Regulation of epithelial sodium channel expression by oestradiol and progestogen in alveolar epithelial cells

Oestrogen (E) and progestogen (P) exert regulatory effects on the epithelial Na+ channel (ENaC) in the kidneys and the colon. However, the effects of E and P on the ENaC and on alveolar fluid clearance (AFC) remain unclear, and the mechanisms of action of these hormones are unknown. In this study, we showed that E and/or P administration increased AFC by more than 25% and increased the expression of the α and γ subunits of ENaC by approximately 35% in rats subjected to oleic acid-induced acute lung injury (ALI). A similar effect was observed in the dexamethasone-treated group. Furthermore, E and/or P treatment inhibited 11β-hydroxysteroid dehydrogenase (HSD) type 2 (11β-HSD2) activity, increased corticosterone expression and decreased the serum adrenocorticotrophic hormone (ACTH) levels. These effects were similar to those observed following treatment with carbenoxolone (CBX), a nonspecific HSD inhibitor. Further investigation showed that CBX further significantly increased AFC and α-ENaC expression after treatment with a low dose of E and/or P. In vitro, E or P alone inhibited 11β-HSD2 activity in a dose-dependent manner and increased α-ENaC expression by at least 50%, and E combined with P increased α-ENaC expression by more than 80%. Thus, E and P may augment the expression of α-ENaC, enhance AFC, attenuate pulmonary oedema by inhibiting 11β-HSD2 activity, and increase the active glucocorticoid levels in vivo and in vitro.