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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 4, October, 2001 507-514

Retinoic Acid Protects against Hyperoxia-Mediated Cell-Cycle Arrest of Lung Alveolar Epithelial Cells by Preserving Late G1 Cyclin Activities

Elodie Nabeyrat, Sophie Corroyer, Valérie Besnard, Véronique Cazals-Laville, Jacques Bourbon, and Annick Clement

Département de Pneumologie Pédiatrique-INSERM U515, Hôpital Trousseau; and INSERM U3 19, Université Denis Diderot, Paris, France

The epithelium of the lung alveolus is a major target for oxidant injury, and its proper repair after injury is dependent on the proliferative response of the alveolar epithelial type 2 cells. Recently, we have provided evidence that retinoic acid (RA) stimulates proliferation of type 2 cells. In the present study, we examined the effects of RA on the proliferative response of alveolar type 2 cells exposed to elevated oxygen (O2). We showed that pretreatment by RA was able to prevent the growth arrest and cell loss of O2-exposed cells. To gain insights into the mechanisms involved, we studied the effects of RA on the cyclin-dependent kinase (CDK) system. The activity of cyclin E-CDK2 complex was found to be decreased in O2-exposed cells. Interestingly, this decrease was no longer observed when cells were pretreated with RA. Analysis of p21CIP1, an inhibitor of CDK, revealed an increased expression in O2-exposed cells that was no longer observed in cells treated with RA. These effects were associated with a reduced association of p21CIP1 with cyclin E-CDK2 complexes in the presence of RA. In addition, studies of Smad activity strongly suggest that the mechanisms through which RA preserves late G1 cyclin-CDK complex activity may involve interference with the transforming growth factor-beta signaling pathway.

Abbreviations: cyclin-dependent kinase, CDK; CDK inhibitor, CKI; dithiothreitol, DTT; ethylenediaminetetraacetic acid, EDTA; electrophoretic mobility shift assay, EMSA; messenger RNA, mRNA; retinoic acid, RA; RA receptor, RAR; retinoid X receptor, RXR; Smad binding element, SBE; sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE; transforming growth factor, TGF.




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