Am. J. Respir. Cell Mol. Biol., Volume 20, Number 2, February, 1999 181-188

Proliferation and Differentiation Defects during Lung Development in Corticotropin-Releasing Hormone-Deficient Mice

Louis J. Muglia, Donald S. Bae, Todd T. Brown, Sherri K. Vogt, Juan G. Alvarez, Mary E. Sunday, and Joseph A. Majzoub

Departments of Pediatrics and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri; Division of Endocrinology, Children's Hospital, Boston; Department of Obstetrics and Gynecology, Beth Israel Hospital, Boston; and Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts

Corticotropin-releasing hormone-deficient (CRH-KO) mice, which as a consequence are also glucocorticoid-insufficient, exhibit neonatal lethality when derived from CRH-KO mothers. Death is due to respiratory insufficiency as a result of abnormal pulmonary development, and can be prevented by prenatal administration of glucocorticoids. In the study described here, we used CRH-KO mice as a model of genetically altered in utero glucocorticoid action to elucidate the role of endogenous glucocorticoids in lung maturation. The histologic appearance of the lungs of these mice is normal until Day 17.5 of gestation, at which point failure of septal thinning and air-space formation is observed. These morphologic alterations in the CRH-KO mouse lung are the result of continued cell division in cellular compartments that by this time in gestation have ceased proliferating in wild-type mice, rather than the result of a failure of apoptosis. In accord with this observation, the CRH-KO lung exhibits delayed induction of type II pneumocyte biochemical parameters, such as messenger RNAs (mRNAs) for surfactant protein-A (SP-A) and SP-B, and fatty acid synthase, as well as delayed Clara cell maturation. In contrast, surfactant phospholipid synthesis is not impaired during CRH-KO lung development. Our findings indicate that an essential role of endogenous glucocorticoids in pulmonary maturation in utero is to stimulate a developmental program in late gestation that affects epithelial and mesenchymal cell proliferation and differentiation throughout the parenchyma.

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