Immature epithelial Na+ channel expression is one of the pathogenetic mechanisms leading to human neonatal respiratory distress syndrome.
Noninfective acute respiratory disease develops in approximately 1% of all newborn infants and results in their admission to a critical care unit. Transient tachypnea of the newborn occurs as a result of a delay in the clearance of fetal lung liquid; however, respiratory distress syndrome, typically thought to be exclusively a problem of relative surfactant deficiency, is now suspected to be characterized by an even greater air space fluid burden from the inability to absorb fetal lung liquid. In vivo experiments have demonstrated that the lung epithelium secretes Cl and fluid throughout gestation and develops the ability to actively reabsorb Na+ only during late gestation. At birth, the mature lung switches from active Cl- (fluid) secretion to active Na+ (fluid) absorption in response to circulating catecholamines. Changes in oxygen tension augment the Na(+)-transporting capacity of the epithelium and increase gene expression for the epithelial Na+ channel (ENaC). The inability of the immature fetal lung to switch from fluid secretion to fluid absorption results, at least in large part, from an immaturity in the expression of ENaC, which can be upregulated by glucocorticosteroids. Both pharmacological blockade of the lung's epithelial Na+ channel and genetic knockout experiments using mice deficient in the ENaC pore-forming subunit have demonstrated the critical physiological importance of lung Na+ transport at birth. When Na+ transport is ineffective, newborn animals develop respiratory distress and hypoxemia, retain their fetal lung liquid and, in the case of the ENaC knockout mice, die. Bioelectrical studies of human infants' nasal epithelia demonstrate that both transient tachypnea of the newborn and respiratory distress syndrome have defective amiloride-sensitive Na+ transport. These results suggest that neonatal respiratory distress syndrome has, in addition to a relative deficiency in surfactant, defective Na+ transport, which plays a mechanistic role in the development of the disease.
O'Brodovich
H M
HM
MRC Group in Lung Development, Hospital for Sick Children, Toronto, Ontario, Canada.
D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D053503:Epithelial Sodium Channels; D004848:Epithelium / Q000378:metabolism; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D007231:Infant, Newborn; D051379:Mice; D018345:Mice, Knockout; D012127:Respiratory Distress Syndrome, Newborn / Q000209:etiology*; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000096:biosynthesis* / Q000235:genetics; D013256:Steroids / Q000494:pharmacology
D002712:Chlorides; D053503:Epithelial Sodium Channels; D015222:Sodium Channels; D013256:Steroids; D012964:Sodium