放射性心肌纤维化分子生物学机制研究进展

刘丽娜; 武亚晶; 王军

doi:10.13201/j.issn.1001-1439.2017.02.003

放射性心肌纤维化分子生物学机制研究进展

- 河北医科大学第四医院放疗一科(石家庄, 050011)

详细信息

通讯作者: 王军,E-mail:wangjunzr@163.com

中图分类号: R542.2

收稿日期: 2016-07-13

修回日期: 2016-12-14

Molecular mechanisms of radiation-induced myocardial fibrosis

- Department of Radiotherapy Oncology, the 4 th Hospital of Hebei Medical University, Shijiazhuang, 050011, China

More Information

Corresponding author: WANG Jun, E-mail: wangjunzr@163.com

Received Date: 13 July 2016

Revised Date: 14 December 2016

摘要

摘要: 放射性心肌纤维化是放射性心脏损伤(radiation-induced heart disease,RIHD)的重要病理过程,可导致心脏功能下降、心肌重塑等,影响患者生存质量。既往多位学者在细胞、分子、基因等层面对此进行了研究,一般认为是纤维母细胞异常分化、微血管内皮损伤、炎症、氧化应激反应、转化生长因子-β1(TGF-β1)信号转导、基因表达改变等多种因子及信号通路相互作用的结果,但分子生物学机制错综复杂,仍未完全明确,目前尚无有效的临床干预措施。本文旨在探讨RIHD心肌纤维化的发生机制及临床干预措施,并对其新进展、面临的挑战以及未来的发展方向做一概述。
- 放射性心脏损伤 /
- 放射性心肌纤维化 /
- 发病机制
Abstract: Radiation-induced myocardial fibrosis is the important pathological characteristic of radiation-induced heart disease(RIHD).It can lead to decreased cardiac function and cardiac remodeling, affecting the life quality of patients severly. Some researches had been carried out on how irradiation acts on a cellular, molecular, and genetic levels, etc.It is thought to be the result of interaction of signaling pathways, including abnormal fibroblast differentiation, microvascular endothelial injury, inflammation, oxidative stress, TGF-beta1 signal transduction, gene expression changes, and so on. But its molecular mechanisms are complex and not to be clarified, and there are not effective interventions to reverse radiation-induced myocardial fibrosis. This manuscript aims to review the mechanism and clinical interventions of radiation-induced myocardial fibrosis, and overview new progress, challenges and research prospective direction of the field.
- radiation-induced heart disease /
- radiation-induced myocardial fibrosis /
- Mechanism

HTML全文

参考文献(41)

[1]	DARBY S C,CUTTER D J,BOERMA M,et al.Radiation-related heart disease:current knowledge and future prospects[J].Int J Radiat Oncol Biol Phys,2010,76:656-665.
[2]	YUSUF S W,SAMI S,DAHER I N.Radiation-induced heart disease:a clinical update[J].Cardiol Res Pract,2011,27:317659.
[3]	WYNN T A.Fibrotic disease and the TH1/TH2 paradigm[J].Nat Rev Immunol,2004,4:583-594.
[4]	WEIGEL C,SCHMEZER P,PLASS C,et al.Epigenetics in radiation-induced fibrosis[J].Oncogene,2015,34:2145-2155.
[5]	JUDGE J L,OWENS K M,POLLOCK S J,et al.Ionizing radiation induces myofibroblast differentiation via lactate dehydrogenase[J].Am J Physiol Lung Cell Mol Physiol,2015,309:L879-887.
[6]	SARRAZY V,BILLET F,MICALLEF L,et al.Mechanisms of pathological scarring:role of myofibroblasts and current developments[J].Wound Repair Regen,2011,19:s10-15.
[7]	GRSESI,ZEREN M,SERIN M,et al.Histopathological evaluation of melatonin as a protective agent in heart injury induced by radiation in a rat model[J].Pathol Res Pract,2014,210:863-871.
[8]	SCHULTZ-HECTOR S,TROTT K R.Radiation-induced cardiovascular diseases:is the epidemiologic evidence compatible with the radiobiologic data?[J].Int J Radiat Oncol Biol Phys,2007,67:10-18.
[9]	武亚晶,王雪峰,王军,等.急性期放射性心肌损伤病理学表现及损伤机制研究[J].中华放射肿瘤学,2016,25(10):1117-1122.
[10]	WEINTRAUB N L,JONES W K,MANKA D.Understanding Radiation-Induced Vascular Disease[J].JAm Coll Cardiol,2010,55:1237-1239.
[11]	HALLE M,GABRIELSEN A,PAULSSON-BERNEG,et al.Sustained inflammation due to nuclear factorkappa B activation in irradiated human arteries[J].JAm Coll Cardiol,2010,55:1227-1236.
[12]	YARNOLD J,BROTONS M C.Pathogenetic mechanisms in radiation fibrosis[J].Radiother Oncol,2010,97:149-161.
[13]	GAUGLER M H,VEREYCKEN-HOLLER V,SQUIBAN C,et al.Pravastatin limits endothelial activation after irradiation and decreases the resulting inflammatory and thrombotic responses[J].Radiat Res,2005,163:479-487.
[14]	吴荣,马天馨,曾越灿,等.血管紧张素Ⅱ型受体拮抗剂在大鼠放射性心脏损伤中保护作用的研究[J].中国医科大学学报,2015,44(1):20-26.
[15]	宋扬,吴荣,曾越灿,等.放射性心脏损伤模型大鼠接受吡格列酮干预的心脏保护作用[J].中国组织工程研究,2015,19(5):674-680.
[16]	VAN DER VEEN S J,GHOBADI G,DE BOER R A,et al.ACE inhibition attenuates radiation-induced cardiopulmonary damage[J].Radiother Oncol,2015,114:96-103.
[17]	AZIMZADEH O,SIEVERT W,SARIOGLU H,et al.Integrative proteomics and targeted transcriptomics analyses in cardiac endothelial cells unravel mechanisms of long-term radiation-induced vascular dysfunction[J].J Proteome Res,2015,14:1203-1219.
[18]	KIM E J,LEE J,JUNG Y R,et al.Involvement of corin downregulation in ionizing radiation-induced senescence of myocardial cells[J].Int J Mol Med,2015,35:731-738.
[19]	STORCH K,DICKREUTER E,ARTATI A,et al.BEMER Electromagnetic Field Therapy Reduces Cancer Cell Radioresistance by Enhanced ROS Formation and Induced DNA Damag[J].PLoS One,2016,11:e0167931.
[20]	TSUTSUI H,KINUGAWA S,MATSUSHIMA S.Oxidative stress and heart failure[J].Am J Physiol Heart Circ Physiol,2011,301:2181-2190.
[21]	DEWHIRST M W,CAO Y,MOELLER B.Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response[J].Nat Rev Cancer,2008,8:425-437.
[22]	TAUNK N K,HAFFTY B G,KOSTIS J B,et al.Radiation-induced heart disease:pathologic abnormalities and putative mechanisms[J].Front Oncol,2015,5:39.
[23]	GABRIELLI A,SVEGLIATI S,MORONCINI G,et al.Oxidative stress and the pathogenesis of scleroderma:the Murrell's hypothesis revisited[J].Semin Immunopathol,2008,30:329-337.
[24]	GU J,LIU K,LI H,et al.Astragalus saponin attenuates the expression of fibrosis-related molecules in irradiated cardiac fibroblasts[J].Acta Biochim Biophys Sin(Shanghai),2014,46:492-501.
[25]	王军,武亚晶,王媛,等.X线照射对大鼠心脏缺血再灌注损伤影响[J].中华放射肿瘤学,2016,25(6):640-645.
[26]	BARJAKTAROVIC Z,SHYLA A,AZIMZADEH O,et al.Ionising radiation induces persistent alterations in the cardiac mitochondrial function of C57BL/6 mice 40 weeks after local heart exposure[J].Radiother Oncol,2013,106:404-410.
[27]	SRIDHARAN V,TRIPATHI P,AYKIN-BURNS N,et al.A tocotrienol-enriched formulation protects against radiation-induced changes in cardiac mitochondria without modifying late cardiac function or structure[J].Radiat Res,2015,183:357-366.
[28]	WANG J,ZHENG H,OU X,et al.Deficiency of microvascular thrombomodulin and up-regulation of protease-activated receptor-1in irradiated rat intestine:possible link between endothelial dysfunction and chronic radiation fibrosis[J].Am J Pathol,2002,160:2063-2072.
[29]	MILLIAT F,SABOURIN J C,TARLET G,et al.Essential role of plasminogen activator inhibitor type-1in radiation enteropathy[J].Am J Pathol,2008,172:691-701.
[30]	BOERMA M,KRUSE J J,VAN LOENEN M,et al.Increased deposition of von Willebrand factor in the rat heart after local ionizing irradiation[J].Strahlenther Onkol,2004,180:109-116.
[31]	ZENG Y C,CHI F,XING R,et al.Sestrin protects the myocardium against radiation-induced damage[J].Radiat Environ Biophys,2016,55:195-202.
[32]	WANG J,ALBERTSON C M,ZHENG H,et al.Short-term inhibition of ADP-induced platelet aggregation by clopidogrel ameliorates radiation-induced toxicity in rat small intestine[J].Thromb Haemost,2002,87:122-128.
[33]	BOERMA M,WANG J,SRIDHARAN V,et al.Pharmacological induction of transforming growth factorbetal in rat models enhances radiation injury in the intestine and the heart[J].PloS one,2013,8:e70479.
[34]	MAIER P,HARTMANN L,WENZ F,et al.Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization[J].Int JMol Sci,2016,17:pii:E102.
[35]	KRUSE J J,FLOOT B G,TE POELE J A,et al.Radiation-induced activation of TGF-βsignaling pathways in relation to vascular damage in mouse kidneys[J].Radiat Res,2009,171:188-197.
[36]	GOUMANS M J,VALDIMARSDOTTIR G,ITOHS,et al.Activin receptor-like kinase(ALK)1is an antagonistic mediator of lateral TGFβ/ALK5signaling[J].Mol Cell,2003,12:817-828.
[37]	王祎,王军,程云杰,等.血清细胞因子TGF-β1和IL-1β表达水平对急性放射性心脏损伤发生的影响[J].中华放射医学与防护杂志,2012,32(5):488-491.
[38]	LIU H,XIONG M,XIA Y F,et al.Studies on pentoxifylline and tocopherol combination for radiation-induced heart disease in rats[J].Int J Radiat Oncol Biol Phys,2009,73:1552-1559.
[39]	ANGELINI A,LI Z,MERICSKAY M,et al.Regulation of Connective Tissue Growth Factor and Cardiac Fibrosis by an SRF/MicroRNA-133aAxis[J].PLoSOne,2015,10:e0139858.
[40]	VOZENIN-BROTONS M C,MILLIAT F,SAB-OURIN J C,et al.Fibrogenic signals in patients with radiation enteritis are associated with increased connective tissue growth factor expression[J].Int J Radiat Oncol Biol Phys,2003,56:561-572.
[41]	BAKER J E,FISH B L,SU J,et al.10Gy total body irradiation increases risk of coronary sclerosis,degeneration of heart structure and function in a rat model[J].Int J Radiat Biol,2009,85:1089-1100.