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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- β signaling pathway.