NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells.
The need to both understand and minimize the side effects of brain irradiation is heightened by the ever-increasing number of patients with brain metastases that require treatment with whole brain irradiation (WBI); some 200,000 cancer patients/year receive partial or WBI. At the present time, there are no successful treatments for radiation-induced brain injury, nor are there any known effective preventive strategies. Data support a role for chronic oxidative stress in radiation-induced late effects. However, the pathogenic mechanism(s) involved remains unknown. One candidate source of reactive oxygen species (ROS) is nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase, which converts molecular oxygen (O(2)) to the superoxide anion (O(2)(-)) on activation. We hypothesize that brain irradiation leads to activation of NADPH oxidase. We report that irradiating rat brain microvascular endothelial cells in vitro leads to increased (i) intracellular ROS generation, (ii) activation of the transcription factor NFkappaB, (iii) expression of ICAM-1 and PAI-1, and (iv) expression of Nox4, p22(phox), and p47(phox). Pharmacologic and genetic inhibition of NADPH oxidase blocked the radiation-mediated upregulation of intracellular ROS, activation of NFkappaB, and upregulation of ICAM-1 and PAI-1. These results suggest that activation of NADPH oxidase may play a role in radiation-induced oxidative stress.
Collins-Underwood
J Racquel
JR
Department of Radiation Oncology, and Brain Tumor Center of Excellence, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
Zhao
Weiling
W
Sharpe
Jessica G
JG
Robbins
Mike E
ME
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D002461:Cell Line, Transformed; D002560:Cerebrovascular Circulation / Q000528:radiation effects*; D017931:DNA Primers; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects*; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000528:radiation effects*; D016133:Polymerase Chain Reaction; D051381:Rats
D017931:DNA Primers; D019255:NADPH Oxidases