Oxidant-dependent Sensitizing, Protective and Mitigative Effects in X-ray Irradiated Pulmonary Endothelial Cells.

The primary response of proliferating BPAEC (bovine pulmonary artery endothelial cells) after x-ray irradiation ({less than or equal to} 10 Gy) is shown to be transient cell-cycle arrest. Accompanying oxidant-linked functional changes within the mitochondria are readily measured, but not increased autophagy. Radiation-induced apoptosis is negligible in this line - important, because cells undergoing apoptosis release oxygen-derived species that can overwhelm/mask the radiation-associated species and their effects that we wish to investigate. Cells irradiated and cultured at 3% oxygen exhibited delayed cell-cycle arrest (6-8 hr after 10 Gy irradiation) compared to those maintained at 20% oxygen (2-4 hr after 10 Gy irradiation). At 3% oxygen either during, or after irradiation, results intermediate between 20% and 3% oxygen were obtained. No variability in cell-cycle distribution was observed for unirradiated cells cultured under different prevailing oxygen levels. Mitochondrially-localized MnSOD delayed the x-ray-induced cell-cycle changes when over-expressed in BPAEC, indicating superoxide to be one of the key oxygen-derived cytotoxic species involved in the radiobiological response. Also, the peroxynitrite biomarker 3-nitrotyrosine was elevated, while hydrogen peroxide levels were not. Lastly, the utility of the BPAEC for screening potential countermeasures to ionizing radiation is demonstrated with some quinoline derivatives. Three of the five compounds appeared mitigative and all were protective. It is suggested that the oxidation-reduction chemistry of these compounds probably offers a reasonable explanation for their observed ameliorative properties. Furthermore, the results suggest a promising new direction in the search for lead compounds as countermeasures to the effects of ionizing radiation.

Informations de copyright

Copyright © 2024 American Society for Pharmacology and Experimental Therapeutics.