Epithelial cells along the conducting airways can be more or less continuously exposed to DNA-damaging agents, which should limit their proliferation by inducing cell cycle checkpoints. Yet, paradoxically, airway epithelial cells frequently show a hyperplastic response when exposed to such agents. In this in vitro study, we assessed the hypothesis that normal human bronchial epithelial cells (BECs) are more resistant to the cell cycle-arresting effects of DNA damage than are human lung fibroblasts (HLFs), a cell type often investigated in the context of cell cycle checkpoints. Using ionizing radiation as a DNA-damaging insult, we have found that BECs indeed show less pronounced G1 and G2 delays than do fibroblasts. Unlike the HLFs, which ultimately enter a condition of apparently terminal arrest in the G1 phase of the cell cycle, BECs continue proliferating following their initial, transient G1 and G2 delays. Radiation-induced p53 and p21Cip1 increases were greater in HLFs than in BECs, whereas preexposure, basal levels of p53 were higher in BECs than in HLFs. The results of this investigation indicate that BECs may be less susceptible to the cell cycle-arresting effects of DNA-damaging agents, perhaps because of their higher basal levels of p53. Extension of these findings to the in vivo condition provides a possible explanation for airway epithelial cell hyperplastic responses that occur in a background of DNA-damaging stresses. Moreover, the attenuated DNA damage-induced, cell cycle checkpoint responses in BECs potentially may favor the transmission of DNA lesions to cell progeny.
The investigation was funded by a Department of Energy project entitled “Low Dose Ionizing Radiations, Reactive Oxygen Species, and Genomic Instability” and by the Los Alamos National Laboratory Flow Cytometry Resource (NIH Grant p41-RR01315).