Abstract
BackgroundGlucocorticoids exert recognized positive effects on lung development. The genes involved in the classical pathway of glucocorticoid synthesis normally occurring in adrenals were found to be expressed on gestation day (GD) 15.5 in the developing mouse lung. Recently, expression of two of these genes was also detected on GD 17.5 suggesting a more complex temporal regulation than previously expected. Here, we deepen the knowledge on expression of “adrenal” glucocorticoid synthesis genes in the mouse lung during the perinatal period and we also study expression of the gene encoding for the steroid inactivating enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD).ResultsWe performed an ontogenic study of P450scc, 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase 1 (3β-HSD1), 21-hydroxylase, 11β-hydroxylase, 11β-HSD1, and 11β-HSD2 expression up to post natal day (PN) 15. The substrate (progesterone) and the product (deoxycorticosterone) of 21-hydroxylase are substrates of 20α-HSD, thus 20α-HSD (Akr1c18) gene expression was investigated. In lung samples collected between GD 15.5 and PN 15, 11β-hydroxylase was only detected on GD 15.5. In contrast, all the other tested genes were expressed throughout the analyzed period with different temporal expression patterns. P450scc, 21-hydroxylase, 20α-HSD and 11β-HSD2 mRNA levels increased after birth with different patterns including an increase from PN 3 with a possible sex difference for 21-hydroxylase mRNA. Also, the 21-hydroxylase protein was observed by Western blot in perinatal lungs with higher levels after birth.ConclusionProgesterone is present at high levels during gestation and the product of 21-hydroxylase, deoxycorticosterone, can bind the glucocorticoid receptor with an affinity close to that of corticosterone. Detection of 21-hydroxylase at the protein level during antenatal lung development is the first evidence that the adrenal-like glucocorticoid synthesis pathway detected during lung development has the machinery to produce glucocorticoids in the fetal lung. Glucocorticoids from lung 21-hydroxylase appear to modulate lung ontogenesis through paracrine/intracrine actions.
Highlights
Glucocorticoids exert recognized positive effects on lung development
The P450 side-chain cleavage (P450scc), 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase 1 (3β-HSD1) and 21-hydroxylase genes were expressed after gestation day (GD) 15.5 at least up to post natal day (PN) 15 in the alveolar stage (Figure 2)
Expression of 3β-HSD1 did not show significant temporal or sexual regulation, a slight significant trend for decreased expression was observed over developmental time (Figure 2C-D and Table 1)
Summary
The genes involved in the classical pathway of glucocorticoid synthesis normally occurring in adrenals were found to be expressed on gestation day (GD) 15.5 in the developing mouse lung. We deepen the knowledge on expression of “adrenal” glucocorticoid synthesis genes in the mouse lung during the perinatal period and we study expression of the gene encoding for the steroid inactivating enzyme 20α-hydroxysteroid dehydrogenase (20α-HSD). Glucocorticoids (GCs) play an essential role in fetal lung development [1,2] They exert various effects including thinning of alveolar septa, increase in the number of type I pneumonocytes, decrease in pneumonocyte cell division, and stimulation of secretion of fibroblast paracrine factors that play a role in type II pneumonocyte maturation [3]. The overall failure of lung development was characterized by hypercellularity of the mesenchymal compartment and decreased expression of mRNAs associated with mature lung epithelial cells such as those of surfactant protein (SP)-A, SP-B and CCP10
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