Amiloride-Sensitive Nasal Potential Difference Is Not Changed by Estradiol and Progesterone Replacement But Relates to BPD or Death in a Randomized Trial on Preterm Infants

Abstract

Postnatal replacement of placental estradiol (E2) and progesterone (P) in preterm infants may improve lung function, possibly mediated through enhanced epithelial Na ϩ transport and alveolar fluid clearance. Preterm infants of Ͻ29 wk gestational age and Ͻ1000 g birth weight requiring mechanical ventilation within 12 h of birth were randomized to receive either 2.5 mg/kg E2 and 22.5 mg/kg P per day (E2/P), or vehicle placebo. Epithelial Na ϩ transport was assessed in 29 infants by measuring total nasal potential difference (NPD) and amiloride-sensitive NPD (ASNPD) on postnatal days of life 1, 3, 5, and 7, and mean values of all four measurements were calculated. Bronchopulmonary dysplasia (BPD) was defined as need for supplemental oxygen (goal SaO 2 90%) or mechanical ventilation at 36 wk corrected postmenstrual age. Mean ASNPD was Ϫ6.5 Ϯ 2.8 mV in infants receiving E2/P and Ϫ6.1 Ϯ 2.6 mV in infants receiving placebo (not significant). NPD was Ϫ10.6 Ϯ 3.8 mV and Ϫ10.7 Ϯ 3.6 mV, respectively. The ASNPD was significantly higher in infants surviving without BPD (Ϫ7.1 Ϯ 2.5 mV) than in infants developing BPD or not surviving (Ϫ5.2 Ϯ 2.4 mV). In conclusion, ASNPD is not changed by postnatal replacement of E2 and P. A steady improvement of preterm infant survival and respiratory morbidity was observed from 1990 until 1998 and was attributed to the introduction of exogenous surfactant and antenatal steroids (1). Thereafter, the frequencies of adverse outcomes showed a plateau. Many infants still develop respiratory distress syndrome (RDS) despite surfactant administration, and the incidence of BPD appeared to be increasing again recently (1). Novel therapies are needed to further reduce respiratory morbidity.Aside from producing surfactant, alveolar type II cells (AT2) are responsible for postnatal clearance of excess fluid from the airspaces by moving Na ϩ ions from the apical to the basolateral side, which creates a measurable electrochemical gradient as well as an osmotic gradient driving water movement in the same direction (2). The importance of this process is best demonstrated by mice lacking the pore-forming ␣-subunit of the epithelial Na ϩ channel (ENaC), which invariably die from pulmonary edema and respiratory failure within 40 h of birth (3). Infant RDS may in part be caused by inadequate epithelial Na ϩ transport (4). Furthermore, survival of adults suffering from acute RDS has been related to alveolar fluid clearance (5). Lung water content (6) and epithelial ion transport (7) have also been related to pulmonary compliance.Epithelial ion transport is inaccessible inside the lungs of intact subjects, but the transport mechanisms are expressed in all respiratory epithelia including the trachea and nose. The resulting electrochemical gradient can be readily measured at the nasal epithelium and is known as the NPD. The contribution of ENaC-dependent Na ϩ transport to total NPD can be determined by the ASNPD, defined as the decrease in potential following the application of the ENaC blocker amiloride....

Expression and activity of epithelial sodium channel in hyperoxia‐induced bronchopulmonary dysplasia in neonatal rats

“…28,29 Moreover, a previous study showed that cultured rat fetal distal lung epithelial cells (FDLE), when switched from fetal (3%) to postnatal (21%) O2 concentration, had increased ENaC mRNA levels and amiloride-sensitive Na + transport. 33 However, in contrast to our results, Thome et al reported that infants at high risk of developing BPD had lower amiloridesensitive nasal potential difference (ASNPD) values in the immediate postnatal period; 13 Gaillard et al reported that at 29 days of age infants with BPD had significantly lower nasal potential difference (N-PD) than those without BPD. 12 The above researchers chose nasal epithelial cells as substitute for alveolar epithelial cells, so the conflicting results with ours may be due to different study methods and cell types.…”

“…However, in contrast to our results, Thome et al . reported that infants at high risk of developing BPD had lower amiloride‐sensitive nasal potential difference (ASNPD) values in the immediate postnatal period; 13 Gaillard et al . reported that at 29 days of age infants with BPD had significantly lower nasal potential difference (N‐PD) than those without BPD 12 .…”

“…and Thome et al . indicated that pathogenesis of BPD may be related to Na + transport disorders 12,13 . Therefore, we adopted a classic hyperoxia‐induced BPD model in neonatal rats and examined the dynamic changes in ENaC expression levels.…”

“…Two studies by Gaillard et al and Thome et al indicated that pathogenesis of BPD may be related to Na + transport disorders. 12,13 Therefore, we adopted a classic hyperoxia-induced BPD model in neonatal rats and examined the dynamic changes in ENaC expression levels. Meanwhile, we primarily cultured neonatal rat ATII cells and determined the correlation between expression and activity of ENaC in the hyperoxia-exposed ATII cells by Western blot and whole-cell patch clamp technique, respectively.…”

Systematic review and meta-analysis of nasal potential difference in hypoxia-induced lung injury

“…Eleven case-control studies including 4 randomized, placebo-controlled and 7 nonrandomized controlled studies, from the United States, France, German, Swiss, and Finland in last two decades were finally selected per the inclusion criteria. Among these included studies, seven studies were on high altitude pulmonary edema (HAPE) 16 18 19 28 29 30 31 , and the other four studies on respiratory distress syndrome (RDS) 25 27 32 33 . These studies encompassed NPD data obtained with a similar recording procedure: basal level → applied amiloride (100 μM) or Na + -free solution → Cl − free medium and CFTR activator, isoproterenol (10 μM) ( Table 1 ).…”