Regulation of alveolar epithelial cell phenotypes in fetal sheep: roles of cortisol and lung expansion

Our aim was to determine whether cortisol's effect on alveolar epithelial cell (AEC) phenotypes in the fetus is mediated via a sustained alteration in lung expansion. Chronically catheterized fetal sheep were exposed to 1) saline infusion, 2) cortisol infusion (122-131 days' gestation, 1.5-4.0 mg/day), 3) saline infusion plus reduced lung expansion, or 4) cortisol infusion plus reduced lung expansion. The proportions of type I and II AECs were determined by electron microscopy, and surfactant protein (SP)-A, -B, and -C mRNA levels were determined by Northern blot analysis. Cortisol infusions significantly increased type II AEC proportions (to 38.2+/-2.2%), compared with saline-infused fetuses (23.8+/-2.4%), and reduced type I AEC proportions (to 59.0+/-2.2%), compared with saline-infused fetuses (70.4+/-2.4%). Reduced lung expansion also increased type II AEC proportions (to 52.9+/-3.5%) and decreased type I AEC proportions (to 34.2+/-3.7%), compared with control, saline-infused fetuses. The infusion of cortisol into fetuses exposed to reduced lung expansion tended to further increase type II (to 60.3+/-2.1%, P=0.066) and reduce type I AEC ( to 26.6+/-2.3%, P=0.07) proportions. SP-A, -B, and -C mRNA levels changed in parallel with the changes in type II AEC proportions. These results indicate that cortisol alters the proportion of type I and type II AECs via a mechanism unrelated to the degree of fetal lung expansion. However, reductions in fetal lung expansion appear to have a greater impact on the proportion of AECs than cortisol.