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放射性心脏损伤心肌纤维化发病机制研究进展
姚晔, 钟亚华, 谢丛华
430071 武汉大学中南医院放化疗科 肿瘤生物学行为湖北省重点实验室
Research progress in pathogenesis of myocardial fibrosis in radiation-induced heart damage
Yao Ye,Zhong Yahua,Xie Conghua
Department of Radiation Oncology and Medical Oncology,Zhongnan Hospital,Wuhan University,Wuhan 430071,China;Hubei Cancer Clinical Study Center,Hubei Key Laboratory of Tumor Biological Behaviors,Zhongnan Hospital,Wuhan University,Wuhan 430071,China.
Abstract： Myocardial fibrosis is a predominant pathological change of radiation-induced heart disease (RIHD) in late stage. It often occurs several or more than ten years after radiotherapy and can lead to myocardial remodeling, impaired cardiac function, and heart failure. At present there is no effective method to prevent or reverse the development of radiation-induced myocardial fibrosis. Many cells, cytokines, and other factors are involved in the development and progression of myocardial fibrosis in RIHD and some of them have been validated. But most investigators focused on the pathological changes and related mechanisms in early stage, and myocardial fibrosis was just regarded as an endpoint event. The definitive mechanisms of myocardial fibrosis in late stage remain unclear. This paper reveiws the studies about general mechanisms of myocardial fibrosis in RIHD and summarizes the roles of microcirculation dysfunction, mast cells, several cytokines, hypoxia, oxidative stress, and renin-angiotensin system, and points out the future research direction of the pathogenesis of myocardial fibrosis in RIHD. It provides new ideas for discovering the potential targets for clinical intervention of myocardial fibrosis in RIHD.
Yao Ye,Zhong Yahua,Xie Conghua. Research progress in pathogenesis of myocardial fibrosis in radiation-induced heart damage[J]. Chinese Journal of Radiation Oncology, 2017, 26(5): 598-602.
[1] Davis M,Witteles RM.Radiation-induced heart disease:an under-recognized entity?[J].Curr Treat Options Cardio Med,2014,16(6):317.DOI:10.1007/s11936-014-0317-2. [2] Boerma M,Hauer-Jensen M.Potential targets for intervention in radiation-induced heart disease[J].Curr Drug Targets,2010,11(11):1405-1412. [3] Ramyar A,Shafiei M,Moazzami K,et al. Severe valvular toxicity and pericarditis early after radiation therapy in a patient treated for Hodgkin′s lymphoma[J].Turk J Pediatr,2010,52(4):423-425. [4] Berry GJ,Jorden M.Pathology of radiation and anthracycline cardiotoxicity[J].Pediatr Blood Cancer,2005,44(7):630-637.DOI:10.1002/pbc.20346. [5] Fajardo LF,Stewart JR.Experimental radiation-induced heart disease. I.Light microscopic studies[J].Am J Pathol,1970,59(2):299-316. [6] Lauk S.Endothelial alkaline phosphatase activity loss as an early stage in the development of radiation-induced heart disease in rats[J].Radiat Res,1987,110(1):118-128.DOI:10.2307/3576889. [7] Schultz-Hector S.Radiation-induced heart disease:review of experimental data on dose reponse and pathogenesis[J].Int J Radiat Biol,1992,61(2):149-160.DOI:10.1080/09553009214550761. [8] Lauk S,Trott KR.Endothelial cell proliferation in the rat heart following local heart irradiation[J].Int J Radiat Biol,1990,57(5):1017-1030.DOI:10.1080/09553009014551131. [9] Andratschke N,Maurer J,Molls M,et al. Late radiation-induced heart disease after radiotherapy. Clinical importance,radiobiological mechanisms and strategies of prevention[J].Radiother Oncol,2011,100(2):160-166.DOI:10.1016/j.radonc.2010.08.010. [10] Kim M,Choi SH,Jin YB,et al. The effect of oxidized low-density lipoprotein (ox-LDL) on radiation-induced endothelial-to-mesenchymal transition[J].Int J Radiat Biol,2013,89(5):356-363.DOI:10.3109/09553002.2013.763193. [11] Basavaraju SR,Easterly CE.Pathophysiological effects of radiation on atherosclerosis development and progression,and the incidence of cardiovascular complications[J].Med Phys,2002,29(10):2391-2403.DOI:10.1118/1.1509442. [12] Boerma M,Wang JR,Wondergem J,et al. Influence of mast cells on structural and functional manifestations of radiation-induced heart disease[J].Cancer Res,2005,65(8):3100-3107.DOI:10.1158/0008-5472.CAN-04-4333. [13] Verrecchia F,Mauviel A.Transforming growth factor-beta and fibrosis[J].World J Gastroenterol,2007,13(22):3056-3062. [14] Wynn TA.Cellular and molecular mechanisms of fibrosis[J].J Pathol,2008,214(2):199-210.DOI:10.1002/path.2277. [15] Willis BC,duBois RM,Borok Z.Epithelial origin of myofibroblasts during fibrosis in the lung[J].Proc Am Thorac Soc,2006,3(4):377-382.DOI:10.1513/pats.200601-004TK. [16] Boban I,Barisic-Dujmovic T,Clark SH.Parabiosis and transplantation models show no evidence of circulating dermal fibroblast progenitors in bleomycin-induced skin fibrosis[J].J Cell Physiol,2008,214(1):230-237.DOI:10.1002/jcp.21182. [17] Krüse JJ,Bart CI,Visser A,et al. Changes in transforming growth factor-beta (TGF-beta 1),procollagen types I and Ⅱ mRNA in the rat heart after irradiation[J].Int J Radiat Biol,1999,75(11):1429-1436.DOI:10.1080/095530099139296. [18] Boerma M,Roberto KA,Hauer-Jensen M.Prevention and treatment of functional and structural radiation injury in the rat heart by pentoxifylline and alpha-tocopherol[J].Int J Radiat Oncol Biol Phys,2008,72(1):170-177.DOI:10.1016/j.ijrobp.2008.04.042. [19] Liu H,Xiong M,Xia YF,et al. Studies on pentoxifylline and tocopherol combination for radiation-induced heart disease in rats[J].Int J Radiat Oncol Biol Phys,2009,73(5):1552-1559.DOI:10.1016/j.ijrobp.2008.12.005. [20] Boerma M,Wang JR,Sridharan V,et al. Pharmacological induction of transforming growth factor-beta1 in rat models enhances radiation injury in the intestine and the heart[J].PLoS One,2013,8(7):e70479.DOI:10.1371/journal.pone.0070479. [21] Hu SY,Chen YD,Li LB,et al. Effects of adenovirus-mediated delivery of the human hepatocyte growth factor gene in experimental radiation-induced heart disease[J].Int J Radiat Oncol Biol Phys,2009,75(5):1537-1544.DOI:10.1016/j.ijrobp.2009.07.1697. [22] Sridharan V,Sharma SK,Moros EG,et al. Effects of radiation on the epidermal growth factor receptor pathway in the heart[J].Int J Radiat Biol,2013,89(7):539-547.DOI:10.3109/09553002.2013.782110. [23] Gu A,Jie Y,Sun L,et al. RhNRG-1β protects the myocardium against irradiation-induced damage via the ErbB2-ERK-SIRT1 signaling pathway[J].PLoS One,2015,10(9):e0137337.DOI:10.1371/journal.pone.0137337. [24] Yarnold J,Brotons MCV.Pathogenetic mechanisms in radiation fibrosis[J].Radiother Oncol,2010,97(1):149-161.DOI:10.1016/j.radonc.2010.09.002. [25] Sridharan V,Tripathi P,Sharma S,et al. Effects of late administration of pentoxifylline and tocotrienols in an image-guided rat model of localized heart irradiation[J].PLoS One,2013,8(7):e68762.DOI:10.1371/journal.pone.0068762. [26] Gu J,Liu K,Li HL,et al. Astragalus saponin attenuates the expression of fibrosis-related molecules in irradiated cardiac fibroblasts[J].Acta Biochim Biophys Sin (Shanghai),2014,46(6):492-501.DOI:10.1093/abbs/gmu021. [27] 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(3):404-410.DOI:10.1016/j.radonc.2013.01.017. [28] Sridharan V,Aykin-Burns N,Tripathi P,et al. Radiation-induced alterations in mitochondria of the rat heart[J].Radiat Res,2014,181(3):324-334.DOI:10.1667/RR13452.1. [29] Wu R,Zeng Y.Does angiotensin Ⅱ-aldosterone have a role in radiation-induced heart disease?[J].Med Hypotheses,2009,72(3):263-266.DOI:10.1016/j.mehy.2008.09.051. [30] Schlattner U,Tokarska-Schlattner M,Wallimann T.Mitochondrial creatine kinase in human health and disease[J].Biochim Biophys Acta,2006,1762(2):164-180.DOI:/10.1016/j.bbadis.2005.09.004. [31] Boveris A,Chance B.The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen[J].Biochem J,1973,134(3):707-716.DOI:10.1042/bj1340707. [32] Azimzadeh O,Sievert W,Sarioglu H,et al. PPAR alpha:a novel radiation target in locally exposed Mus musculus heart revealed by quantitative proteomics[J].J Proteome Res,2013,12(6):2700-2714.DOI:10.1021/pr400071 g. [33] Zahner MR,Li DP,Chen SR,et al. Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats[J].J Physiol,2003,551(2):515-523.DOI:10.1113/jphysiol.2003.048207. [34] Anand IS,Gurden J,Wander GS,et al. Cardiovascular and hormonal effects of calcitonin gene-related peptide in congestive heart failure[J].J Am Coll Cardiol,1991,17(1):208-217.DOI:10.1016/0735-1097(91)90729-S. [35] Holdright DR,Clarke D,Fox K,et al. The effects of intracoronary substance P and acetylcholine on coronary blood flow in patients with idiopathic dilated cardiomyopathy[J].Eur Heart J,1994,15(11):1537-1544. [36] Sridharan V,Tripathi P,Sharma S,et al. Roles of sensory nerves in the regulation of radiation-induced structural and functional changes in the heart[J].Int J Radiat Oncol Biol Phys,2014,88(1):167-174.DOI:10.1016/j.ijrobp.2013.10.014. [37] Ron D,Walter P.Signal integration in the endoplasmic reticulum unfolded protein response[J].Nat Rev Mol Cell Biol,2007,8(7):519-529.DOI:10.1038/nrm2199. [38] Gu J,Li HL,Wu HY,et al. Sodium tanshinone ⅡA sulfonate attenuates radiation-induced fibrosis damage in cardiac fibroblasts[J].J Asian Nat Prod Res,2014,16(9):941-952.DOI:10.1080/10286020.2014.935769.
2017, Vol. 26 
