Enhanced epithelial sodium channel activity in neonatal Scnnlb mouse lung attenuates high oxygen-induced lung injury

摘要

Prolonged oxygen therapy leads to oxidative stress, epithelial dysfunction, and acute lung injury in preterm infants and adults. Heterozygous Scnnib mice, which overexpress lung epithelial sodium channels (ENaC), and their wild-type (WT) C57BI6 litter-mates were utilized to study the pathogenesis of high fraction inspired oxygen (F_I_O_2)-induced lung injury. Exposure to high F_I_O_2 from birth to postnatal (PN) day 11 was used to model oxidative stress. Chronic exposure of newborn pups to 85% O_2 increased glutathione disulfide (GSSG) and elevated the GSH/GSSG redox potential (E_h) of bronchoalveolar lavage fluid (BALF). Longitudinal X-ray imaging and Evans blue-labeled-albumin assays showed that chronic 85% O_2 and acute GSSG (400 muM) exposures decreased alveolar fluid clearance (AFC) in the WT lung. Morphometric analysis of WT pups insufflated with GSSG (400 muM) or amiloride (1muM) showed a reduction in alveologenesis and increased lung injury compared with age-matched control pups. The Scnnib mouse lung phenotype was not further aggravated by chronic 85% O_2 exposure. These outcomes support the hypothesis that exposure to hyperoxia increases GSSG, resulting in reduced lung fluid reabsorption due to inhibition of amilor-ide-sensitive ENaC. Flavin adenine dinucleotide (FADH_2; 10muM) was effective in recycling GSSG in vivo and promoted alveologenesis, but did not impact AFC nor attenuate fibrosis following high F_I_O_2 exposure. In conclusion, the data indicate that FADH_2 may be pivotal for normal lung development, and show that ENaC is a key factor in promoting alveologenesis, sustaining AFC, and attenuating fibrotic lung injury caused by prolonged oxygen therapy in WT mice.