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Radiotherapy of thoracic neoplasms and accidental radiation exposure often results in pneumonitis and fibrosis of lungs. Here, we investigated the potential of amifostine analogs: DRDE-07, DRDE-30, and DRDE-35, in alleviating radiation-induced lung damage.C57BL/6 mice were exposed to 13.5 Gy thoracic irradiation, 30 min after intraperitoneal administration of the analogs, and assessed for modulation of the pathological response at 12 and 24 weeks.DRDE-07, DRDE-30 and DRDE-35 increased the survival of irradiated mice from 20% to 30%, 80% and 70% respectively. Reduced parenchymal opacity (X-ray CT) in the lungs of DRDE-30 pre-treated mice corroborated well with the significant decrease in Ashcroft score (p 0.01). Two-fold increase in SOD and catalase activities (p 0.05), coupled with a 50% increase in GSH content and a 60% decrease in MDA content (p 0.05) suggested restoration of the antioxidant defence system. A 20% to 40% decrease in radiation-induced apoptotic and mitotic death in the lung tissue (micronuclei: p 0.01), resulted in attenuated lung and vascular permeability (FITC-Dextran leakage) by 50% (p 0.01), and a commensurate reduction (~50%) in leukocyte infiltration in the injured tissue (p 0.05). DRDE-30 abrogated the activation of pro-inflammatory NF-κB and p38/MAPK signaling cascades, suppressing the release of pro-inflammatory cytokines (IL-1β: p 0.05; TNF-α: p 0.05; IL-6: p 0.05) and up-regulation of CAMs on the endothelial cell surface. Reduction in hydroxyproline content (p 0.01) and collagen suggested inhibition of lung fibrosis which was associated with attenuation of TGF-β/Smad pathway-mediated-EMT.DRDE-30 could be a potential prophylactic agent against radiation-induced lung injury. |
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