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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 Jane´r, MD, Olli Pitka¨nen, MD, PhD, Sture Andersson, MD, PhD

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

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

ABSTRACT

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 ageⱖ37]: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␣-,␤-, and␥-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

expres-sion of␣- and␤-epithelial sodium channel. By 22 to 28 hours after birth, only the

expression of ␤-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

␣-,␤-, and␥-epithelial sodium channel subunits in the airway epithelium may

contribute to the development of respiratory distress in the preterm infant.

www.pediatrics.org/cgi/doi/10.1542/ peds.2007-0100

doi:10.1542/peds.2007-0100

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

Accepted for publication 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@helsinki.fi

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T

HE FETAL LUNGsecretes chloride, and through this active transport, water is secreted into the lung lu-men. Lung liquid is required for normal lung

develop-ment.1,2A switch from secretion to net absorption takes

place perinatally, allowing for rapid lung liquid removal

at birth.3The apically located epithelial sodium channel

(ENaC) is considered the rate-limiting factor in the

pro-cess of liquid removal; ␣-ENaC– knockout mice die

shortly after birth as a result of respiratory distress

char-acterized by an excess of lung liquid.4,5The- and

-sub-units of ENaC were previously considered to possess a regulatory role, and recent observation of increased

␤-ENaC expression leading to cystic fibrosis–like

symp-toms in rodents has further increased interest in this

subunit.6In 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, proges-terone, intracellular pH, and intra-alveolar oxygen

ten-sion.10–14 Also, glucocorticoids have been shown to

in-crease ENaC expression in vitro, in animal models, and in preterm infants who were treated with

dexametha-sone for severe bronchopulmonary dysplasia (BPD).15–18

In developing mouse lung, ␣-ENaC is not apparent

before fetal day 16,19whereas in fetal human lung,

ex-pression 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; how-ever, a significantly lower airway epithelial ENaC activ-ity, as measured by nasal potential difference (N-PD), has been demonstrated in preterm infants with respira-tory distress syndrome (RDS) and in term infants with

transient tachypnea of the newborn.23–25In 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

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 betametha-sone, 4 had from preeclampsia, and 1 had chorioamnio-nitis. 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 diag-nosed by an attending clinician and BPD according to

requirement of additional oxygen at 36 weeks’ GA.27

The samples were prepared and quantified as

de-scribed previously.26Total RNA quantification of the

ep-ithelial 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 spectroflu-orometer (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 manufac-turer’s instructions. Samples were analyzed by real-time polymerase chain reaction (PCR), which was performed with specific TaqMan predeveloped primers and probes

(␣-ENaC,␤-ENaC, and␥-ENaC; Applied Biosystems)

us-ing an Applied Biosystems Prism 7700 Sequence Detec-tion System. Primers and probes for cytokeratin 18 were designed with Primer Express software (Applied Biosys-tems). The PCRs were run as singleplex in duplicate wells. The ENaC expression of each sample was normal-ized 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. In-formed consent was obtained from the parents.

TABLE 1 Clinical Characteristics of the Newborn Infants

Characteristic Preterm

(GA⬍37 wk)

Term (GAⱖ37 wk)

Patients 29 61

Female/male 14/15 27/34

Vaginal delivery/cesarean section 3/26 28/33

Gestational age, wk 31.1⫾3.5 39.6⫾1.0

Birth weight, kg 1.83⫾1.16 3.66⫾0.37

1-min Apgar score 7 9

Cord blood pH 7.29⫾0.06 7.30⫾0.05

Ventilator, yes/no 13/16 —

Surfactant, yes/no 14/15 —

Antenatal betamethasone, yes/no 24/5 —

RDS, yes/no 15/14 —

BPD, yes/no 6/23 —

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RESULTS

Expression of␣-,␤-, and␥-ENaC or cytokeratin 18 was

found in all epithelial samples. At 1 to 5 hours after birth, a significant correlation existed between the

ex-pression of␣- and␤-ENaC and GA (␣-ENaC:n⫽89,r

0.418,P⬍.0001;␤-ENaC:n⫽82,r⫽0.338,P⫽.0019;

Fig 1). In contrast, no significant correlation was found

between␥-ENaC and GA (Fig 1).

In preterm infants, the expression of␣-ENaC did not

change significantly during the study period. In term

infants,␣-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,␤-ENaC expression was

signif-icantly lower at 22 to 28 than at 1 to 5 hours after birth

(preterm: P ⫽.0044; term: P ⬍ .0001; Fig 2). In term

infants,␥-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␣-,␤-, and

␥-ENaC, respectively). In term infants who were born

via cesarean section, only the expression of ␤-ENaC

decreased significantly (P⫽.0013).

At 1 to 5 hours after birth, expressions of␣-,␤-, and

␥-ENaC subunits were significantly lower in preterm

infants than in term infants (␣-ENaC: P ⬍ .0001;

␤-ENaC: P ⫽ .0039; ␥-ENaC: P ⫽ .0065; Fig 2). The

differences in the levels of expression of all ENaC sub-units between the 2 groups were no more significant at 22 to 28 hours after birth.

The mothers of 24 preterm infants had received an-tenatal betamethasone. GA of the preterm infants whose

mothers had received betamethasone was 30.1 ⫾ 2.8

weeks, whereas GA of the preterm infants whose

moth-ers had not received betamethasone was 36.1 ⫾ 0.5

weeks (P⫽.0017). The time between last dose of

ante-FIGURE 1

Correlation between ENaC subunit expression and gestational age in airway epithelium in newborn infants 1 to 5 hours after birth. A,␣-ENaC; B,␤-ENaC; C,␥-ENaC. CK18 indicates cytokeratin 18; NS, not significant.

FIGURE 2

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natal 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

subse-quently developed BPD (GA: 27.6⫾ 1.6 vs 32.0⫾3.2

weeks in preterm infants without BPD [n ⫽ 23]; P

.0033). Expression of␣-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

␣-ENaC or BPD (not significant). The 6 infants who had

BPD had a mean␣-ENaC expression of 2.4 ⫾0.9, and

the remaining 8 infants had a mean␣-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

ⱕ31 full weeks, those with unadjusted␣-ENaC

expres-sion⬍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␤- and

␥-ENaC (P ⫽ .039 and .007, respectively) than term

infants who were born via cesarean section. The

differ-ence in expression of␣-ENaC did not reach significance

(P⫽.063).

DISCUSSION

A strong correlation existed between GA and airway

epithelial expression of␣- and␤-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 ␤-ENaC

oc-curred in all infants, whereas the change in postnatal

expression of␣- and ␥-ENaC was present only in term

infants.

Animal experiments show that ␣-ENaC– knockout

mice succumb at birth to RDS-like symptoms and die

from respiratory distress.4Preterm infants are prone to

developing RDS, which, in addition to lack of surfactant production, has been attributed to insufficient lung

liq-uid clearance.3In our previous study15performed

with-out 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

differ-ence 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

ac-tivity of airway ENaC is significantly lower in infants

with RDS.25 An explanation for the seeming

contradic-tion 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␣-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,26term infants who were born via

cesarean section tended to have a greater increase in postnatal lung compliance and a higher airway epithelial

␣- and␥-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

expres-sion of␣-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 so-dium absorption remains higher during the first 28 hours of life.

Expression of␥-ENaC varied greatly throughout our

study. Infants with high␥-ENaC levels did not differ in

regard to clinical parameters or pathologies from the rest

of the study population. The role of ␥-subunit in the

activity of ENaC is unclear. Although␤-ENaC– deficient

mice do not have respiratory distress at birth,28␥-ENaC–

knockout mice, although showing a milder phenotype

than␣-ENaC– deficient mice, also exhibit impaired lung

liquid clearance.29Furthermore,-ENaC has been

sug-gested to possess a possible regulatory role.30In addition,

the␥-subunit has been demonstrated to be more

impor-tant than the ␤-subunit for ENaC trafficking.31Because

ENaC and lung liquid absorption are considered key elements in postnatal adaptation, our finding empha-sizes 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.20,22In humans, the importance of the ENaC in

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expres-sion is low, pseudohypoaldosteronism type I, reports on perinatal respiratory function have been somewhat

con-tradictory33–35; 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 pre-term and pre-term newborn infants: prepre-term newborn in-fants with RDS have demonstrated low

amiloride-induc-ible 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 cor-relate 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 epi-thelium, any effect in levels of ENaC expression were likely to have passed. Indeed, the bioactivity of antena-tally 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 addi-tional glucocorticoid treatment. Accordingly, future studies should include infants who are born closer to the last dose of antenatal betamethasone.

CONCLUSIONS

As determined by this study, ENaC expression in hu-mans 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 expres-sion. Additional studies are needed to assess functional correlates of ion transport in addition to gene expres-sion.

ACKNOWLEDGMENTS

This work was supported by the National School of Clinical Investigation, the Sigrid Juse´lius Foundation, Finska La¨karesa¨llskapet, the Foundation for Pediatric Research, the Finnish Special Government Subsidy for Health Sciences, the Biomedicum Helsinki Foundation, the Orion Corporation Research Foundations, the Finn-ish 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 coopera-tion; Marita Suni and Marjatta Vallas for excellent tech-nical assistance; Petteri Hovi, MD, for statistical analysis; and the Pediatric Graduate School of the University of Helsinki for support.

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DOI: 10.1542/peds.2007-0100

2007;120;1311

Pediatrics

Otto Helve, Cecilia Janér, Olli Pitkänen and Sture Andersson

Infants Depends on Gestational Age

Expression of the Epithelial Sodium Channel in Airway Epithelium of Newborn

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The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

Figure

TABLE 1Clinical Characteristics of the Newborn Infants
FIGURE 2

References

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