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中华损伤与修复杂志(电子版) ›› 2025, Vol. 20 ›› Issue (03) : 265 -270. doi: 10.3877/cma.j.issn.1673-9450.2025.03.013

综述

放射性肺纤维化细胞和分子机制的研究进展
谌莉1, 冉永红1, 傅仕艳1, 李文润1, 冉新泽1, 郝玉徽1,()   
  1. 1. 400038 重庆,陆军军医大学军事预防医学系 创伤与化学中毒全国重点实验室
  • 收稿日期:2025-01-10 出版日期:2025-06-01
  • 通信作者: 郝玉徽
  • 基金资助:
    重庆市教委科学技术研究计划重点项目(KJZDK202312801)重庆市自然科学基金面上项目(2022NSCQ-MSX4675)

A review of cellular and molecular mechanisms of radiation-induced pulmonary fibrosis

Li Shen1, Yonghong Ran1, Shiyan Fu1, Wenrun Li1, Xinze Ran1, Yuhui Hao1,()   

  1. 1. National Key Laboratory of Trauma and Chemical Poisoning, Department of Military Preventive Medicine, Army Medical University, Chongqing 400038, China
  • Received:2025-01-10 Published:2025-06-01
  • Corresponding author: Yuhui Hao
引用本文:

谌莉, 冉永红, 傅仕艳, 李文润, 冉新泽, 郝玉徽. 放射性肺纤维化细胞和分子机制的研究进展[J/OL]. 中华损伤与修复杂志(电子版), 2025, 20(03): 265-270.

Li Shen, Yonghong Ran, Shiyan Fu, Wenrun Li, Xinze Ran, Yuhui Hao. A review of cellular and molecular mechanisms of radiation-induced pulmonary fibrosis[J/OL]. Chinese Journal of Injury Repair and Wound Healing(Electronic Edition), 2025, 20(03): 265-270.

放射性肺纤维化(RIPF)是胸部肿瘤患者接受放射治疗后的严重并发症之一,其发生机制复杂,包括多种细胞和分子的参与。该过程始于放射线对肺组织细胞的直接损伤,导致上皮细胞和内皮细胞凋亡并引发局部炎症。受损细胞释放的炎症介质吸引免疫细胞入侵,加重炎症反应。成纤维细胞在转化生长因子β(TGF-β)的影响下,过度合成胶原蛋白,促进纤维化进程。此外,受损细胞释放TGF-β、肿瘤坏死因子α(TNF-α)、血小板衍生生长因子(PDGF)和血管内皮生长因子(VEGF)等信号分子,启动信号转导途径,激活下游TGF-β/Smad3、PI3K/Akt、MAPK和NF-κB等通路,调控纤维化相关基因的表达,促进纤维化发生发展。深入了解RIPF的分子机制,能够为其诊断、治疗和预后评估提供理论基础。

Radiation-induced pulmonary fibrosis (RIPF) is a severe and often irreversible complication in patients undergoing radiotherapy for thoracic malignancies.The underlying mechanisms remain incompletely understood and involes the participation of multiple cells and molecules.This process begins with the direct damage of radiation to lung tissuces cells, leading to apoptosis of epithelial cells and endothelial cells and triggering local inflammation.These cytokines recruit immune cells, amplifying the inflammatory cascade.Central to RIPF pathogenesis is the activation of fibroblasts by transforming growth factor-β (TGF-β),leading to excessive collagen synthesis and extracellular matrix deposition.Furthermore, damaged cells release key signaling molecules, such as TGF-β, tumor necrosis factor-α (TNF-α), platelet-derived growth factor(PDGF) and vascular endothelial growth factor (VEGF), which initiate signal transduction pathways and activate downstream pathways such as TGF-β/Smad3, PI3K/Akt, MAPK, and NF-κB, driving the expression of fibrosis-related genes and promoting the occurrence and development of fibrosis.Understanding the molecular mechanisms of RIPF can provide a theoretical foundation for its diagnosis, treatment, and prognosis.

[1]
Chen Z, Wu Z, Ning W.Advances in molecular mechanisms and treatment of radiation-induced pulmonary fibrosis [J].Transl Oncol, 2019, 12: 162-169.
[2]
Wang M, Xu S, Zhu H.Radiation recall pneumonitis induced by sintilimab: a case report and literature review [J].Front Immunol,2022, 13: 823767.
[3]
Suri GS, Kaur G, Jha CK, et al.Understanding idiopathic pulmonary fibrosis - Clinical features, molecular mechanism and therapies[ J].Exp Gerontol, 2021, 153: 111473.
[4]
Deutsch E, Meziani L.Radiation-induced pulmonary fibrosis: new potential targets[ J].Cancer Radiother, 2023, 27(6-7): 491-493.
[5]
Ruaro B, Salton F, Braga L, et al.The history and mystery of alveolar epithelial type Ⅱ cells: focus on their physiologic and pathologic role in lung[ J].Int J Mol Sci, 2021, 22(5): 2566.
[6]
Liu K, Meng X, Liu Z, et al.Tracing the origin of alveolar stem cells in lung repair and regeneration[ J].Cell, 2024, 187( 10):2428-2445.e20.
[7]
Wang Y, Wang L, Ma S, et al.Repair and regeneration of the alveolar epithelium in lung injury[ J].Faseb J, 2024, 38(8): e23612.
[8]
Parimon T, Yao C, Stripp BR, et al.Alveolar epithelial type Ⅱcells as drivers of lung fibrosis in idiopathic pulmonary fibrosis[ J].Int J Mol Sci, 2020, 21(7): 2269.
[9]
Wang P, Yan Z, Zhou PK, et al.The promising therapeutic approaches for radiation-induced pulmonary fibrosis: targeting radiation-induced mesenchymal transition of alveolar type Ⅱepithelial cells[ J].Int J Mol Sci, 2022, 23(23) :15014.
[10]
Cui T, Wangpaichitr M, Schally AV, et al.Alveolar epithelial cell growth hormone releasing hormone receptor in alveolar epithelial inflammation[ J].Exp Lung Res, 2023, 49(1): 152-164.
[11]
Aegerter H, Lambrecht BN, Jakubzick CV.Biology of lung macrophages in health and disease[ J].Immunity, 2022, 55(9):1564-1580.
[12]
Li M, Liu P, Ke Y, et al.Research progress on macrophage in radiation induced lung injury[ J].Zhejiang Da Xue Xue Bao Yi Xue Ban, 2020, 49(5): 623-628.
[13]
Ni J, Guo T, Zhou Y, et al.STING signaling activation modulates macrophage polarization via CCL2 in radiation-induced lung injury[ J].J Transl Med, 2023, 21(1): 590.
[14]
Tabraue C, Lara PC, De Mirecki-garrido M, et al.LXR signaling regulates macrophage survival and inflammation in response to ionizing radiation[ J].Int J Radiat Oncol Biol Phys, 2019, 104(4):913-923.
[15]
Wynn TA, Vannella KM.Macrophages in tissue repair,regeneration, and fibrosis[ J].Immunity, 2016, 44(3): 450-462.
[16]
Kishore A, Petrek M.Roles of macrophage polarization and macrophage-derived miRNAs in pulmonary fibrosis [J].Front Immunol, 2021, 12: 678457.
[17]
Zhang L, Wang Y, Wu GR, et al.Macrophages: friend or foe in idiopathic pulmonary fibrosis?[J].Respiratory Research,2018, 19(1): 170.
[18]
Dong T, Chen X, Xu H, et al.Mitochondrial metabolism mediated macrophage polarization in chronic lung diseases[ J].Pharmacol Ther, 2022, 239: 108208.
[19]
Chen YL, Li Y, He YJ, et al.Targeted lung therapy with rosmarinic acid encapsulated in PLGA microspheres for radiationinduced pulmonary fibrosis[ J].J Drug Deliv Sci Technol, 2024,96: 105710.
[20]
Tang PC, Chung JY, Xue VW, et al.Smad3 promotes cancerassociated fibroblasts generation via macrophage-myofibroblast transition[ J].Adv Sci( Weinh), 2022, 9(1): e2101235.
[21]
Cavgnero KJ, Gallo RL.Essential immune functions of fibroblasts in innate host defense[ J].Front Immunol, 2022, 13: 1058862.
[22]
Zhao M, Wang L, Wang M, et al.Targeting fibrosis, mechanisms and cilinical trials[ J].Signal Transduct Target Ther, 2022, 7(1):206.
[23]
Younesi FS, Miller AE, Barker TH, et al.Fibroblast and myofibroblast activation in normal tissue repair and fibrosis[ J].Nat Rev Mol Cell Biol, 2024, 25(8): 617-638.
[24]
Talbott HE, Mascharak S, Griffin M, et al.Wound healing,fibroblast heterogeneity, and fibrosis[ J].Cell Stem Cell, 2022,29(8): 1161-1180.
[25]
Buechler MB, Fu W, Turley SJ.Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer[ J].Immunity, 2021,54(5): 903-915.
[26]
Lan HY.Diverse roles of TGF-β/Smads in renal fibrosis and inflammation[ J].Int J Biol Sci, 2011, 7(7): 1056-1067.
[27]
Morikawa M, Derynck R, Miyazono K.TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology[ J].Cold Spring Harb Perspect Biol, 2016, 8(5): a021873.
[28]
Larson C, Oronsky B, Carter CA, et al.TGF-beta: a master immune regulator[ J].Expert Opin Ther Targets, 2020, 24(5):427-438.
[29]
Deng Z, Fan T, Xiao C, et al.TGF-β signaling in health,disease, and therapeutics [J].Signal Transduct Target Ther,2024, 9(1): 61.
[30]
Hanson I, Pitman KE, Edin NFJ.The role of TGF-β3 in radiation response[ J].Int J Mol Sci, 2023, 24(8): 7614
[31]
Massagué J, Seoane EJ, Wotton D.Smad transcription factors[ J].Genes Dev, 2005, 19(23): 2783-2810.
[32]
Lee JH, Sánchez-rivera FJ, He L, et al.TGF-β and RAS jointly unmask primed enhancers to drive metastasis[ J].Cell, 2024,187(22):6182-6199.e29.
[33]
Meng XM, Nikolic-paterson DJ, Lan HY.TGF-β: the master regulator of fibrosis[ J].Nat Rev Nephrol, 2016, 12(6): 325-338.
[34]
Verma S, Dutta A, Dahiya A, et al.Quercetin-3-Rutinoside alleviates radiation-induced lung inflammation and fibrosis via regulation of NF-κB/TGF-β1 signaling [J].Phytomedicine,2022, 99: 154004.
[35]
Wang S, Li J, He Y, et al.Protective effect of melatonin entrapped PLGA nanoparticles on radiation-induced lung injury through the miR-21/TGF-β1/Smad3 pathway[ J].Int J Pharm,2021, 602: 120584.
[36]
Shen L, Fu S, Chen Y, et al.Mannosylated polydopamine nanoparticles alleviate radiation- induced pulmonary fibrosis by targeting M2 macrophages and inhibiting the TGF-β1/Smad3 signaling pathway [J].Colloids Surf B Biointerfaces,2023, 227: 113353.
[37]
Distler JHW, Györfi AH, Ramanujam M, et al.Shared and distinct mechanisms of fibrosis[ J].Nat Rev Rheumatol, 2019,15(12): 705-730.
[38]
Ersahin T, Tuncbag N, Cetin-atalay R.The PI3K/AKT/mTOR interactive pathway[ J].Mol Biosyst, 2015, 11(7): 1946-1954.
[39]
Yang J, Nie J, Ma X, et al.Targeting PI3K in cancer:mechanisms and advances in clinical trials [J].Mol Cancer,2019, 18(1): 26.
[40]
Manning BD, Toker A.AKT/PKB signaling: navigating the network[ J].Cell, 2017, 169(3): 381-405.
[41]
Gupta S, Kumar M, Chaudhuri S, et al.The non-canonical nuclear functions of key players of the PI3K-AKT-MTOR pathway[ J].J Cell Physiol, 2022, 237(8): 3181-3204.
[42]
Xiu AY, Ding Q, Li Z, et al.Doxazosin attenuates liver fibrosis by inhibiting autophagy in hepatic stellate cells via activation of the PI3K/Akt/mTOR signaling pathway[ J].Drug Des Devel Ther,2021, 15: 3643-3659.
[43]
Wang J, Hu K, Cai X, et al.Targeting PI3K/AKT signaling for treatment of idiopathic pulmonary fibrosis[ J].Acta Pharm Sin B,2022, 12(1): 18-32.
[44]
杨依,陈凡,冯瑞兴,等.通过PI3K/Akt信号通路调控p21 对放射性肺损伤的防护作用 [J].中国高原医学与生物学杂志,2023, 44(3): 172-177.
[45]
Laddha AP, Kulkarni YA.VEGF and FGF-2: promising targets for the treatment of respiratory disorders[ J].Respir Med, 2019,156: 33-46.
[46]
Ferrara N, Gerber HP, Lecouter J.The biology of VEGF and its receptors[ J].Nat Med, 2003, 9(6): 669-676.
[47]
Sun Y, Liu WZ, Liu T, et al.Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis[ J].J Recept Signal Transduct Res, 2015, 35(6): 600-604.
[48]
Park JI.MAPK-ERK Pathway[ J].Int J Mol Sci, 2023, 24(11):9666.
[49]
Qu H, Liu L, Liu Z, et al.Blocking TBK1 alleviated radiationinduced pulmonary fibrosis and epithelial-mesenchymal transition through Akt-Erk inactivation[ J].Exp Mol Med, 2019, 51(4): 1-17.
[50]
Ying H, Zhou C, Hang Q, et al.The preventive effect of endostar on radiation-induced pulmonary fibrosis [J].Curr Mol Med,2024, 24(5): 610-619.
[51]
Zheng J, Wu J, Xie L, et al.Paclitaxel aggravating radiationinduced pulmonary fibrosis is associated with the down-regulation of the negative regulatory function of Spry2[ J].J Pharmacol Exp Ther, 2024, 389(2): 197-207.
[52]
Yang Q, Zhanng P, Liu T, et al.Magnesium isoglycyrrhizinate ameliorates radiation-induced pulmonary fibrosis by inhibiting fibroblast differentiation via the p38MAPK/Akt/Nox4 pathway[ J].Biomed Pharmacother, 2019, 115: 108955.
[53]
黄婷,邓博,程志强.平肺口服液对急性放射性肺损伤大鼠肺损伤及p38 MAPK/Nrf2/HO-1信号通路的影响[ J].现代中西医结合杂志,2022,31(21): 2934-2938,2984.
[54]
张广辉,亓润智,王青,等.基于p38 MAPK/NF-κB通路探究沙参桔梗汤治疗放射性肺损伤的效应机制[J].中华中医药杂志,2023, 38(11): 5197-5202.
[55]
Steele H, Cheng J, Willicut A, et al.TNF superfamily control of tissue remodeling and fibrosis[J].Front Immunol, 2023, 14:1219907.
[56]
Kalliolias GD, Ivashkiv LB.TNF biology, pathogenic mechanisms and emerging therapeutic strategies [J].Nat Rev Rheumatol,2016, 12(1): 49-62.
[57]
Lawrence T.The nuclear factor NF-kappaB pathway in inflammation[ J].Cold Spring Harb Perspect Biol, 2009, 1(6):a001651.
[58]
Sun SC.Non-canonical NF-κB signaling pathway[ J].Cell Res,2011, 21(1): 71-85.
[59]
Yu H, Lin L, Zhang Z, et al.Targeting NF-κB pathway for the therapy of diseases: mechanism and clinical study [J].Signal Transduct Target Ther, 2020, 5(1): 209.
[60]
Chen J, Chen ZJ.Regulation of NF-κB by ubiquitination[ J].Curr Opin Immunol, 2013, 25(1): 4-12.
[61]
Luedde T, Schwabe RF.NF-κB in the liver-linking injury,fibrosis and hepatocellular carcinoma[ J].Nat Rev Gastroenterol Hepatol, 2011, 8(2): 108-118.
[62]
Wang D, Liu Z, Yan Z, et al.MiRNA-155-5p inhibits epitheliumto-mesenchymal transition (EMT) by targeting GSK-3β during radiation-induced pulmonary fibrosis[ J].Arch Biochem Biophys,2021, 697: 108699.
[63]
武忠宝,徐莹,柳云恩,等.基于蛋白组学探讨放射性肺损伤致病机制[ J].临床军医杂志,2024, 52(7): 661-665,670.
[64]
张旭东,刘浩昂,王志浩,等.Smad3通过p38/MAPK信号通路调控细胞自噬及凋亡促进胰腺癌进程 [J].陆军军医大学学报,2022, 44(19): 1968-1978.
[65]
Suwanabol PA, Seedial SM, Zhang F, et al.TGF-β and Smad3 modulate PI3K/Akt signaling pathway in vascular smooth muscle cells[ J].Am J Physiol Heart Circ Physiol, 2012, 302(11):H2211-H2219.
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