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Retinoblastoma Function Is Essential for Establishing Lung Epithelial Quiescence after Injury

Pathology and Laboratory Medicine and Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio

Requests for reprints: Kathryn A. Wikenheiser-Brokamp, Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center 3333 Burnet Avenue, MLC 7029 Cincinnati, OH 45229-3039. Phone: 513-803-0239; Fax: 513-636-7868; E-mail: Kathryn.Wikenheiser-Brokamp{at}cchmc.org.

Key Words: RB • Cre-LoxP • lung injury

The retinoblastoma gene product (RB) regulates cell cycle, quiescence, and survival in a cell type–dependent and environment-dependent manner. RB function is critical in the pulmonary epithelium, as evidenced by nearly universal RB inactivation in lung cancer and increased lung cancer risk in persons with germline RB gene mutations. Lung carcinomas occur in the context of epithelial remodeling induced by cytotoxic damage. Whereas the role of RB in development and normal organ homeostasis has been extensively studied, RB function in the context of cellular injury and repair has remained largely unexplored. In the current studies, the RB gene was selectively deleted in the respiratory epithelium of the mouse. Although RB was not required for establishing or maintaining quiescence during lung homeostasis, RB was essential for establishing quiescence during epithelial repair after injury. Notably, aberrant cell cycle progression was sustained for 9 months after injury in RB-deficient lungs. Prenatal and postnatal RB ablation had similar effects, providing evidence that timing of RB loss was not critical to the outcome and that the injury-induced phenotype was not secondary to compensatory alterations occurring during development. These data show that RB is essential for repair of the respiratory epithelium after cytotoxic damage and support a critical unique role for RB in the context of epithelial remodeling after injury. Because human cancers are associated with chronic cellular damage, these findings have important new implications for RB-mediated tumor suppression. [Cancer Res 2008;68(11):4068–76]

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