At birth the mammalian airway switches from liquid secretion to absorption, an important mechanism in lung liquid clearance. Airway ion transport was examined on the first postnatal day in 38 moderately preterm infants (29–36 weeks gestation). The absorptive airway ion transport capacity was well developed regardless of respiratory condition and there was little capacity for Cl− secretion.
- ENaC, epithelial sodium channel
- PD, potential difference
- airway epithelium
- chloride transport
- epithelial sodium channel
- respiratory distress
- sodium transport
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The fetal airway actively secretes Cl− into the lung lumen.1 During birth, Na+ absorption, largely mediated through the epithelial sodium channel (ENaC), becomes the predominant airway ion transport process and remains so throughout postnatal life.1 This switch from a secretory to an absorptive airway epithelium plays a major role in the clearance of lung liquid in the transition to postnatal air breathing.2,3
Extreme prematurity is associated with increased lung liquid content and reduced ENaC mediated Na+ absorptive airway ion transport.4 There are no airway ion transport data in moderately preterm infants.
We performed nasal potential difference (PD) measurements in 38 moderately preterm infants on the first postnatal day to characterise their airway ion transport characteristics.
The study was designed to test two hypotheses: (a) increased gestational age is associated with greater ENaC mediated Na+ transport; (b) moderately preterm infants with respiratory disease have reduced ENaC mediated Na+ absorption.
The study was approved by the Liverpool Health Authority Local Ethics Committee. A single investigator (EAG) performed nasal PD measurements using a perfusion protocol suitable for neonates.5 We determined (a) stable maximal baseline PD, (b) the change in PD after perfusion with amiloride (10−4 M), an ENaC inhibitor (Δamil), and (c) the change in PD after perfusion with a zero Cl− solution containing amiloride (ΔzeroCl−).
A multiple stepwise regression model was constructed and tested for normal distribution, homoscedasticity, linearity, and independence of error terms to examine the relation between the primary outcome measure (stable maximal baseline PD) and predictor variables (gestation, birth weight, sex, requirement for mechanical ventilation at time of study, oxygen requirement at time of study, presence or absence of antenatal steroids, vaginal or caesarean section delivery). In addition, relations between these variables and the secondary outcomes (Δamil and ΔzeroCl−) were examined. Analysis was performed using SPSS 10.0 (SPSS Inc, Chicago, Illinois, USA). For comparisons between groups, the Mann-Whitney U test was used.
Thirty eight infants (25 male) between 29 and 36 weeks gestation were recruited (median birth weight 1873 g (range 615–3095)). A valid regression model showed a higher magnitude of PD with increasing maturity. Birth weight was also associated with stable maximal baseline PD but less strongly than gestational age. This variable was therefore removed from the regression model. In addition, high stable maximal baseline PD was associated with male sex, mechanical ventilation at the time of study, and caesarean delivery (table 1; adjusted r2 = 0.45, SE of the estimate 9.81) but not with antenatal steroids and requirement for supplemental oxygen. Overall median stable maximal baseline PD was −32.5 mV (range −14 to −69). After perfusion with amiloride, the PD fell by a median of 80% (range 43–100). There was no relation between any of the nasal PD variables and the time that the measurement was made (median age 14.5 hours (range 2–24)).
In a second regression model (adjusted r2 = 0.38; SE of the estimate 10.22), the secondary outcome measure, Δamil, was significantly greater in male infants (β = −0.44; p<0.005), and in those who were mechanically ventilated (β = 0.43; p<0.01), but was not associated with gestation (β = 0.31; p = 0.06).
The median capacity for Cl− secretion (ΔzeroCl−) on the first postnatal day was −5 mV (range 6 to −29 (n = 36)). There was no association between stable maximal baseline PD and ΔzeroCl−. None of the predictor variables (gestational age, sex, mechanical ventilation at time of study, mode of delivery) were related to ΔzeroCl−.
Under normal circumstances a large proportion of the airway liquid is cleared at birth with a steady decline thereafter over several days.1 Extremely preterm infants, especially those with respiratory distress, have reduced lung liquid absorptive capacity4 and increased lung liquid content.6 This is the first report of airway ion transport processes in moderately preterm infants, and our findings are consistent with a previous study showing a relation between absorptive airway ion transport and gestation.4 Our moderately preterm infants, especially those born at 34–36 weeks gestation, had higher PDs than well term infants recently reported by our group (fig 1).5 Whether this represents a compensatory mechanism to clear increased lung liquid content warrants clarification. Our data are also consistent with reports of increasing ENaC expression and distribution in the developing lung.7
Although these data are generated by measurements in the proximal airway, these results probably represent distal ion transport processes. That these infants have a well developed absorptive airway ion transport capacity is supported by the sizeable response to amiloride (median, 80% reduction in PD). Barker et al4 reported smaller responses but used a less concentrated amiloride solution (10−5 M).
The median capacity for Cl− secretion in our cohort was −5 mV. Taken together these results suggest that, in moderately preterm infants, the airway is predominantly absorptive with little capacity for Cl− secretion on the first postnatal day.
Our second hypothesis, that infants with neonatal respiratory disease have reduced absorptive airway ion transport capacity, was not supported by the high PDs found in mechanically ventilated infants. None of these infants had severe lung disease and all were breathing room air spontaneously on the third postnatal day. Gowen et al8 reported high PDs in term infants with transient tachypnoea of the newborn on the first postnatal day compared with a healthy control group. After three days, PD in these infants had returned to levels seen in well term infants in the first 24 hours after birth. Although counter intuitive, these findings may represent a compensatory mechanism for increased lung liquid in those infants on the first postnatal day.
Our results suggest a difference in airway ion transport between male and female infants. It is difficult to explain how the higher PDs in male infants relates to reported differences in respiratory outcome.
The residual PD after perfusion with amiloride was higher in preterm than term infants,5 as was the increase in PD after perfusion with a zero Cl− solution. These differences were small and do not suggest that increased capacity for Cl− secretion in preterm infants is clinically significant, but further studies are needed to clarify this finding.
In summary, this is the first study to report a significant relation between ENaC mediated Na+ absorption and gestation in moderately preterm infants. Our data suggest these infants have well developed absorptive airway ion transport capacity on the first postnatal day.
We thank the families who supported this project. We are indebted to Dr Pierre Barker, University of North Carolina at Chapel Hill, for his continuing help and advice and to Dr Gill Lancaster for statistical advice. We would also like to thank the staff on the neonatal intensive care unit and the midwives at Liverpool Women’s Hospital for their support.
Funding: EAG was supported by the Liverpool Women’s Hospital “Newborn Appeal”. HLW was supported by the Medical Research Council, UK.
Competing interests: none declared
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