Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model.
Mammalian Target of Rapamycin Inhibition With Rapamycin Mitigates Radiation-Induced Pulmonary Fibrosis in a Murine Model.
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DOI：
10.1016/j.ijrobp.2016.07.026
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发表时间：
2016-11-15
影响因子：
7
通讯作者：
Citrin, Deborah E.
中科院分区：
文献类型：
--
作者：
Chung, Eun Joo;Sowers, Anastasia;Thetford, Angela;McKay-Corkum, Grace;Chung, Su I.;Mitchell, James B.;Citrin, Deborah E.
放射诱发的肺纤维化（RIPF）是放射治疗的晚期毒性。 mTOR 信号传导驱动 RIPF 中涉及的多个过程，包括炎症细胞因子的产生、成纤维细胞增殖和上皮衰老。我们试图确定雷帕霉素抑制 mTOR 是否会减轻 RIPF。 C57BL/6NCr 小鼠在接受每日 5 次 6 Gy 胸部照射 (IR) 照射前两天接受用雷帕霉素（14 mg/kg 食物）配制的饮食或对照饮食，并在暴露后持续 16 周。用马森三色染色和羟脯氨酸测定评估纤维化。通过定量实时PCR评估细胞因子表达。通过β-半乳糖苷酶活性染色来评估衰老。与对照饮食相比，给予雷帕霉素可将受辐射小鼠的中位生存期从 116 天延长至 156 天（对数等级 p=0.006）。与对照饮食相比，雷帕霉素治疗降低了羟脯氨酸含量（IR+载体：45.9±11.8，IR+雷帕霉素：21.4±6.0，p=0.001）并且减少了可见的纤维化病灶。与对照饮食相比，雷帕霉素治疗减弱了受辐射肺中 IL-1β 和 TGF-β 的诱导。第 16 周时雷帕霉素治疗可减少 IR 后的 II 型肺细胞衰老（第 16 周时减少三倍，p<0.001）。雷帕霉素在小鼠模型中可预防 RIPF。雷帕霉素治疗可减少 II 型肺细胞的炎症细胞因子表达、细胞外基质产生和衰老。
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. 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. 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). Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extra cellular matrix production, and senescence in type II pneumocytes.
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DOI：
10.18632/aging.100443
发表时间：
2012-03
期刊：
Aging
影响因子：
--
作者：
Blagosklonny MV
通讯作者：
Blagosklonny MV
影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
影响因子：
2.8
作者：
Gravina, Giovanni Luca;Marampon, Francesco;Festuccia, Claudio
通讯作者：
Festuccia, Claudio
影响因子：
4.3
作者：
Demidenko, Zoya N.;Zubova, Svetlana G.;Blagosklonny, Mikhail V.
通讯作者：
Blagosklonny, Mikhail V.