IL-1beta-induced cortisol stimulates lung fluid absorption in fetal guinea pigs via SGK-mediated Nedd4-2 inhibition.

We tested the hypothesis that interleukin (IL)-1beta-induced cortisol synthesis stimulates distal lung fluid absorption in fetal guinea pigs via induction of serum- and glucocorticoid-regulated kinase (SGK) and inhibition of neural precursor cell expressed, developmentally downregulated protein 4-2 (Nedd4-2). IL-1beta was subcutaneously administered daily to timed-pregnant guinea pigs over 3 days. Fetuses were obtained by abdominal hysterotomy at gestation day (GD)61 and GD68 and instilled with an isosmolar 5% albumin solution into the lungs. Distal lung fluid movement was measured over 1 h from the change in distal air space protein concentration. Fetal lungs were secreting lung fluid at GD61 while absorbing lung fluid at GD68. Distal lung fluid absorption was induced at GD61 by IL-1beta but unaffected at GD68. Plasma cortisol concentrations were increased by IL-1beta at GD61 and endogenously at GD68. Distal lung fluid absorption was measured and correlated to SGK and Nedd4-2 expression and to alpha-epithelial Na channel (ENaC) expression. SGK was increased by IL-1beta and late during gestation (GD68), while Nedd4-2 was decreased by IL-1beta and late during gestation. alpha-ENaC was induced by IL-1beta at GD61 and increased late during gestation. Thus our study suggests that cortisol-stimulated fetal lung fluid absorption is mediated by increased ENaC expression and may be governed by the SGK/Nedd4-2 pathway. These observations may explain why babies delivered preterm after intrauterine inflammation have a reduced risk of developing severe respiratory distress.