Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis.
Combined inhibition of TGFβ and PDGF signaling attenuates radiation-induced pulmonary fibrosis.
复制标题
TGFβ和PDGF信号传导的结合抑制减弱了辐射诱导的肺纤维化。
DOI：
10.1080/2162402x.2015.1123366
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发表时间：
2016-05
期刊：
影响因子：
7.2
通讯作者：
Huber PE
中科院分区：
文献类型：
--
作者：
Dadrich M;Nicolay NH;Flechsig P;Bickelhaupt S;Hoeltgen L;Roeder F;Hauser K;Tietz A;Jenne J;Lopez R;Roehrich M;Wirkner U;Lahn M;Huber PE
背景资料：放射治疗（RT）是治疗肺癌的主要手段，但有效剂量往往受到放射性肺炎和肺纤维化的限制。转化生长因子β（Transforming growth factor β，TGFβ）和血小板源性生长因子（platelet-derived growth factor，PDGF）在这些疾病的发生发展中起着至关重要的作用，但双重生长因子抑制对肺纤维化发展的影响尚不清楚。方法：C57 BL/6小鼠胸部照射20戈伊，诱导肺纤维化。RT后单独或联合应用PDGF受体抑制剂SU 9518和SU 14816（伊马替尼）和TGFβ受体抑制剂galunisertib。通过高分辨率CT和MRI测量肺密度和间隔纤维化。进行肺组织学和基因表达分析，并研究骨桥蛋白水平。结果如下：SU 9518、SU 14816或galunisertib单独治疗可减轻放射诱导的肺部炎症和纤维化，并减少肺损伤的放射学和组织学体征。在小鼠模型中，联合使用PDGF和TGFβ抑制剂显示出可行性和安全性，与单独阻断任一途径相比，双重抑制显著减弱了辐射诱导的肺损伤并延长了小鼠存活期。经照射肺组织的基因表达分析显示，胸部照射可上调PDGF和TGFβ依赖性信号传导成分，上调模式显示PDGF和TGFβ通路下游介质之间存在串扰。结论：联合小分子抑制PDGF和TGFβ信号传导是一种安全有效的治疗小鼠辐射诱导的肺部炎症和纤维化的方法，并可能为治疗人类纤维化肺病提供一种新方法。翻译声明：RT是一种有效的癌症治疗方式，但由于急性和慢性毒性而受到限制，其中TGFβ和PDGF发挥关键作用。在这里，我们表明，TGFβ和PDGF信号的联合抑制在减轻辐射诱导的肺损伤方面比单独阻断任一途径更有效。我们使用了TGFβ-受体I抑制剂galunisertib（一种在临床前模型中有效的抗癌化合物）和PDGFR抑制剂伊马替尼和SU 9518（一种舒尼替尼类似物）。我们的信号数据表明，TGFβ和PDGF信号的减少和SPP 1（骨桥蛋白）表达的减弱可能是观察到的益处的原因。随着目前I/II期临床试验中类似化合物作为癌症治疗剂或已批准用于某些癌症或特发性肺纤维化（IPF）的临床可用性，我们的研究表明，TGFβ和PDGF信号传导的小分子抑制剂的联合应用可能提供一种有希望的方法来治疗肺癌RT中的辐射相关毒性。
Background: Radiotherapy (RT) is a mainstay for the treatment of lung cancer, but the effective dose is often limited by the development of radiation-induced pneumonitis and pulmonary fibrosis. Transforming growth factor β (TGFβ) and platelet-derived growth factor (PDGF) play crucial roles in the development of these diseases, but the effects of dual growth factor inhibition on pulmonary fibrosis development remain unclear. Methods: C57BL/6 mice were treated with 20 Gy to the thorax to induce pulmonary fibrosis. PDGF receptor inhibitors SU9518 and SU14816 (imatinib) and TGFβ receptor inhibitor galunisertib were applied individually or in combinations after RT. Lung density and septal fibrosis were measured by high-resolution CT and MRI. Lung histology and gene expression analyses were performed and Osteopontin levels were studied. Results: Treatment with SU9518, SU14816 or galunisertib individually attenuated radiation-induced pulmonary inflammation and fibrosis and decreased radiological and histological signs of lung damage. Combining PDGF and TGFβ inhibitors showed to be feasible and safe in a mouse model, and dual inhibition significantly attenuated radiation-induced lung damage and extended mouse survival compared to blockage of either pathway alone. Gene expression analysis of irradiated lung tissue showed upregulation of PDGF and TGFβ-dependent signaling components by thoracic irradiation, and upregulation patterns show crosstalk between downstream mediators of the PDGF and TGFβ pathways. Conclusion: Combined small-molecule inhibition of PDGF and TGFβ signaling is a safe and effective treatment for radiation-induced pulmonary inflammation and fibrosis in mice and may offer a novel approach for treatment of fibrotic lung diseases in humans. Translational statement: RT is an effective treatment modality for cancer with limitations due to acute and chronic toxicities, where TGFβ and PDGF play a key role. Here, we show that a combined inhibition of TGFβ and PDGF signaling is more effective in attenuating radiation-induced lung damage compared to blocking either pathway alone. We used the TGFβ-receptor I inhibitor galunisertib, an effective anticancer compound in preclinical models and the PDGFR inhibitors imatinib and SU9518, a sunitinib analog. Our signaling data suggest that the reduction of TGFβ and PDGF signaling and the attenuation of SPP1 (Osteopontin) expression may be responsible for the observed benefits. With the clinical availability of similar compounds currently in phase-I/II trials as cancer therapeutics or already approved for certain cancers or idiopathic lung fibrosis (IPF), our study suggests that the combined application of small molecule inhibitors of TGFβ and PDGF signaling may offer a promising approach to treat radiation-associated toxicity in RT of lung cancer.