Impairment of Rat Postnatal Lung Alveolar Development by Glucocorticoids: Involvement of the p21CIP1 and p27KIP1 Cyclin-Dependent Kinase Inhibitors

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 g/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 p21 CIP1 and p27 KIP1 . Indeed, we observed an increase in p21 CIP1and p27 KIP1 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. Glucocorticoids are essential anti-inflammatory molecules widely used in the treatment of a large variety of lung diseases. The early postnatal use of glucocorticoids is often motivated by a positive effect on lung maturation in preterm born babies, who otherwise stand a high risk of developing chronic lung disease also called bronchopulmonary dysplasia. However, as a side effect, it has been demonstrated in a number of animal models that glucocorticoids may impair postnatal lung maturation and growth (1-5).The morphologic descriptions of the effects of glucocorticoids on postnatal lung development have established that the acceleration of alveolar wall thinning and microvascular maturation is associated with a reduction in the outgrowth of new interalveolar septa and, therefore, with an inhibition of alveolar formation (4). These data are consistent with the involvement of glucocorticoids in the processes of cellular differentiation and proliferation (6). In normal situations, the balanced action of endogenous glucocorticoids on both processes results in adequate lung maturation. In situations with increased levels of glucocorticoids, it is likely that this balance is no longer maintained resulting in an impairment in lung development.The observations that glucocorticoid treatment was associated with decreased formation of new alveoli strongly suggests an inhibitory effect of these hormones on cell growth, and, therefore, on cell cycle progression. T...

Identification of glucocorticoid‐regulated genes that control cell proliferation during murine respiratory development

“…Glucocorticoids have previously been shown to regulate protein levels of both CKIs in isolated and cultured lung epithelium. Dexamethasone treatment induced p21 CIP1 protein levels in early postnatal lung and lung cancer cell lines (Corroyer et al 2002; Greenberg et al 2002) and a glucocorticoid responsive region has been characterized in the promoter region of the p21 CIP1 gene (Cha et al 1998). Similarly, dexamethasone increased p57 KIP2 mRNA levels in human bronchial epithelial cells (Puddicombe et al 2003) and a functional GRE has been described in the promoter region of the human p57 KIP2 gene (Alheim et al 2003), Interestingly, another report has shown an increase of protein, but not increased mRNA levels of p21 CIP1 in cultured neonatal type II AECs following dexamethasone treatment (Corroyer et al 1997).…”

A Placebo-Controlled Comparison of Effects of Repetitive Doses of Betamethasone and Dexamethasone on Lung Maturation and Lung, Liver, and Body Weights of Mouse Pups

“…Figure 1. In the study of Corroyer et al (24), newborn rats were given a 4-d treatment with DEX (0.1-0.01 g/g body weight DEX sodium phosphate daily on d 1-4), or saline. There was no significant difference between the male and female sets (p Ͼ 0.05); however, the male and female sets were analyzed separately and it was found that there were significant differences among the sets within the female and male groups (p Ͻ 0.05).…”

Rat lungs show a biphasic formation of new alveoli during postnatal development

“…The animals used were part of our studies about the pulmonary effects of a neonatal high-dose short-term glucocorticoid treatment of rats (11,22,29,30,34,42). In addition, the controls of this experiments were used in other studies analyzing lung development (14 -16, 27, 33, 43).…”