High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects

Abstract

High-altitude pulmonary oedema (HAPE) occurs in predisposed individuals at altitudes w2,500 m. Defective alveolar fluid clearance secondary to a constitutive impairment of the respiratory transepithelial sodium transport contributes to its pathogenesis. Hypoxia impairs the transepithelial sodium transport in alveolar epithelial type II cells in vitro. If this impairment is also present in vivo, high-altitude exposure could aggravate the constitutive defect in sodium transport in HAPE-prone subjects, and thereby further facilitate pulmonary oedema.Therefore, the aim of the current study was to measure the nasal potential difference (PD) in 21 HAPE-prone and 29 HAPE-resistant subjects at low altitude and 30 h after arrival at high altitude (4,559 m).High-altitude exposure significantly decreased the mean¡SD nasal PD in HAPEprone (18.0¡6.2 versus 12.5¡6.8 mV) but not in HAPE-resistant subjects (25.6¡9.4 versus 22.9¡9.2 mV). This altitude-induced decrease was not associated with an altered amiloride-sensitive fraction, but was associated with a significantly lower amilorideinsensitive fraction of the nasal PD.These findings provide evidence in vivo that an environmental factor may impair respiratory transepithelial sodium transport in humans. They are consistent with the concept that in high-altitude pulmonary oedema-susceptible subjects, the combination of a constitutive and an acquired defect in this transport mechanism facilitates the development of pulmonary oedema during high-altitude exposure. High-altitude pulmonary oedema (HAPE) is a lifethreatening condition that occurs in predisposed but otherwise healthy individuals at altitudes w2,500 m. Augmented alveolar fluid flooding related to exaggerated hypoxic pulmonary vasoconstriction plays an important role in its pathogenesis, secondary to endothelial dysfunction and sympathetic overactivity [1][2][3]. However, recent observations indicate that this mechanism may not be sufficient to cause high-altitude pulmonary oedema [4].Active sodium transport across the alveolar epithelium plays an important role in keeping the lungs free of fluid [5,6]. In alveolar epithelial cells, sodium enters the apical membrane primarily through the amiloride-sensitive cation channels (mainly ENaC), and is then transported across the basolateral membrane into the interstitium by the ouabain-inhibitable Na-K-ATPase [5][6][7][8].A genetic impairment of the transepithelial sodium transport mechanism facilitates pulmonary oedema in transgenic mice [9,10] and possibly also in humans, as suggested by HAPE-prone subjects who have a smaller nasal potential difference (PD) (an indirect marker of vectorial sodium transport in the distal airways) [11] than mountaineers resistant to this condition [12]. Consistent with this concept, prophylactic stimulation of this transport mechanism with the b 2 -adrenergic agonist salmeterol, at a dose that stimulates respiratory sodium transport in vitro [8] and increases alveolar fluid clearance in vivo [13], decreased the incidence of HAPE in h...

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

“…In our extremely preterm infants, we have found lower values for ASNPD and NPD than previously described in more mature preterm infants (8,24), term infants (7,25,26), and adults (27) and no increase during the first week of life or correlation to gestational age. The reason may again be the extreme immaturity, rendering the infants unable to increase their ASNPD and NPD during the first postnatal week.…”

High‐altitude Pulmonary Edema: Review

“…Decreased potential difference and reduced Na + transport were reported in HAPE-susceptible subjects as predisposing factor to HAPE in the in vivo study done by Sartori et al They demonstrated that an environmental factor may impair respiratory transepithelial sodium transport in humans 47) , thus suggesting that a combination of genetic and environmental mechanisms facilitates HAPE. Keeping in view the possible role of reduced alveolar fluid clearance in HAPE, prophylactic inhalation of the adrenergic agonist salmeterol, which up-regulates the clearance of alveolar fluid in animal models, was studied, and it was shown to reduce the incidence of HAPE by 50% 47,48) . Swenson et al (2002), in their study using BAL performed within a day of ascent to 4,559 m, showed that early HAPE is characterized by a protein-rich fluid containing albumin in high concentrations and an elevated red blood cell count, both in clinically ill HAPE subjects and subjects who developed HAPE in the next 24 hours 48) .…”

“…Due to the inability to assess alveolar transport activity directly, nasal transepithelial Na + transport activity is used as a surrogate marker to study the ion transport. Hypoxic conditions of high altitudes hamper nasal transepithelial Na + transport, thus impairing fluid absorption in the human lungs 47) . Decreased potential difference and reduced Na + transport were reported in HAPE-susceptible subjects as predisposing factor to HAPE in the in vivo study done by Sartori et al They demonstrated that an environmental factor may impair respiratory transepithelial sodium transport in humans 47) , thus suggesting that a combination of genetic and environmental mechanisms facilitates HAPE.…”

“…Hypoxic conditions of high altitudes hamper nasal transepithelial Na + transport, thus impairing fluid absorption in the human lungs 47) . Decreased potential difference and reduced Na + transport were reported in HAPE-susceptible subjects as predisposing factor to HAPE in the in vivo study done by Sartori et al They demonstrated that an environmental factor may impair respiratory transepithelial sodium transport in humans 47) , thus suggesting that a combination of genetic and environmental mechanisms facilitates HAPE. Keeping in view the possible role of reduced alveolar fluid clearance in HAPE, prophylactic inhalation of the adrenergic agonist salmeterol, which up-regulates the clearance of alveolar fluid in animal models, was studied, and it was shown to reduce the incidence of HAPE by 50% 47,48) .…”

High-Altitude Pulmonary Vascular Diseases

“…Although not as definitively established, polymorphisms of many genes involved in vasoactive mediator generation, inflammation, and the HIF pathway have been proposed, 11,[41][42][43] along with a reduced capacity to actively reabsorb sodium and water by the alveolar epithelium. 44,45 Prevention and Treatment of HAPE A gradual ascent to high altitude such that the sleeping elevation gain is less than 500 meters per day with rest days incorporated after every 3 or 4 days has been recommended to prevent acute altitude illnesses including HAPE. 46 In those with a prior history of HAPE, prophylactic nifedipine is advised based on a randomized controlled trial in 21 HAPE-susceptible volunteers who ascended to 4559 meters.…”