The cyclin-dependent kinase inhibitor p21 protects the lung from oxidativestress

The lung is a major target tissue for oxidative stress, including hyperoxia used to relieve tissue hypoxia. Unfortunately, severe hyperoxia damages DN A, inhibits proliferation, and kills cells, resulting in morbidity and mort ality. Although hyperoxia induces the tumor suppressor p53 and its downstre am target, the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1) (p21), their role in pulmonary injury remains unknown. Using p53- and p21-deficie nt mice we demonstrate that hyperoxia induces p21 in the absence of p53, su ggesting that previous conclusions that p53 does not modify hyperoxic lung injury cannot be extrapolated to p21. In fact, mean survival of p21-deficie nt mice decreased by 40% and was associated with terminal deoxyribonucleoti dyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling staining of alveolar debris, indicative of DNA fragmentation and cell deat h. Ultrastructural analyses revealed that alveolar endothelial and type I e pithelial cells died rapidly by necrosis. Although hyperoxia decreased DNA replication in p21-wild-type lungs, it had no effect on replication in p21- deficient lungs. Our findings suggest that p21 protects the lung from oxida tive stress, in part, by inhibiting DNA replication and thereby allowing ad ditional time to repair damaged DNA. Our findings have implications for pat ients suffering from the toxic effects of supplemental oxygen therapies.