissue that was excised from a healthy turbinate during rhinoplasty served as a known standard after determination by quantitative competitive reverse transcriptase–PCR as described previously.15

Clinical data are presented as means ± SD and study data as means ± SEM. Comparisons were performed with the Wilcoxon matched pairs test or the Mann-Whitney U test. Correlations were calculated with the Spearman nonparametric test. The Ethics Committee of the Hospital for Children and Adolescents of the Helsinki University Central Hospital approved the study. Informed consent was obtained from the parents.


   RESULTS
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DISCUSSION
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Expression of {alpha}-, β-, and {gamma}-ENaC or cytokeratin 18 was found in all epithelial samples. At 1 to 5 hours after birth, a significant correlation existed between the expression of {alpha}- and β-ENaC and GA ({alpha}-ENaC: n = 89, r = 0.418, P < .0001; β-ENaC: n = 82, r = 0.338, P = .0019; Fig 1). In contrast, no significant correlation was found between {gamma}-ENaC and GA (Fig 1).


Figure 1
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  		FIGURE 1 Correlation between ENaC subunit expression and gestational age in airway epithelium in newborn infants 1 to 5 hours after birth. A, {alpha}-ENaC; B, β-ENaC; C, {gamma}-ENaC. CK18 indicates cytokeratin 18; NS, not significant.

 
In preterm infants, the expression of {alpha}-ENaC did not change significantly during the study period. In term infants, {alpha}-ENaC expression was lower at 22 to 28 hours than at 1 to 5 hours after birth (P = .023; Fig 2); however, in both groups, β-ENaC expression was significantly lower at 22 to 28 than at 1 to 5 hours after birth (preterm: P = .0044; term: P < .0001; Fig 2). In term infants, {gamma}-ENaC expression was significantly lower at 22 to 28 than at 1 to 5 hours after birth (22–28 hours: 4.7 ± 2.8; 1–5 hours: 14.3 ± 3.9; P = .0003; Fig 2). The decrease in expression of ENaC subunits during the first 28 hours was present in term infants who were born vaginally (P = .0021, .0003, and .0009 for {alpha}-, β-, and {gamma}-ENaC, respectively). In term infants who were born via cesarean section, only the expression of β-ENaC decreased significantly (P = .0013).


Figure 2
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  		FIGURE 2 Expression of ENaC subunits in airway epithelium in preterm (open box) and term (striped box) infants 1 to 5 and 22 to 28 hours after birth. A, {alpha}-ENaC; B, β-ENaC; C, {gamma}-ENaC. CK18 indicates cytokeratin 18.

 
At 1 to 5 hours after birth, expressions of {alpha}-, β-, and {gamma}-ENaC subunits were significantly lower in preterm infants than in term infants ({alpha}-ENaC: P < .0001; β-ENaC: P = .0039; {gamma}-ENaC: P = .0065; Fig 2). The differences in the levels of expression of all ENaC subunits between the 2 groups were no more significant at 22 to 28 hours after birth.

The mothers of 24 preterm infants had received antenatal betamethasone. GA of the preterm infants whose mothers had received betamethasone was 30.1 ± 2.8 weeks, whereas GA of the preterm infants whose mothers had not received betamethasone was 36.1 ± 0.5 weeks (P = .0017). The time between last dose of antenatal steroids and first sampling (330 ± 70 hours) did not correlate with the expression of ENaC subunits (data not shown). Of the 29 preterm infants, 15 received a diagnosis of RDS (GA: 28.8 ± 2.6 vs 33.5 ± 2.5 weeks in preterm infants without RDS; P = .0002). Expression of ENaC subunits in infants with RDS did not differ from those without RDS. Of the preterm infants, 6 subsequently developed BPD (GA: 27.6 ± 1.6 vs 32.0 ± 3.2 weeks in preterm infants without BPD [n = 23]; P = .0033). Expression of {alpha}-ENaC in the BPD group at 1 to 5 hours after birth was lower than in preterm infants who survived without BPD (2.4 ± 0.9 vs 5.3 ± 0.7 amol/fmol cytokeratin 18, respectively; P = .0382). The infants who developed BPD were all born at a GA of <31 weeks. To examine this finding further, we made a cutoff point at 31 weeks' GA and analyzed the 14 infants in this group. Within this group, GA had no effect on the expression of {alpha}-ENaC or BPD (not significant). The 6 infants who had BPD had a mean {alpha}-ENaC expression of 2.4 ± 0.9, and the remaining 8 infants had a mean {alpha}-ENaC expression of 4.9 ± 0.8 amol/fmol cytokeratin 18 at 1 to 5 hours of age (P = .05). Among infants who were born at a GA of ≤31 full weeks, those with unadjusted {alpha}-ENaC expression <2.5 amol/fmol cytokeratin 18 at 1 to 5 hours were more likely to develop BPD: 5 of the 6 such infants (and 1 of the 8 infants remaining) developed BPD (OR: 35; 95% confidence interval: 1.7–70.3; sensitivity: 83%; specificity: 88%; positive predictive value: 83%).

At 1 to 5 hours after birth, there was no significant difference in the expressions of ENaC subunits between term infants who were born vaginally and term infants who were born via cesarean section; however, at 22 to 28 hours after birth, the term infants who were born vaginally had significantly lower expressions of β- and {gamma}-ENaC (P = .039 and .007, respectively) than term infants who were born via cesarean section. The difference in expression of {alpha}-ENaC did not reach significance (P = .063).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
A strong correlation existed between GA and airway epithelial expression of {alpha}- and β-ENaC at 1 to 5 hours after birth. Between 1 to 5 and 22 to 28 hours after birth, a significant decrease in the expression of β-ENaC occurred in all infants, whereas the change in postnatal expression of {alpha}- and {gamma}-ENaC was present only in term infants.

Animal experiments show that {alpha}-ENaC–knockout mice succumb at birth to RDS-like symptoms and die from respiratory distress.4 Preterm infants are prone to developing RDS, which, in addition to lack of surfactant production, has been attributed to insufficient lung liquid clearance.3 In our previous study15 performed without an age-matched control group, low expression of ENaC in newborn preterm infants was associated with RDS. In this study, we did not find a significant difference in airway epithelial expression of ENaC between preterm infants with RDS and those without. Although the study was not structured to detect changes of ENaC expression in pathologies such as RDS, this finding is somewhat surprising. Previously, the expression of all subunits was shown to be lower in preterm infants with RDS than in healthy term infants.15 Moreover, the activity of airway ENaC is significantly lower in infants with RDS.25 An explanation for the seeming contradiction of the 2 findings may be that the samples in this study were obtained within hours after birth and not during severe RDS. Alternatively, in RDS, the state of activation of ENaC may have a greater impact on ion transport than the amount of molecules expressed. It is interesting that we found a lower {alpha}-ENaC expression in the 6 preterm infants who subsequently developed BPD than in those who survived without BPD in the same GA group. This finding needs to be confirmed in studies with larger and more age-defined populations.

In a previous study,26 term infants who were born via cesarean section tended to have a greater increase in postnatal lung compliance and a higher airway epithelial {alpha}- and {gamma}-ENaC expression. Our finding of higher ENaC expression at 22 to 28 hours after birth supports the notion that infants who are born via cesarean section may have potential for greater liquid absorption than infants who are born vaginally. In addition, newborn term infants have been shown to have a stable expression of {alpha}-ENaC during the first days of life. In this study, we demonstrate the latter phenomenon in infants who were born via cesarean section only. It is possible that in these infants, the requirement of the potential for sodium absorption remains higher during the first 28 hours of life.

Expression of {gamma}-ENaC varied greatly throughout our study. Infants with high {gamma}-ENaC levels did not differ in regard to clinical parameters or pathologies from the rest of the study population. The role of {gamma}-subunit in the activity of ENaC is unclear. Although β-ENaC–deficient mice do not have respiratory distress at birth,28 {gamma}-ENaC–knockout mice, although showing a milder phenotype than {alpha}-ENaC–deficient mice, also exhibit impaired lung liquid clearance.29 Furthermore, {gamma}-ENaC has been suggested to possess a possible regulatory role.30 In addition, the {gamma}-subunit has been demonstrated to be more important than the β-subunit for ENaC trafficking.31 Because ENaC and lung liquid absorption are considered key elements in postnatal adaptation, our finding emphasizes the importance of GA to the capacity for lung liquid absorption.

In rodents, the expression of ENaC was previously correlated to GA.4,32 In the developing human lung, ENaC expression has been detected already from early gestation.20,22 In humans, the importance of the ENaC in the immediate postnatal pulmonary adaptation remains uncertain. In a situation in which ENaC subunit expression is low, pseudohypoaldosteronism type I, reports on perinatal respiratory function have been somewhat contradictory33–35; however, the dependence of the airway epithelial expression of ENaC on GA suggests that the potential for ENaC activity is higher in later gestation. Our finding of ENaC expression's correlating with GA supports results from functional measurements in preterm and term newborn infants: preterm newborn infants with RDS have demonstrated low amiloride-inducible N-PD,25 and in healthy term newborn infants, sodium transport as measured by N-PD has been shown to correlate positively with lung compliance.26

The focus of our study was to clarify whether the foundations for sodium transport exist at different stages of gestation. All infants who were born before 33 weeks' GA had received corticosteroids antenatally, which are known to upregulate ENaC expression in vitro.17 The administration of antenatal corticosteroids did not correlate to airway epithelial ENaC expression. It is possible that as a result of the long time frame between antenatal administration and perinatal sampling of the nasal epithelium, any effect in levels of ENaC expression were likely to have passed. Indeed, the bioactivity of antenatally administered betamethasone has been shown to be highest at 12 hours after last dose.36 Furthermore, it is possible that the effect of GA on ENaC expression in more preterm infants surpasses the effect of any additional glucocorticoid treatment. Accordingly, future studies should include infants who are born closer to the last dose of antenatal betamethasone.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
As determined by this study, ENaC expression in humans depends on GA. Preterm infants are susceptible to inefficient lung liquid clearance, which, in animals, has been shown to be a consequence of low ENaC expression. Additional studies are needed to assess functional correlates of ion transport in addition to gene expression.


   ACKNOWLEDGMENTS
 
This work was supported by the National School of Clinical Investigation, the Sigrid Jusélius Foundation, Finska Läkaresällskapet, the Foundation for Pediatric Research, the Finnish Special Government Subsidy for Health Sciences, the Biomedicum Helsinki Foundation, the Orion Corporation Research Foundations, the Finnish Medical Foundation, and the University of Helsinki Funds

We thank the personnel of the Neonatal Unit of the Hospital for Children and Adolescents for kind cooperation; Marita Suni and Marjatta Vallas for excellent technical assistance; Petteri Hovi, MD, for statistical analysis; and the Pediatric Graduate School of the University of Helsinki for support.


   FOOTNOTES
 
Accepted Jun 1, 2007.

Address correspondence to Otto Helve, MD, Scientific Laboratory, Hospital for Children and Adolescents, Biomedicum B429b, PO Box 700, 00029-HUS, Helsinki, Finland. E-mail: otto.helve{at}helsinki.fi

The authors have indicated they have no financial relationships relevant to this article to disclose.


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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics

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