放射性肺损伤的发生机制及防治进展

doi:10.3760/cma.j.issn.1007-1245.2022.24.019

摘要/Abstract

摘要： 胸部恶性肿瘤的发病率及病死率长期居高不下，最新发表的中国癌症数据显示，所有癌症患者中肺癌的发病率及病死率所占比例均超半数，仍占据着主导地位。放疗作为非小细胞肺癌、食管癌、乳腺癌等胸部恶性肿瘤的极其重要的一种治疗手段，其所带来的严重不良反应之一便是放射性肺损伤（RILI）。RILI由于其后期进行性、不可逆地发展为肺纤维化的临床特点，吸引着越来越多的临床及科研工作者对其发生机制及相应治疗方案进行探索。本文就RILI的病理生理、发生发展过程中涉及的重要细胞、分子及预防治疗进展作一综述。

关键词: 放射性肺损伤, 放射性肺纤维化, 发病机制, 治疗

Abstract: The incidence and mortality of chest malignant tumors remain high for a long time. The latest published cancer data in China indicate that among all cancer patients, the incidence and mortality of lung cancer account for more than 50%, and still occupy a dominant position. As a significant treatment for chest malignant tumors, such as non-small cell lung cancer, esophageal cancer, breast cancer and so on, radiation therapy has brought serious side effects, one of which is called as radiation induced lung injury (RILI), characterized by progressive and irreversible development into pulmonary fibrosis. And this has attracted more and more clinical and scientific researchers to explore its pathogenesis and corresponding therapeutic schedule. This paper reviews the pathophysiology, important cells and molecules involved in the occurrence, and progress in prevention and treatment of RILI.

Key words: Radiation induced lung injury, Radiation induced lung fibrosis, Pathogenesis, Treatment

张坤韩霞陈绍水. 放射性肺损伤的发生机制及防治进展[J]. 国际医药卫生导报, 2022, 28(24): 3494-.

Zhang Kun, Han Xia, Chen Shaoshui. Radiation induced lung injury: mechanism of occurrence and progress in prevention and treatment[J]. International Medicine and Health Guidance News, 2022, 28(24): 3494-.

参考文献

[1] Arroyo-Hernández M, Maldonado F, Lozano-Ruiz F, et al. Radiation-induced lung injury: current evidence[J]. BMC Pulm Med, 2021, 21(1):9.DOI: 10.1186/s12890-020- 01376-4.
[2] Huang Y, Zhang W, Yu F, et al. The cellular and molecular mechanism of radiation-induced lung injury[J]. Med Sci Monit, 2017, 23: 3446-3450. DOI: 10.12659/msm. 902353.
[3] He Y, Thummuri D, Zheng G, et al. Cellular senescence and radiation-induced pulmonary fibrosis[J]. Transl Res, 2019, 209: 14-21. DOI: 10.1016/j.trsl.2019.03.006.
[4] Kainthola A, Haritwal T, Tiwari M, et al. Immunological aspect of radiation-induced pneumonitis, current treatment strategies, and future prospects[J]. Front Immunol, 2017, 8: 506. DOI: 10.3389/fimmu.2017.00506.
[5] Choi YW, Munden RF, Erasmus JJ, et al. Effects of radiation therapy on the lung: radiologic appearances and differential diagnosis[J]. Radiographics, 2004, 24(4): 985-997. DOI: 10.1148/rg.244035160.
[6] Singh V, Torricelli AA, Nayeb-Hashemi N, et al. Mouse strain variation in SMA(+) myofibroblast development after corneal injury[J]. Exp Eye Res, 2013, 115: 27-30. DOI: 10.1016/j.exer.2013.06.006.
[7] Tatler AL, Jenkins G. TGF-β activation and lung fibrosis[J]. Proc Am Thorac Soc, 2012, 9(3):130-136. DOI: 10.1513/pats.201201-003AW.
[8] El Agha E, Moiseenko A, Kheirollahi V, et al. Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis[J]. Cell Stem Cell, 2017, 20(2): 261-273. DOI: 10.1016/j.stem.2016.10.004.
[9] Hanania AN, Mainwaring W, Ghebre YT, et al. Radiation-induced lung injury: assessment and management[J]. Chest, 2019, 156(1):150-162. DOI: 10.1016/j.chest.2019.03.033.
[10] Jarzebska N, Karetnikova ES, Markov AG, et al. Scarred lung. an update on radiation-induced pulmonary fibrosis[J]. Front Med (Lausanne), 2021, 7: 585756. DOI: 10.3389/fmed.2020.585756.
[11] Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis[J]. Lancet, 2017, 389(10082): 1941-1952. DOI: 10.1016/S0140-6736(17)30866-8.
[12] Choi SH, Hong ZY, Nam JK, et al. A hypoxia-induced vascular endothelial-to-mesenchymal transition in development of radiation-induced pulmonary fibrosis[J]. Clin Cancer Res, 2015, 21(16): 3716-3726. DOI: 10.1158/1078-0432.CCR-14-3193.
[13] Hill C, Jones MG, Davies DE, et al. Epithelial-mesenchymal transition contributes to pulmonary fibrosis via aberrant epithelial/fibroblastic cross-talk[J]. J Lung Health Dis, 2019, 3(2):31-35.
[14] 陈家祯, 王玉, 王存良, 等. 放射性肺损伤发病机制及分子靶向治疗研究进展[J]. 中国辐射卫生, 2021, 30(3): 377-380, 390. DOI: 10.13491/j.issn.1004- 714X.2021.03.023.
[15] Wynn TA. Fibrotic disease and the T(H)1/T(H)2 paradigm[J]. Nat Rev Immunol, 2004, 4(8): 583-594. DOI: 10.1038/nri1412.
[16] Ma LJ, Yang H, Gaspert A, et al. Transforming growth factor-beta-dependent and -independent pathways of induction of tubulointerstitial fibrosis in beta6(-/-) mice[J]. Am J Pathol, 2003, 163(4):1261-1273. DOI: 10.1016/s0002-9440(10)63486-4.
[17] Kaviratne M, Hesse M, Leusink M, et al. IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent[J]. J Immunol, 2004, 173(6): 4020-4029. DOI: 10.4049/jimmunol.173.6.4020.
[18] 李梦瑶,刘盼,柯越海,等. 放射性肺损伤中巨噬细胞作用机制的研究进展[J]. 浙江大学学报(医学版),2020,49(5):623-628. DOI:10.3785/j.issn.1008-9292.2020.10.12.
[19] Lu L, Sun C, Su Q, et al. Radiation-induced lung injury: latest molecular developments, therapeutic approaches, and clinical guidance[J]. Clin Exp Med, 2019, 19(4): 417-426. DOI: 10.1007/s10238-019-00571-w.
[20] 荣建芳,余韬,舒徐. 活性氧调控巨噬细胞极化的研究进展[J]. 基础医学与临床,2019,39(1):92-96. DOI:10.3969/j.issn.1001-6325.2019.01.024.
[21] Araya J, Nishimura SL. Fibrogenic reactions in lung disease[J]. Annu Rev Pathol, 2010, 5: 77-98. DOI: 10.1146/annurev.pathol.4.110807.092217.
[22] Barbazán J, Matic Vignjevic D. Cancer associated fibroblasts: is the force the path to the dark side?[J]. Curr Opin Cell Biol, 2019, 56: 71-79. DOI: 10.1016/j.ceb.2018.09.002.
[23] Grinde MT, Vik J, Camilio KA, et al. Ionizing radiation abrogates the pro-tumorigenic capacity of cancer-associated fibroblasts co-implanted in xenografts[J]. Sci Rep, 2017, 7: 46714. DOI: 10.1038/srep46714.
[24] Barker HE, Paget JT, Khan AA, et al. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence[J]. Nat Rev Cancer, 2015, 15(7): 409-425. DOI: 10.1038/nrc3958.
[25] Arshad A, Deutsch E, Vozenin MC. Simultaneous irradiation of fibroblasts and carcinoma cells repress the secretion of soluble factors able to stimulate carcinoma cell migration[J]. PLoS One, 2015, 10(1): e0115447. DOI: 10.1371/journal.pone.0115447.
[26] 陈志远, 董卓, 魏威, 等. TGF-β1对放射性肺纤维化作用的研究进展[J]. 辐射防护, 2018, 38(2):171-175.
[27] Roberts AB, Russo A, Felici A, et al. Smad3: a key player in pathogenetic mechanisms dependent on TGF-beta[J]. Ann N Y Acad Sci, 2003, 995: 1-10. DOI: 10.1111/j.1749-6632.2003.tb03205.x.
[28] Kelley RK, Gane E, Assenat E, et al. A phase 2 study of galunisertib (TGF-β1 receptor type I inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma [J]. Clin Transl Gastroenterol, 2019, 10(7): e00056. DOI: 10.14309/ctg.0000000000000056.
[29] Lu Z, Ma Y, Zhang S, et al. Transforming growth factor-β1 small interfering RNA inhibits growth of human embryonic lung fibroblast HFL-I cells in vitro and defends against radiation-induced lung injury in vivo[J]. Mol Med Rep, 2015, 11(3): 2055-2061. DOI: 10.3892/mmr.2014.2923.
[30] Qin W, Liu B, Yi M, et al. Antifibrotic agent pirfenidone protects against development of radiation-induced pulmonary fibrosis in a murine model[J]. Radiat Res, 2018, 190(4): 396-403. DOI: 10.1667/RR15017.1.
[31] De Ruysscher D, Granton PV, Lieuwes NG, et al. Nintedanib reduces radiation-induced microscopic lung fibrosis but this cannot be monitored by CT imaging: a preclinical study with a high precision image-guided irradiator[J]. Radiother Oncol, 2017, 124(3): 482-487. DOI: 10.1016/j.radonc.2017.07.014.
[32] Varone F, Sgalla G, Iovene B, et al. Nintedanib for the treatment of idiopathic pulmonary fibrosis[J]. Expert Opin Pharmacother, 2018, 19(2): 167-175. DOI: 10.1080/14656566.2018.1425681.
[33] Xin Y, Cereda M, Yehya N, et al. Imatinib alleviates lung injury and prolongs survival in ventilated rats[J]. Am J Physiol Lung Cell Mol Physiol, 2022, 322(6): L866-L872. DOI: 10.1152/ajplung.00006.2022.
[34] Li M, Abdollahi A, Gröne HJ, et al. Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model[J]. Radiat Oncol, 2009, 4: 66. DOI:10.1186/1748-717X-4-66.
[35] 李营歌,宋启斌,姚颐,等. 抗氧化治疗在放射性肺损伤中的研究进展[J]. 中国肺癌杂志,2019,22(9):579-582. DOI:10.3779/j.issn.1009-3419.2019.09.05.
[36] Käsmann L, Dietrich A, Staab-Weijnitz CA, et al. Radiation-induced lung toxicity - cellular and molecular mechanisms of pathogenesis, management, and literature review[J]. Radiat Oncol, 2020, 15(1):214. DOI: 10.1186/s13014-020-01654-9.
[37] 赵春阳, 杨立超, 蔡佳怡, 等. ACEI对放射性肺损伤保护作用的Meta分析[J]. 医药导报, 2018, 37(11): 1404-1408. DOI:10.3870/j.issn.1004-0781.2018.11.027.
[38] Ziegler V, Henninger C, Simiantonakis I, et al. Rho inhibition by lovastatin affects apoptosis and DSB repair of primary human lung cells in vitro and lung tissue in vivo following fractionated irradiation[J]. Cell Death Dis, 2017, 8(8): e2978. DOI: 10.1038/cddis.2017.372.
[39] Monceau V, Pasinetti N, Schupp C, et al. Modulation of the Rho/ROCK pathway in heart and lung after thorax irradiation reveals targets to improve normal tissue toxicity[J]. Curr Drug Targets, 2010, 11(11): 1395-1404. DOI: 10.2174/1389450111009011395.
[40] Ozturk B, Egehan I, Atavci S, et al. Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer: a double-blind randomized trial[J]. Int J Radiat Oncol Biol Phys, 2004, 58(1):213-219. DOI: 10.1016/s0360-3016(03)01444-5.
[41] Bickelhaupt S, Erbel C, Timke C, et al. Effects of CTGF blockade on attenuation and reversal of radiation-induced pulmonary fibrosis[J].J Natl Cancer Inst, 2017, 109(8):10. DOI: 10.1093/jnci/djw339
[42] Richeldi L, Fernández Pérez ER, Costabel U, et al. Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial[J]. Lancet Respir Med, 2020, 8(1): 25-33. DOI: 10.1016/S2213-2600(19)30262-0.
[43] Qu H, Liu L, Liu Z, et al. Blocking TBK1 alleviated radiation-induced pulmonary fibrosis and epithelial-mesenchymal transition through Akt-Erk inactivation[J]. Exp Mol Med, 2019, 51(4): 1-17. DOI: 10.1038/s12276-019-0240-4.
[44] Gong L, Wu X, Li X, et al. S1PR3 deficiency alleviates radiation-induced pulmonary fibrosis through the regulation of epithelial-mesenchymal transition by targeting miR-495-3p[J]. J Cell Physiol, 2020, 235(3): 2310-2324. DOI: 10.1002/jcp.29138.
[45] 万志杰,赵松韵,杨彦勇,等. 基因修饰的间充质干细胞在放射性肺损伤治疗中的实验研究进展[J]. 中华放射医学与防护杂志,2021,41(8):595-601. DOI:10.3760/cma.j.issn.0254-5098.2021.08.006.
[46] Shao L, Zhang Y, Shi W, et al. Mesenchymal stromal cells can repair radiation-induced pulmonary fibrosis via a DKK-1-mediated Wnt/β-catenin pathway[J]. Cell Tissue Res, 2021, 384(1): 87-97. DOI: 10.1007/s00441-020- 03325-3.
[47] 李杰, 冉永红, 郝玉徽. 放射性肺损伤的分子机制及其治疗进展[J/CD]. 中华肺部疾病杂志(电子版), 2021, 14(3): 390-392. DOI: 10.3877/cma.j.issn.1674-6902.2021.03.037.
[48] Li X, Xu G, Qiao T, et al. Effects of CpG Oligodeoxynucleotide 1826 on transforming growth factor-beta 1 and radiation-induced pulmonary fibrosis in mice[J]. J Inflamm (Lond), 2016, 13: 16. DOI: 10.1186/s12950-016-0125-4.
[49] Zhang C, Zhao H, Li BL, et al. CpG-oligodeoxynucleotides may be effective for preventing ionizing radiation induced pulmonary fibrosis[J]. Toxicol Lett, 2018, 292: 181-189. DOI: 10.1016/j.toxlet.2018.04.009.
[50] Zhao H, Wang Y, Qiu T, et al. Autophagy, an important therapeutic target for pulmonary fibrosis diseases[J]. Clin Chim Acta, 2020, 502: 139-147. DOI: 10.1016/j.cca.2019. 12.016.
[51] 郝志强,杨海祥,朱巍,等. 深部热疗预防非小细胞肺癌患者放疗后放射性肺损伤的临床效果[J]. 内蒙古医学杂志,2021,53(2):158-160,166. DOI:10.16096/J.cnki.nmgyxzz. 2021.53.02.010.
[52] 王远飞,李曙芳,王新钢,等. 亚低温对放射性肺损伤大鼠的保护作用[J]. 中国实验动物学报,2018,26(5):624-630. DOI:10.3969/j.issn.1005-4847.2018.05.014.
[53] 林贤雷,林泽晨,钟亚珍,等. 中药治疗恶性肿瘤患者放射性肺损伤的疗效及安全性的Meta分析[J]. 中国现代医生,2021,59(25):133-139,封3.
[54] 苏昕妍,金灿,池永学. 精氨酸对肺损伤的保护效应及机制的进展[J]. 国际医药卫生导报,2022,28(4):449-452. DOI:10.3760/cma.j.issn.1007-1245.2022.04.002.