Please wait a minute...
浙江大学学报（医学版）
浙江大学学报（医学版）  2020, Vol. 49 Issue (5): 623-628    DOI: 10.3785/j.issn.1008-9292.2020.10.12
综述     
放射性肺损伤中巨噬细胞作用机制的研究进展
李梦瑶(),刘盼,柯越海,张雪*()
浙江大学医学院基础医学系, 浙江 杭州 310058
Research progress on macrophage in radiation induced lung injury
LI Mengyao(),LIU Pan,KE Yuehai,ZHANG Xue*()
School of Basic Medical Sciences, Zhejiang University, Hangzhou 310058, China
 全文: PDF(1055 KB)   HTML( 29 )
摘要：

放射性肺损伤（RILI）是肺癌、食管癌等恶性肿瘤患者进行放射治疗时产生的不良反应，包括急性放射性肺炎和慢性放射性肺纤维化。肺巨噬细胞是维持肺部稳态的一种天然免疫细胞，在RILI整个病理过程中均发挥关键作用。在RILI早期，肺巨噬细胞发生M1型活化，分泌炎性细胞因子，诱导炎症反应，同时通过促进活性氧诱导的活性氧级联反应产生大量活性氧，进一步损伤肺组织。在RILI中晚期，肺巨噬细胞向M2型转化，分泌促纤维细胞因子，促进放射性肺纤维化的发展。本文总结了肺巨噬细胞在RILI发病机制中的作用以及潜在的临床应用前景。
关键词： 巨噬细胞;  放射性肺损伤;  活性氧;  炎症;  肺纤维化;  综述    
Abstract:

Radiation-induced lung injury (RILI), including acute radiation pneumonitis and chronic radiation-induced pulmonary fibrosis (RIPF), is a side effect of radiotherapy for lung cancer and esophageal cancer. Pulmonary macrophages, as a kind of natural immune cells maintaining lung homeostasis, play a key role in the whole pathological process of RILI. In the early stage of RILI, classically activated M1 macrophages secrete proinflammatory cytokines to induce inflammation and produce massive reactive oxygen species (ROS) through ROS-induced cascade to further impair lung tissue. In the later stage of RILI, alternatively activated M2 macrophages secrete profibrotic cytokines to promote the development of RIPF. The roles of macrophage in the pathogenesis of RILI and the related potential clinical applications are summarized in this review.
Key words: Macrophages    Radiation-induced lung injury    Reactive oxygen species    Inflammation    Pulmonary fibrosis    Review
收稿日期: 2020-02-03 出版日期: 2020-11-19
:  R818  
基金资助: 浙江省自然科学基金(LY18H010001);国家自然科学基金(81873418, 31870901)
通讯作者: 张雪     E-mail: 21818541@zju.edu.cn;zhangxue@zju.edu.cn
作者简介: 李梦瑶(1995-), 女, 硕士研究生, 主要从事放射性肺损伤的研究; E-mail:21818541@zju.edu.cn; https://orcid.org/0000-0001-7988-8759
服务　　
把本文推荐给朋友
加入引用管理器
E-mail Alert
RSS
作者相关文章　　
李梦瑶
刘盼
柯越海
张雪

引用本文:

李梦瑶,刘盼,柯越海,张雪. 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.

LI Mengyao,LIU Pan,KE Yuehai,ZHANG Xue. Research progress on macrophage in radiation induced lung injury. J Zhejiang Univ (Med Sci), 2020, 49(5): 623-628.

链接本文:

http://www.zjujournals.com/med/CN/10.3785/j.issn.1008-9292.2020.10.12    或    http://www.zjujournals.com/med/CN/Y2020/V49/I5/623

作用机制 药物 参考文献序号
减轻氧化损伤
  清除氧自由基并维持细胞内超氧化物歧化酶和谷胱甘肽水平 橙皮苷 30
  抑制高速泳动族蛋白B1/Toll样受体4/核因子κB途径 GTS-21 31
  抑制巨噬细胞-NADPH氧化酶-活性氧-肌成纤维细胞轴 雷公藤内酯 32
  抵抗脂质过氧化 褪黑素 33
减轻炎症反应
  调节巨噬细胞促炎编程，抑制M1型活化 鬼臼毒素和芦丁(G-003M) 34
  抑制巨噬细胞中的黑色素瘤缺乏因子炎性小体介导的炎症反应 穿心莲内酯 35
  抑制巨噬细胞浸润 姜黄素 36
  抑制趋化因子配体8表达和巨噬细胞募集 尼卡芬 37
  抑制白细胞介素4-白细胞介素4受体α1-双氧化酶2途径 二甲双胍、褪黑素 38
  抑制微小RNA-30e/NOD样受体家族3途径 褪黑素 38
  抑制巨噬细胞M1型活化及减少炎性细胞因子分泌 2-甲氧基雌二醇 39
抑制纤维化形成
  阻断水通道蛋白4，减少M2型巨噬细胞浸润 TGN-020 40
  抑制高速泳动族蛋白B1及其他促纤维化因子 丙酮酸乙酯 41
  抑制转化生长因子β1-Smad依赖性途径 CpG-寡脱氧核苷酸 42
  减少巨噬细胞浸润和促纤维化因子表达 岩藻依聚糖 43
  抑制过氧化物酶1/核因子κB/缺氧诱导因子1α途径 β-榄香烯 44
减少促炎因子生成和Nrf信号转录，抑制转化生长因子β介导的纤维化 克拉霉素 45
表 1  放射性肺损伤中的巨噬细胞靶向药物研究一览
1 YOSHINO H , KUMAI Y , KASHIWAKURA I . Effects of endoplasmic reticulum stress on apoptosis induction in radioresistant macrophages[J]. Mol Med Rep, 2017, 15 (5): 2867- 2872
doi: 10.3892/mmr.2017.6298
2 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
3 DENG G , LIANG N , XIE J et al. Pulmonary toxicity generated from radiotherapeutic treatment of thoracic malignancies[J]. Oncol Lett, 2017, 14 (1): 501- 511
doi: 10.3892/ol.2017.6268
4 李成城, 张秋宁, 王小虎 . 活性氧与放射性肺损伤的相关研究进展[J]. 辐射研究与辐射工艺学报, 2019, 37 (6): 1- 7
LI Chengcheng , ZHANG Qiuning , WANG Xiaohu . A review of the relationship of reactive oxygen species with radiation-induced lung injuries[J]. Journal of Radiation Research and Radiation Processing, 2019, 37 (6): 1- 7
doi: 10.11889/j.1000-3436.2019.rrj.37.060101
5 FELDMAN N , ROTTER-MASKOWITZ A , OKUN E . DAMPs as mediators of sterile inflammation in aging-related pathologies[J]. Ageing Res Rev, 2015, 24 (Pt A): 29- 39
doi: 10.1016/j.arr.2015.01.003
6 YAHYAPOUR R , SHABEEB D , CHEKI M et al. Radiation protection and mitigation by natural antioxidants and flavonoids:implications to radiotherapy and radiation disasters[J]. Curr Mol Pharmacol, 2018, 11 (4): 285- 304
doi: 10.2174/1874467211666180619125653
7 GIURANNO L , IENT J , DE RUYSSCHER D et al. Radiation-induced lung injury (RILI)[J]. Front Oncol, 2019, 9 877
doi: 10.3389/fonc.2019.00877
8 ABERNATHY L M , FOUNTAIN M D , ROTHSTEIN S E et al. Soy isoflavones promote radioprotection of normal lung tissue by inhibition of radiation-induced activation of macrophages and neutrophils[J]. J Thorac Oncol, 2015, 10 (12): 1703- 1712
doi: 10.1097/JTO.0000000000000677
9 MEZIANI L , MONDINI M , PETIT B et al. CSF1R inhibition prevents radiation pulmonary fibrosis by depletion of interstitial macrophages[J]. Eur Respir J, 2018, 51 (3): 1702120
doi: 10.1183/13993003.02120-2017
10 FLECKENSTEIN K , ZGONJANIN L , CHEN L et al. Temporal onset of hypoxia and oxidative stress after pulmonary irradiation[J]. Int J Radiat Oncol Biol Phys, 2007, 68 (1): 196- 204
doi: 10.1016/j.ijrobp.2006.12.056
11 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
RONG Jianfang , YU Tao , SHU Xu . Research progress of ROS in regulating macrophage polarization[J]. Basic & Clinical Medicine, 2019, 39 (1): 92- 96
doi: 10.16352/j.issn.1001-6325.2019.01.032
12 XU Q , CHOKSI S , QU J et al. NADPH oxidases are essential for macrophage differentiation[J]. J Biol Chem, 2016, 291 (38): 20030- 20041
doi: 10.1074/jbc.M116.731216
13 GNANAPRAKASAM J N R , ESTRADA-MU?IZ E , VEGA L . The anacardic 6-pentadecyl salicylic acid induces macrophage activation via the phosphorylation of ERK1/2, JNK, P38 kinases and NF-κB[J]. Int Immunopharmacol, 2015, 29 (2): 808- 817
doi: 10.1016/j.intimp.2015.08.038
14 CHUNG S I , HORTON J A , RAMALINGAM T R et al. IL-13 is a therapeutic target in radiation lung injury[J]. Sci Rep, 2016, 6 39714
doi: 10.1038/srep39714
15 LIEROVA A , JELICOVA M , NEMCOVA M et al. Cytokines and radiation-induced pulmonary injuries[J]. J Radiat Res, 2018, 59 (6): 709- 753
doi: 10.1093/jrr/rry067
16 KRISHNAMURTHY P M , SHUKLA S , RAY P et al. Involvement of p38-betaTrCP-Tristetraprolin-TNFalpha axis in radiation pneumonitis[J]. Oncotarget, 2017, 8 (29): 47767- 47779
doi: 10.18632/oncotarget.17770
17 MALAVIYA R , GOW A J , FRANCIS M et al. Radiation-induced lung injury and inflammation in mice:role of inducible nitric oxide synthase and surfactant protein D[J]. Toxicol Sci, 2015, 144 (1): 27- 38
doi: 10.1093/toxsci/kfu255
18 SIVA S, MACMANUS M, KRON T, et al. A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer[J/OL]. PLoS One, 2014, 9(10): e109560. DOI: 10.1371/journal.pone.0109560.
19 SONG Y H , CHAI Q , WANG N L et al. X-rays induced IL-8 production in lung cancer cells via p38/MAPK and NF-κB pathway[J]. Int J Radiat Biol, 2020, 1- 8
doi: 10.1080/09553002.2020.1683643
20 PARK H , JO S , JUNG U . Ionizing radiation promotes epithelial-to-mesenchymal transition in lung epithelial cells by TGF-β-producing M2 macrophages[J]. In Vivo, 2019, 33 (6): 1773- 1784
doi: 10.21873/invivo.11668
21 TOMASEK J J , GABBIANI G , HINZ B et al. Myofibroblasts and mechano-regulation of connective tissue remodelling[J]. Nat Rev Mol Cell Biol, 2002, 3 (5): 349- 363
doi: 10.1038/nrm809
22 陈志远, 董卓, 魏威 . 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
CHEN Zhiyuan , DONG Zhuo , WEI Wei . Research progress of TGF-β1 on radiation-induced pulmonary fibrosis[J]. Radiation Protection, 2018, 38 (2): 171- 175
23 MACIAS M J , MARTIN-MALPARTIDA P , MASSAGUé J . Structural determinants of Smad function in TGF-β signaling[J]. Trends Biochem Sci, 2015, 40 (6): 296- 308
doi: 10.1016/j.tibs.2015.03.012
24 GRATCHEV A . TGF-β signalling in tumour associated macrophages[J]. Immunobiology, 2017, 222 (1): 75- 81
doi: 10.1016/j.imbio.2015.11.016
25 FARHOOD B , KHODAMORADI E , HOSEINI-GHAHFAROKHI M et al. TGF-β in radiotherapy:Mechanisms of tumor resistance and normal tissues injury[J]. Pharmacol Res, 2020, 155 104745
doi: 10.1016/j.phrs.2020.104745
26 DE LEVE S , WIRSD?RFER F , CAPPUCCINI F et al. Loss of CD73 prevents accumulation of alternatively activated macrophages and the formation of prefibrotic macrophage clusters in irradiated lungs[J]. FASEB J, 2017, 31 (7): 2869- 2880
doi: 10.1096/fj.201601228R
27 YAMAGISHI T , KODAKA N , KUROSE Y et al. Analysis of predictive parameters for the development of radiation-induced pneumonitis[J]. Ann Thorac Med, 2017, 12 (4): 252- 258
doi: 10.4103/atm.ATM_355_16
28 GROVES A M , JOHNSTON C J , WILLIAMS J P et al. Role of infiltrating monocytes in the development of radiation-induced pulmonary fibrosis[J]. Radiat Res, 2018, 189 (3): 300- 311
doi: 10.1667/RR14874.1
29 GROVES A M , JOHNSTON C J , MISRA R S et al. Whole-lung irradiation results in pulmonary macrophage alterations that are subpopulation and strain specific[J]. Radiat Res, 2015, 184 (6): 639- 649
doi: 10.1667/RR14178.1
30 HADDADI G H , REZAEYAN A , MOSLEH-SHIRAZI M A et al. Hesperidin as radioprotector against radiation-induced lung damage in rat:a histopathological study[J]. J Med Phys, 2017, 42 (1): 25- 32
doi: 10.4103/jmp.JMP_119_16
31 MEI Z , TIAN X , CHEN J et al. α7-nAchR agonist GTS21 reduces radiation induced lung injury[J]. Oncol Rep, 2018, 40 (4): 2287- 2297
doi: 10.3892/or.2018.6616
32 CHEN C , YANG S , ZHANG M et al. Triptolide mitigates radiation-induced pulmonary fibrosis via inhibition of axis of alveolar macrophages-NOXes-ROS-myofibroblasts[J]. Cancer Biol Ther, 2016, 17 (4): 381- 389
doi: 10.1080/15384047.2016.1139229
33 TAHAMTAN R , SHABESTANI MONFARED A , TAHAMTANI Y et al. Radioprotective effect of melatonin on radiation-induced lung injury and lipid peroxidation in rats[J]. Cell J, 2015, 17 (1): 111- 120
doi: 10.22074/cellj.2015.517
34 NADELLA V , RANJAN R , SENTHILKUMARAN B et al. Podophyllotoxin and rutin modulate M1(iNOS+) macrophages and mitigate lethal radiation (LR) induced inflammatory responses in mice[J]. Front Immunol, 2019, 10 106
doi: 10.3389/fimmu.2019.00106
35 GAO J , PENG S , SHAN X et al. Inhibition of AIM2 inflammasome-mediated pyroptosis by andrographolide contributes to amelioration of radiation-induced lung inflammation and fibrosis[J]. Cell Death Dis, 2019, 10 (12): 957
doi: 10.1038/s41419-019-2195-8
36 CHO Y J , YI C O , JEON B T et al. Curcumin attenuates radiation-induced inflammation and fibrosis in rat lungs[J]. Korean J Physiol Pharmacol, 2013, 17 (4): 267- 274
doi: 10.4196/kjpp.2013.17.4.267
37 YAN C , LUO L , URATA Y et al. Nicaraven reduces cancer metastasis to irradiated lungs by decreasing CCL8 and macrophage recruitment[J]. Cancer Lett, 2018, 418 204- 210
doi: 10.1016/j.canlet.2018.01.037
38 AZMOONFAR R , AMINI P , SAFFAR H et al. Metformin protects against radiation-induced pneumonitis and fibrosis and attenuates upregulation of dual oxidase genes expression[J]. Adv Pharm Bull, 2018, 8 (4): 697- 704
doi: 10.15171/apb.2018.078
39 ELZAYAT M A , BAYOUMI A , ABDEL-BAKKY M S et al. Ameliorative effect of 2-methoxyestradiol on radiation-induced lung injury[J]. Life Sci, 2020, 255 117743
doi: 10.1016/j.lfs.2020.117743
40 LI Y , LU H , LV X et al. Blockade of aquaporin 4 inhibits irradiation-induced pulmonary inflammation and modulates macrophage polarization in mice[J]. Inflammation, 2018, 41 (6): 2196- 2205
doi: 10.1007/s10753-018-0862-z
41 CHEN B , NA F , YANG H et al. Ethyl pyruvate alleviates radiation-induced lung injury in mice[J]. Biomed Pharmacother, 2017, 92 468- 478
doi: 10.1016/j.biopha.2017.05.111
42 ZHANG C , ZHAO H , LI B L 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
43 YU H H , CHENGCHUAN KO E , CHANG C L et al. Fucoidan inhibits radiation-induced pneumonitis and lung fibrosis by reducing inflammatory cytokine expression in lung tissues[J]. Mar Drugs, 2018, 16 (10): 392
doi: 10.3390/md16100392
44 YU X , LI Z , ZHANG Y et al. β-elemene inhibits radiation and hypoxia-induced macrophages infiltration via Prx-1/NF-κB/HIF-1α signaling pathway[J]. Onco Targets Ther, 2019, 12 7713- 7714
doi: 10.2147/OTT.S229714
45 LEE S J, YI C O, HEO R W, et al. Clarithromycin attenuates radiation-induced lung injury in mice[J/OL]. PLoS One, 2015, 10(6): e0131671. DOI: 10.1371/journal.pone.0131671.
46 TIAN X , WANG F , LUO Y et al. Protective role of nuclear factor-erythroid 2-related factor 2 against radiation-induced lung injury and inflammation[J]. Front Oncol, 2018, 8 542
doi: 10.3389/fonc.2018.00542
47 HAN G , LU K , XU W et al. Annexin A1-mediated inhibition of inflammatory cytokines may facilitate the resolution of inflammation in acute radiation-induced lung injury[J]. Oncol Lett, 2019, 18 (1): 321- 329
doi: 10.3892/ol.2019.10317
48 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):
doi: 10.1093/jnci/djw339
[1] 韩雪, 蒋国军, 石巧娟. 降血糖药对内皮祖细胞作用的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(5): 629-636.
[2] 段润平, 许叶圣, 郑利斌, 姚玉峰. 病毒感染性眼病病原学诊断的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(5): 644-650.
[3] 吴唯,徐键. 正五聚蛋白3在多囊卵巢综合征中的作用研究进展[J]. 浙江大学学报（医学版）, 2020, 49(5): 637-643.
[4] 徐清霖,楼国东,王甜甜,张力三. 发作性睡病的药物治疗进展[J]. 浙江大学学报（医学版）, 2020, 49(4): 419-424.
[5] 蒋沛然,王志萍. 模式生物神经轴突再生的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(4): 500-507.
[6] 徐亦鸣,吕丹丹,应可净. 2019冠状病毒病(COVID-19)患者出凝血功能障碍的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(3): 340-346.
[7] 张胜,李丹萍,陈华忠,郑丹,周益萍,陈葆国,石卫武,林荣海. 糖皮质激素治疗一例2019冠状病毒病(COVID-19)危重型患者炎症反应动态观察[J]. 浙江大学学报（医学版）, 2020, 49(2): 220-226.
[8] 俞卿, 熊秀芳, 孙毅. 靶向Cullin-RING E3泛素连接酶的抗肿瘤策略及相关药物研发进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 1-19.
[9] 段玲艳,尹香菊,孟红恩,方学贤,闵军霞,王福俤. 铁稳态代谢表观遗传调控机制的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 58-70.
[10] 李艾,张添源,高建青. 间充质干细胞的肿瘤归巢特性及其肿瘤靶向治疗应用研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 20-34.
[11] 黄耀凭,杨凤,周天华,谢珊珊. Hippo信号通路及其在消化系统肿瘤中的作用研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 35-43.
[12] 钟文,楼燕,邱宸阳,李栋林,张鸿坤. 髂静脉支架植入术后药物治疗策略研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 131-136.
[13] 徐亦鸣,应可净. 中性粒细胞胞外诱捕网与肿瘤相关研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 107-112.
[14] 刘晓晓,郭莉琼,梁成. 抗N-甲基-D-天冬氨酸受体脑炎患者脑电图特点的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 118-123.
[15] 方娟,潘志成,郭晓纲. INK4基因座中反义非编码RNA调控细胞增殖与凋亡影响动脉粥样硬化的研究进展[J]. 浙江大学学报（医学版）, 2020, 49(1): 113-117.