Retinoic acid protects against hyperoxia-mediated cell-cycle arrest of lung alveolar epithelial cells by preserving late G1 cyclin activities

The epithelium of the lung alveolus is a major target for oxidant injury, a nd its proper repair after injury is dependent on the proliferative respons e of the alveolar epithelial type 2 cells. Recently, we have provided evide nce that retinoic acid (RA) stimulates proliferation of type 2 cells. In th e present study, we examined the effects of RA on the proliferative respons e of alveolar type 2 cells exposed to elevated oxygen (O-2). We showed that pretreatment by RA was able to prevent the growth arrest and cell loss Of O-2-exposed cells. To gain insights into the mechanisms involved, we studie d the effects of RA on the cyclin-dependent kinase (CDK) system. The activi ty of cyclin E-CDK2 complex was found to be decreased in O-2-exposed cells. Interestingly, this decrease was no longer observed when cells were pretre ated with RA. Analysis of p21(CIP1), an inhibitor of CDK, revealed an incre ased expression in O-2-exposed cells that was no longer observed in cells t reated with RA. These effects were associated with a reduced association of p21(CIP1) with cyclin E-CDK2 complexes in the presence of RA. In addition, studies of Smad activity strongly suggest that the mechanisms through whic h RA preserves late G(1) cyclin-CDK complex activity may involve interferen ce with the transforming growth factor-beta signaling pathway.