Accelerated senescence in skin in a murine model of radiation-induced multi-organ injury.
Accidental high-dose radiation exposures can lead to multi-organ injuries, including radiation dermatitis. The types of cellular damage leading to radiation dermatitis are not completely understood. To identify the cellular mechanisms that underlie radiation-induced skin injury in vivo, we evaluated the time-course of cellular effects of radiation (14, 16 or 17 Gy X-rays; 0.5 Gy/min) in the skin of C57BL/6 mice. Irradiation of 14 Gy induced mild inflammation, observed histologically, but no visible hair loss or erythema. However, 16 or 17 Gy radiation induced dry desquamation, erythema and mild ulceration, detectable within 14 days post-irradiation. Histological evaluation revealed inflammation with mast cell infiltration within 14 days. Fibrosis occurred 80 days following 17 Gy irradiation, with collagen deposition, admixed with neutrophilic dermatitis, and necrotic debris. We found that in cultures of normal human keratinocytes, exposure to 17.9 Gy irradiation caused the upregulation of p21/waf1, a marker of senescence. Using western blot analysis of 17.9 Gy-irradiated mice skin samples, we also detected a marker of accelerated senescence (p21/waf1) 7 days post-irradiation, and a marker of cellular apoptosis (activated caspase-3) at 30 days, both preceding histological evidence of inflammatory infiltrates. Immunohistochemistry revealed reduced epithelial stem cells from hair follicles 14-30 days post-irradiation. Furthermore, p21/waf1 expression was increased in the region of the hair follicle stem cells at 14 days post 17 Gy irradiation. These data indicate that radiation induces accelerated cellular senescence in the region of the stem cell population of the skin.
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Elizabeth A
EA
McCart
Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Rajesh L
RL
Thangapazham
Public Health Activity-Fort Carson, 1661 O'Connell Blvd, Fort Carson, CO 80913, USA.
Eric D
ED
Lombardini
Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, 5001 Campus Drive, College Park, MD 20740, USA.
Steven R
SR
Mog
Molecular and Integrative Physiological Sciences, Harvard TH Chan School of Public Health, 677 Huntington Ave., Boston, MA 02115, USA.
Ronald Allan M
RAM
Panganiban
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Kelley M
KM
Dickson
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Rihab A
RA
Mansur
Department of Radiation Dosimetry, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Vitaly
V
Nagy
Department of Radiology, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Sung-Yop
SY
Kim
Department of Radiology, University of New Mexico, 1 University of New Mexico, Albuquerque, NM 87131, USA.
Reed
R
Selwyn
Radiation Countermeasures Program, Scientific Research Department, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Michael R
MR
Landauer
Department of Dermatology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Thomas N
TN
Darling
Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
Regina M
RM
Day
D053687:Adult Stem Cells / Q000528:radiation effects; D000375:Aging; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D016922:Cellular Senescence / Q000528:radiation effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005355:Fibrosis; D018859:Hair Follicle / Q000473:pathology / Q000528:radiation effects; D015603:Keratinocytes / Q000473:pathology / Q000528:radiation effects; D008810:Mice, Inbred C57BL; D009928:Organ Specificity / Q000528:radiation effects*; D011832:Radiation Injuries / Q000473:pathology*; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D015595:Skin Aging / Q000528:radiation effects*; D014456:Ulcer / Q000473:pathology
accelerated senescence; dermatitis; hair follicle stem cells; ionizing radiation; p21/waf1