Alveolar cells of the lung are injured and killed when exposed to elevated levels of inspired
oxygen. Damaged tissue architecture and pulmonary function is restored during recovery in room air as endothelial and type II epithelial cells proliferate. Although excessive fibroblast proliferation and
inflammation occur when abnormal remodeling occurs, genes that regulate repair remain unknown. Our recent observation that
hyperoxia inhibits proliferation through induction of the
cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1), which also facilitates DNA repair, suggested that p21 may participate in remodeling. This hypothesis was tested in p21-wild-type and -deficient mice exposed to 100% FiO(2) and recovered in room air. p21 increased during
hyperoxia, remained elevated after 1 day of recovery before returning to unexposed levels. Increased proliferation occurred when p21 expression decreased. In contrast, higher and sustained levels of proliferation, resulting in myofibroblast
hyperplasia and monocytic
inflammation, occurred in recovered p21-deficient lungs. Cells with
DNA strand breaks and expressing p53 were observed in hyperplastic regions suggesting that
DNA integrity had not been restored. Normal recovery of endothelial and type II epithelial cells, as assessed by expression of cell-type-specific genes was also delayed in p21-deficient lungs. These results reveal that p21 is required for remodeling the
oxygen-injured lung and suggest that failure to limit replication of damaged
DNA may lead to cell death,
inflammation, and abnormal remodeling. This observation has important implications for therapeutic strategies designed to attenuate long-term chronic
lung disease after
oxidant injury.