Abstract
It has been shown that glucocorticoids accelerate lung development by limiting alveolar formation resulting from a premature maturation of the alveolar septa. Based on these data, the aim of the present work was to analyze the influence of dexamethasone on cell cycle control mechanisms during postnatal lung development. Cell proliferation is regulated by a network of signaling pathways that converge to the key regulator of cell cycle machinery: the cyclin-dependent kinase (CDK) system. The activity of the various cyclin/CDK complexes can be modulated by the levels of the cyclins and their CDKs, and by expression of specific CDK inhibitors (CKIs). In the present study, newborn rats were given a 4-d treatment with dexamethasone (0.1–0.01 μg/g body weight dexamethasone sodium phosphate daily on d 1–4), or saline. Morphologically, the treatment caused a significant thinning of the septa and an acceleration of lung maturation on d 4. Study of cyclin/CDK system at d 1–36 documented a transient down-regulation of cyclin/CDK complex activities at d 4 in the dexamethasone-treated animals. Analysis of the mechanisms involved suggested a role for the CKIs p21CIP1 and p27KIP1. Indeed, we observed an increase in p21CIP1 and p27KIP1 protein levels on d 4 in the dexamethasone-treated animals. By contrast, no variations in either cyclin and CDK expression, or cyclin/CDK complex formation could be documented. We conclude that glucocorticoids may accelerate lung maturation by influencing cell cycle control mechanisms, mainly through impairment of G1 cyclin/CDK complex activation.
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Abbreviations
- CDK:
-
cyclin-dependent kinase
- Rb:
-
retinoblastoma
- CKI:
-
cyclin kinase inhibitor
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The authors thank Dr. Jill Lahti for her help in the elaboration of the manuscript.
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This work was financially supported by grants from Association Claude Bernard, Chancellerie des Universités de Paris (Legs Poix to A.C.), Ligue Nationale contre le Cancer (Fellowship to S.C.; grants 97/RS-BCM100 and 98/RS-BCM43 to A.C.), Ministère de la Santé (PHRC AOB94049 to A.C.), Association pour la Recherche sur le Cancer (grant 9970 to A.C.), Ambassade de France in Switzerland Service Culturel et Scientifique (grant 44-366/84), and the Swiss National Science Foundation (grant 31.55895.98).
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Corroyer, S., Schittny, J., Djonov, V. et al. Impairment of Rat Postnatal Lung Alveolar Development by Glucocorticoids: Involvement of the p21CIP1 and p27KIP1 Cyclin-Dependent Kinase Inhibitors. Pediatr Res 51, 169–176 (2002). https://doi.org/10.1203/00006450-200202000-00008
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DOI: https://doi.org/10.1203/00006450-200202000-00008
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