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Altered Epithelial Cell Proportions in the Fetal Lung of Glucocorticoid Receptor Null Mice

Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria; Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria; Baker Heart Research Institute, Prahran, Victoria; and Department of Physiology, Monash University, Clayton, Victoria, Australia

Address correspondence to: Dr. Timothy J. Cole, Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, 3010, Victoria, Australia. E-mail: tjcole{at}unimelb.edu.au

Glucocorticoids provide important signals for maturation of the fetal lung and antenatal glucocorticoids are used to reduce the respiratory insufficiency suffered by preterm infants. To further understand the role of glucocorticoids in fetal lung maturation, we have analyzed mice with a targeted null mutation for the glucocorticoid receptor (GR) gene, which severely retards lung development. The lungs of fetal GR-null mice have increased lung weight and DNA content, are condensed and hypercellular, with reduced septal thinning leading to a 6-fold increase in the airway to capillary diffusion distance. In fetal GR-null mice, mRNA levels of the type II epithelial cell surfactant protein genes A and C were reduced by 50%. Analysis of epithelial cell types by electron microscopy revealed that the proportions of type II cells were increased by 30%, whereas the proportions of type-I cells were markedly reduced (by 50%). Similarly, we found a 50% reduction in mRNA levels for T1 and aquaporin-5, two type I cell–specific markers, and a 20% reduction in aquaporin-1 mRNA levels. This demonstrates that during murine embryonic development, receptor-mediated glucocorticoid signaling facilitates the differentiation of epithelial cells into type I cells, but is not obligatory for type II cell differentiation.

Abbreviations: corticotrophin-releasing hormone, CRH • epithelial cell, EC • epithelial sodium channel, ENaC • glucocorticoid receptor, GR • mineralocorticoid receptor, MR • post coitum, p.c. • surfactant protein, SP • transmission electron microscopy, TEM • wild type, WT