Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice

Corticotropin-releasing hormone-deficient (CRH-KO) mice, which as a consequ ence 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 CR H-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 forma tion is observed. These morphologic alterations in the CRH-KO mouse lung ar e the result of continued cell division in cellular compartments that by th is time in gestation have ceased proliferating in wild-type mice, rather th an the result of a failure of apoptosis. In accord with this observation, t he 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 maturatio n. In contrast, surfactant phospholipid synthesis is not impaired during CR H-KO lung development. Our findings indicate that an essential role of endo genous glucocorticoids in pulmonary maturation in utero is to stimulate a d evelopmental program in late gestation that affects epithelial and mesenchy mal cell proliferation and differentiation throughout the parenchyma.