title: Distal airway epithelial progenitor cells are radiosensitive to High-LET radiation.
abstract: Exposure to high-linear energy transfer (LET) radiation occurs in a variety of situations, including charged particle radiotherapy, radiological accidents, and space travel. However, the extent of normal tissue injury in the lungs following high-LET radiation exposure is unknown. Here we show that exposure to high-LET radiation led to a prolonged loss of in vitro colony forming ability by airway epithelial progenitor cells. Furthermore, exposure to high-LET radiation induced clonal expansion of a subset of progenitor cells in the distal airway epithelium. Clonal expansion following high-LET radiation exposure was correlated with elevated progenitor cell apoptosis, persistent γ-H2AX foci, and defects in mitotic progression of distal airway progenitors. We discovered that the effects of high-LET radiation exposure on progenitor cells occur in a p53-dependent manner. These data show that high-LET radiation depletes the distal airway progenitor pool by inducing cell death and loss of progenitor function, leading to clonal expansion. Importantly, high-LET radiation induces greater long-term damage to normal lung tissue than the relative equivalent dose of low-LET γ-rays, which has implications in therapeutic development and risk assessment.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC, 27708, USA.|Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: McConnell
authors.affiliation: Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Bindu
authors.initials: B
authors.lastname: Konda
authors.affiliation: Departments of Radiation Oncology and Pharmacology &Cancer Biology, Duke University Medical Center, Durham, NC, 27708, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC, 27708, USA.|Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Stripp