title: Glucocorticoid receptor disruption delays structural maturation in the lungs of newborn mice.
abstract: In order to better understand the regulation of lung maturation by glucocorticoid-glucocorticoid receptor signaling, we studied glucocorticoid receptor (GR) hypomorphic mice with a mixed C57Bl6/129 sv background, in which disruption of exon 2 of the GR gene produces an N-terminal truncated GR protein. Four groups of mice were compared: homozygous mice that die at birth (non-survivors), homozygous mice that survive the neonatal period (survivors), heterozygotes and wild-type mice. Newborn non-survivors had 50% thicker airspace walls and a 46% decrease in the formation of secondary crests (the beginning of alveolar secondary septation) compared to either survivor or wild-type littermates (n = 9 mice in each group). The lung tissue to airspace ratio in homozygous mice not expressing wild-type GR (non-survivor and survivor) was increased compared to heterozygotes and wild-type mice that do express wild-type GR (0.91 +/- 0.08 vs. 0.49 +/- 0.02, n = 4 in each of the four subgroups), suggesting that complete morphological maturation of the lung is dependent on effective glucocorticoid signaling through a fully functional GR. Moreover, the relatively mature lung morphology of survivor versus non-survivor newborns suggests that a partial reduction in mesenchymal thickness is compatible with capillary remodeling, alveolar septation, and viable respiratory function after birth. Our findings suggest that in mice homozygous for disrupted GR, the severity of newborn respiratory insufficiency correlates with the degree of lung structural immaturity.
authors: Physiology and Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Baharak
authors: B
authors: Nemati
authors: Wayhuni
authors: W
authors: Atmodjo
authors: Stéphane
authors: S
authors: Gagnon
authors: Daryl
authors: D
authors: Humes
authors: Colin
authors: C
authors: McKerlie
authors: Feige
authors: F
authors: Kaplan
authors: Neil B
authors: NB
authors: Sweezey
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002196:Capillaries / Q000473:pathology; D042783:Endothelial Cells / Q000473:pathology; D005938:Glucocorticoids / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D006720:Homozygote; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics; D009130:Muscle, Smooth / Q000473:pathology; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012720:Severity of Illness Index; D015398:Signal Transduction
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid