Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model
| Autor: | Angela Thetford, Grace McKay-Corkum, Deborah Citrin, Su I. Chung, Anastasia L. Sowers, Eun Joo Chung, James B. Mitchell |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research Pathology medicine.medical_specialty medicine.medical_treatment Interleukin-1beta Radiation-Protective Agents Pharmacology Radiation Tolerance Article Mice 03 medical and health sciences 0302 clinical medicine Transforming Growth Factor beta Fibrosis Pulmonary fibrosis medicine Animals Radiology Nuclear Medicine and imaging Fibroblast Lung Cellular Senescence Sirolimus Radiation biology business.industry Macrophages TOR Serine-Threonine Kinases Transforming growth factor beta beta-Galactosidase medicine.disease Extracellular Matrix Mice Inbred C57BL Radiation Pneumonitis Hydroxyproline 030104 developmental biology medicine.anatomical_structure Cytokine Oncology Alveolar Epithelial Cells 030220 oncology & carcinogenesis biology.protein Female business Transforming growth factor medicine.drug |
| Zdroj: | International Journal of Radiation Oncology*Biology*Physics. 96:857-866 |
| ISSN: | 0360-3016 |
| DOI: | 10.1016/j.ijrobp.2016.07.026 |
| Popis: | Purpose Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. Signaling of the mammalian target of rapamycin drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mammalian target of rapamycin inhibition with rapamycin would mitigate RIPF. Methods and Materials C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or a control diet 2 days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy of thoracic irradiation. Fibrosis was assessed with Masson trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real-time polymerase chain reaction. Senescence was assessed by staining for β-galactosidase activity. Results Administration of rapamycin extended the median survival of irradiated mice compared with the control diet from 116 days to 156 days ( P =.006, log-rank test). Treatment with rapamycin reduced hydroxyproline content compared with the control diet (irradiation plus vehicle, 45.9 ± 11.8 μg per lung; irradiation plus rapamycin, 21.4 ± 6.0 μg per lung; P =.001) and reduced visible fibrotic foci. Rapamycin treatment attenuated interleukin 1β and transforming growth factor β induction in irradiated lungs compared with the control diet. Type II pneumocyte senescence after irradiation was reduced with rapamycin treatment at 16 weeks (3-fold reduction at 16 weeks, P Conclusions Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production, and senescence in type II pneumocytes. |
| Databáze: | OpenAIRE |
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