These studies identify senescence as an important process in AECII in vivo and indicate that NOX is a critical mediator of radiation-induced AECII senescence and pulmonary fibrosis.
Background
Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. mTOR signaling drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mTOR inhibition with rapamycin would mitigate RIPF.
Methods/Materials
C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or control diet two days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy thoracic irradiation (IR). Fibrosis was assessed with Masson-Trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real time PCR. Senescence was assessed by staining for beta-galactosidase activity.
Results
Administration of rapamycin extended the median survival of irradiated mice compared to control diet from 116 days to 156 days (log rank p=0.006). Treatment with rapamycin reduced hydroxyproline content compared to control diet (IR+vehicle: 45.9±11.8, IR+rapamycin: 21.4±6.0, p=0.001) and reduced visible fibrotic foci. Rapamycin treatment attenuated IL-1β and TGF-β induction in irradiated lung compared to control diet. Type II pneumocyte senescence after IR was reduced with rapamycin treatment at 16 weeks (three-fold reduction at 16 weeks, p<0.001).
Conclusion
Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extra cellular matrix production, and senescence in type II pneumocytes.
Individuals are exposed to ionizing radiation during medical procedures and nuclear disasters, and this exposure can be carcinogenic, toxic, and sometimes fatal. Drugs that protect individuals from the adverse effects of radiation may therefore be valuable countermeasures against the health risks of exposure. In the current study, the LD50/30 (the dose resulting in 50% of exposed mice surviving 30 days after exposure) was determined in control C3H mice and mice treated with the nitroxide radioprotectors Tempol, 3-CP, 16c, 22c, and 23c. The pharmacokinetics of 22c and 23c were measured with magnetic resonance imaging (MRI) in the brain, blood, submandibular salivary gland, liver, muscle, tongue, and myocardium. It was found 23c was the most effective radioprotector of the five studied: 23c increased the LD50/30 in mice from 7.9 ± 0.15 Gy (treated with saline) to 11.47 ± 0.13 Gy (an increase of 45%). Additionally, MRI-based pharmacokinetic studies revealed that 23c is an effective redox imaging agent in the mouse brain, and that 23c may allow functional imaging of the myocardium. The data in this report suggest that 23c is currently the most potent known nitroxide radioprotector, and that it may also be useful as a contrast agent for functional imaging.
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