Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0851184 (thinning)
 11,252 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Proliferation and differentiation defects during lung development in corticotropin-releasing hormone-deficient mice. 992 8

We comprehensively characterized the effects of a unique natural gain-of-function mutation in the glucocorticoid receptor (GR), GRAla610Val, in domestic pigs to expand current knowledge of the phenotypic consequences of GR hypersensitivity. Cortisol levels were consistently reduced in one-week-old piglets, at weaning and in peripubertal age, probably due to a reduced adrenal capacity to produce glucocorticoids (GC), which was indicated by an adrenocortical thinning in GRAla610Val carriers. Adrenocorticotrophic hormone (ACTH) levels were significantly reduced in one-week-old piglets only. Expression analyses in peripubertal age revealed significant downregulation of hypothalamic expression of CRH and AVP, the latter only in females, and upregulation of hepatic expression of SERPINA6, by GRAla610Val Transcriptional repression of proinflammatory genes in peripheral blood mononuclear cells (PBMCs) from GRAla610Val carriers was more sensitive to dexamethasone treatment ex vivo However, no significant effects on growth, body composition, blood chemistry or cell counts were observed under baseline conditions. These results suggest that GRAla610Val-induced GR hypersensitivity elicits a compensatory reduction in endogenous, bioactive glucocorticoid levels via readjustment of the hypothalamus-pituitary-adrenal (HPA) axis early in ontogeny to maintain an adequate response, but carriers are more sensitive to exogenous GC. Therefore, GRAla610Val pigs represent a valuable animal model to explore GR-mediated mechanisms of HPA axis regulation and responses to glucocorticoid-based drugs.
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PMID:A naturally hypersensitive glucocorticoid receptor elicits a compensatory reduction of hypothalamus-pituitary-adrenal axis activity early in ontogeny. 2744 Apr 22