Pulmonary Epithelial Sodium-Channel Dysfunction and Excess Airway Liquid in Pseudohypoaldosteronism

Kerem, Eitan; Bistritzer, Tzvy; Hanukoglu, Aaron; Hofmann, Thomas; Zhou, Zhaoqing; Bennett, William D.; MacLaughlin, Eithne F.; Barker, Pierre; Nash, Martin A.; Quittell, Lynne M.; Boucher, Richard C.; Knowles, Michael R.

doi:10.1056/nejm199907153410304

Cited by 323 publications

(238 citation statements)

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“…A number of mutations in all three ENaC subunits has been described that give rise to the clinical condition of pseudohypoaldosteronism, a saltlosing state that results in severe electrolyte disturbances. In contrast to the respiratory distress seen in ␣-ENaC knockout mice, there is an absence of neonatal respiratory symptoms in these patients (41). However, recent studies suggest that oocytes expressing ENaC sunbunit mutants found in pseudohypoaldosteronism may exhibit significantly more Na ϩ transport than oocytes with an absent ENaC subunit (17,22).…”

Section: Clinical Applicationsmentioning

confidence: 88%

Invited Review: Clearance of lung liquid during the perinatal period

Barker

Olver

2002

Journal of Applied Physiology

105

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Barker, Pierre M., and Richard E. Olver. Invited Review: Clearance of lung liquid during the perinatal period. J Appl Physiol 93: 1542-1548, 2002; 10.1152/japplphysiol.00092.2002.-At birth, the distal lung epithelium undergoes a profound phenotypic switch from secretion to absorption in the course of adaptation to air breathing. In this review, we describe the developmental regulation of key membrane transport proteins and the way in which epinephrine, oxygen, glucocorticoids, and thyroid hormones interact to bring about this crucial change in function. Evidence from molecular, transgenic, cell culture, and whole lung studies is presented, and the clinical consequences of the failure of the physiological mechanisms that underlie perinatal lung liquid absorption are discussed. lung liquid; sodium absorption; chloride secretion; epithelial sodium channel; cystic fibrosis transmembrane conductance regulator THE MECHANISMS RESPONSIBLE for lung liquid clearance during the neonatal period develop gradually during the latter part of the third trimester of pregnancy, but the phenotypic switch of the lung epithelium from net secretion to net absorption, triggered by events at birth, is sudden. Although lung liquid absorption at birth is "a performance without rehearsal," the lung may be called on for an encore in later life when these same mechanisms are activated to clear accumulated edema liquid.Many of the early studies of perinatal lung liquid clearance, which were mostly undertaken on the intact lungs of rabbits and sheep in the 1970s and 1980s, provided information in vivo on the time course and regulation of lung liquid clearance in a fully integrated physiological context. These data have been supported and augmented in the past decade by cloning of genes that regulate transepithelial ion transport [particularly the sodium pump (Na ϩ -K ϩ -ATPase) and the epithelial Na ϩ channel (ENaC)] and the use of molecular approaches that have uncovered information at a subcellular level.

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Section: Clinical Applicationsmentioning

confidence: 88%

Invited Review: Clearance of lung liquid during the perinatal period

Barker

Olver

2002

Journal of Applied Physiology

105

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“…29 Interestingly, patients who have pseudohypoaldosteronism, the 'human a-ENaC subunit knockout', 30 do not have a comparable marked impairment in clearance of lung liquid at birth, as evidenced by lack of RDS at birth. 31 There are several potential explanations for this variation between species, including the possibility that low levels of a-ENaC subunits rescue the pseudohypoaldosteronism lung, 32 that the b-ENaC subunit may be the rate-limiting subunit in human respiratory epithelium as it is for murine lung airway epithelial Na þ transport 33 or that other Na þ -permeate ion channels compensate for deficient ENaC activity. Recently, it has been shown that a significant amount of Na þ transport and fluid movement across the apical lung epithelium occurs via amiloride-insensitive pathways, and 'atypical EnaC' was suggested as the sodium channels responsible for this portion of total sodium transport.…”

Section: Lung Fluid During and Immediately After Birthmentioning

confidence: 99%

Clinical implication of lung fluid balance in the perinatal period

2011

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At birth, lung fluid produced during fetal life must be cleared immediately and efficiently before the first breath takes place, in order for infants to achieve a normal and successful transition from prenatal to postnatal life. Postnatal lung fluid resorption is mediated through activation of airway epithelial sodium channels (ENaC). The observation that ENaC expression is a gestational age-dependent process contributes to our understanding of the development of respiratory distress in both term and preterm infants due to impaired clearing of fluid from their lungs. As fluid absorption, mediated by ENaC activity, in postnatal life has a significant biological role in preventing respiratory distress, any strategy that enhances ENaC activity can potentially help to decrease its incidence and associated morbidity.

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“…Children with PHA type 1 based on mutations in genes coding for the a-or b-ENaC have an increased volume of liquid in the airways due to absorption failure 6 and present with recurrent pulmonary problems, such as wheezing, cough, tachypnea and lower respiratory tract infections. 7,8 There are, however, no reports about respiratory distress immediately after birth in PHA patients born at term, 6 whereas one preterm infant (gestational age 31 weeks) with PHA had severe respiratory distress that was poorly responsive to surfactant replacement therapy.…”

Section: Casementioning

confidence: 99%

“…7,8 There are, however, no reports about respiratory distress immediately after birth in PHA patients born at term, 6 whereas one preterm infant (gestational age 31 weeks) with PHA had severe respiratory distress that was poorly responsive to surfactant replacement therapy. 9 Although the renal phenotype of this patient was very severe, some residual ENaC activity might be sufficient for postnatal lung water clearance, in conjunction with other sodium channels.…”

Section: Casementioning

confidence: 99%