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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Normal remodeling of the oxygen-injured lung requires the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1).

Authors: Staversky, Rhonda J; Watkins, Richard H; Wright, Terry W; Hernady, Eric; LoMonaco, Michael B; D'Angio, Carl T; Williams, Jacqueline P; Maniscalco, William M; O'Reilly, Michael A

Published In Am J Pathol, (2002 Oct)

Abstract: 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.

PubMed ID: 12368211 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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