外泌体与放射性肺损伤相关性的研究进展
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摘要
目前放射治疗是治疗恶性肿瘤的主要手段之一,但对正常细胞也有损伤,放射性肺损伤(RILI)是胸部放疗常见并发症,包括放射性肺炎和放射性肺纤维化,其发生机制已有较多研究。外泌体是一种纳米大小的细胞外小泡,外泌体内含有多种生物分子,包括RNA、DNA、脂质和蛋白质等,最近研究发现,外泌体可以介导细胞通信,参与肿瘤转移、进展和治疗过程,在炎症和免疫方面有很多研究,也越来越受到研究者的重视,但在外泌体参与放射性肺损伤的发病机制尚不清楚,还需进一步研究。
Radiotherapy is one of the main methods for the treatment of malignant tumors. However,radiotherapy is also harmful to normal cells. Radiation-induced lung injury is a common complication of thoracic radiotherapy,including radiation-induced pneumonitis and radiation-induced pulmonary fibrosis. There are many research on the pathogenesis in this field. Exosomes are nano-sized extracellular vesicles containing a variety of biological molecules,including RNA,DNA,lipids and proteins. Recent studies have found that exosomes can mediate cell communication,participate in the process of tumors metastasis,progression and treatment. There are many studies about the relation between inflammation,immunity and exosomes. More and more research in exosomes has been done. However,the pathogenesis of exosomes involvement in radiation-induced lung injury remains unclear,so further studies are neede
Radiotherapy is one of the main methods for the treatment of malignant tumors. However,radiotherapy is also harmful to normal cells. Radiation-induced lung injury is a common complication of thoracic radiotherapy,including radiation-induced pneumonitis and radiation-induced pulmonary fibrosis. There are many research on the pathogenesis in this field. Exosomes are nano-sized extracellular vesicles containing a variety of biological molecules,including RNA,DNA,lipids and proteins. Recent studies have found that exosomes can mediate cell communication,participate in the process of tumors metastasis,progression and treatment. There are many studies about the relation between inflammation,immunity and exosomes. More and more research in exosomes has been done. However,the pathogenesis of exosomes involvement in radiation-induced lung injury remains unclear,so further studies are neede
引文
[1]Tiankai X,Yuyu Z,Pengyu C,et al.Mesenchymal stem cell-based therapy for radiation-induced lung injury[J].Stem Cell Res Ther,2018,9(1):18.
[2]Kubo H.Extracellular vesicles in lung disease[J].Chest,2018,153(1):210-216.
[3]Selmaj I,Mycko MP,Raine CS,et al.The role of exosomes in CNSinflammation and their involvement in multiple sclerosis[J].J Neuroimmunol,2017,306:1-10.
[4]Barile L,Moccetti T,Marban E,et al.Roles of exosomes in cardioprotection[J].Eur Heart J,2017,38(18):1372-1379.
[5]Terrasini N,Lionetti V.Exosomes in critical illness[J].Crit Care Med,2017,45(6):1054-1060.
[6]Vallabhaneni KC,Penfornis P,Dhule S,et al.Extracelluar versicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA,proteins,and metabolites[J].Oncotarget,2015,6(7):4953-4967.
[7]Batagov AO,Kurochkin IV.Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3'-untranslated regions[J].Biol Direct,2013,8:12.
[8]Yuan Z,Bedi B,Sadikot RT.Bronchoalveolar lavage exosomes in lpopolysaccharide-induced septic lung injury[J].J Vis Exp,2018(135).
[9]Corrado C,Raimondo S,Chiesi A,et al.Exosomes as intercellular signaling organelles involved in health and disease:Basic science and clinical applications[J].Int J Mol Sci,2013,14(3):5338-5366.
[10]Zhenhua W,Xinyu W,Rong Y,et al.Effects of carbon ion beam irradiation on lung injury and pulmonary fibrosis in mice[J].Exp Ther Med,2013,5(3):771-776.
[11]Yu S,Yujun Du,Hui Z,et al.Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice[J].J Radiat Res,2016,57(5):505-511.
[12]Deyun Z,Hongjin Q,Jiaming G,et al.Protective effects of myrtol standardized against radiation-induced lung injury[J].Cell Physiol Biochem,2016,38(2):619-634.
[13]Haiying Y,Rensheng W.放射性肺损伤机制研究进展[J].中华放射肿瘤学杂志,2014,5(23):230-233.
[14]Xuan L,Guoxiong X,Tiankui Q,et al.Effects of CpG oligodeoxynucleotide 1826 on acute radiation-induced lung injury in mice[J].Biol Res,2016,49:8.
[15]Mahmood J,Jelveh S,Zaidi A,et al.Mitigation of radiationinduced lung injury with EUK-207 and genistein:Effects in adolescent rats[J].Radiat Res,2013,179(2):125-134.
[16]Selman M,King T,Pardo A.Idiopathic pulmonary fibrosis:Prevailing and evolving hypotheses about its pathogenesis and implications for therapy[J].Ann Intern Med,2001,134(2):136-151.
[17]Tajima G,Delisle AJ,Hoang K,et al.Immune system phenotyping of radiation and radiation combined injury in outbred mice[J].Radiat Res,2013,179(1):101-112.
[18]Wynn TA.Integrating mechanisms of pulmonary fibrosis[J].J Exp Med,2011,208(7):1339-1350.
[19]Balli D,Ustiyan V,Zhang Y,et al.Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition[J].EMBO J,2013,32(2):231-244.
[20]Yijuan H,Weiqiang Z,Fangrong Y,et al.The cellular and molecular mechanism of radiation-induced lung injury[J].Med Sci Monit,2017,(23):3446-3450.
[21]Moon HG,Cao Y,Yang J,et al.Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway[J].Cell Death Dis,2015,6:e2016.
[22]Yan W,Xiwei W,Weiying Z,et al.Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells[J].Nat Cell Biol,2018,20(5):597-609.
[23]Kortlever RM,Sodir NM,Wilson CH,et al.Myc cooperates with ras by programming inflammation and immune suppression[J].Cell,2017,171(6):1301-1315.
[24]Lianhong Y,Jianhua Y,Guoqian L,et al.Pathophysiological responses in rat and mouse models of radiation-induced brain injury[J].Mol Neurobiol,2017,54(2):1022-1032.
[25]Yumo D,Zhuansun YX,Rui C,et al.Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma[J].Exp Cell Res,2018,363(1):114-120.
[26]Shanshan X,Xiujie P,Long X,et al.Regulatory T Cells Promote beta-Catenin-Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis[J].Int J Radiat Oncol Biol Phys,2015,93(2):425-435.
[27]Lai RC,Tan SS,Teh BJ,et al.Proteolytic Potential of the MSCExosome Proteome:Implications for an Exosome-Mediated Delivery of Therapeutic Proteasome[J].Int J Proteomics,2012,2012:971907.
[28]Kojima M,Gimenes-Junior JA,Chan TW,et al.Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4[J].FASEB J,2018,32(1):97-110.
[29]Kim JS,Son Y,Jung MG,et al.Geranylgeranylacetone alleviates radiation-induced lung injury by inhibiting epithelial-to-mesenchymal transition signaling[J].Mol Med Rep,2016,13(6):4666-4670.
[30]Eldh M,Ekstrom K,Valadi H,et al.Exosomes communicate protective messages during oxidative stress;possible role of exosomal shuttle RNA[J].PLo S One,2010,5(12):e15353..
[31]Arslan F,Lai RC,Smeets MB,et al.Mesenchymal stem cellderived exosomes increase ATP levels,decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury[J].Stem Cell Res,2013,10(3):301-312.
[32]Ezquer F,Quintanilla ME.Intranasal delivery of mesenchymal stem cell-derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post-deprivation relapse drinking[J/OL].Addict Biol,2018[2018-10-01].https://onlinelibrary.wiley.com/doi/abs/10.1111/adb.12675[publised online ahead of print Sep 21,2018].
[33]Yan W,Ranzun Z,Debin L,et al.Exosomes derived from miR-214-Enriched bone marrow-derived mesenchymal stem cells regulate oxidative damage in cardiac stem cells by targeting Ca MKⅡ[J].Oxid Med Cell Longev,2018,72(16):c94.
[34]Minna L,Limin L,Ming B,et al.Hypoxia-induced activation of Twist/miR-214/E-cadherin axis promotes renal tubular epithelial cell mesenchymal transition and renal fibrosis[J].Biochem Biophys Res Commun,2018,495(3):2324-2330.
[35]Tang MKS,Yue PYK,Ip PP.Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface[J].Nat Commun,2018,9(1):2270.
[36]MA X,Becker Buscaglia LE,Barker JR,et al.MicroRNAs in NF-kappaB signaling[J].J Mol Cell Biol,2011,3(3):159-166.
[37]Fujita Y,Kadota T,Araya J,et al.Extracellular Vesicles:New Players in Lung Immunity[J].Am J Respir Cell Mol Biol,2018,58(5):560-565.
[38]Doxaki C,Kampranis SC.Coordinated Regulation of miR-155 and miR-146a Genes during Induction of Endotoxin Tolerance in Macrophages[J].J Immunol,2015,195(12):5750-5761.
[39]Alexander M,Hu R,Runtsch MC,et al.Exosome-delivered microRNAs modulate the inflammatory response to endotoxin[J].Nat Commun,2015,6:7321.
[40]Sanchez-Vidaurre S,Eldh M,Larssen P,et al.RNA-containing exosomes in induced sputum of asthmatic patients[J].J Allergy Clin Immunol,2017,140(5):1459-1461.
[41]Njock MS,Guiot J,Henket MA,et al.Sputum exosomes:Promising biomarkers for idiopathic pulmonary fibrosis[J].Thorax,2018,74(3):309-312.
[42]Mariathasan S,Weiss DS,Newton K,et al.Cryopyrin activates the inflammasome in response to toxins and ATP[J].Nature,2006,440(7081):228-232.
[43]Qu Y,Franchi L,Nunez G,et al.Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages[J].J Immuno,2007,179(3):1913-1925.
[44]Chao Z,Wenfeng Z,Yi Y,et al.Naringenin ameliorates radiationinduced lung injury by lowering IL-1beta level[J].J Pharmacol Exp Ther,2018,366(2):341-348.
[45]Huaidong L,Qingxiao Z,Zhi M,et al.Exogenous interleukin-10attenuates hyperoxia-induced acute lung injury in mice[J].Exp Physiol,2015,100(3):331-340.
[46]Haiyang Z,Yi W.Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA[J].Cancer Sci,2018,109(3):629-641.
[47]Zhang B,Yeo RWY,Lai RC,et al.Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigenpresenting cell-mediated pathway[J].Cytotherapy,2018,20(5):687-696.
[48]Marchand-Adam S,Fabre A,Mailleux AA,et al.Defect of prohepatocyte growth factor activation by fibroblasts in idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med,2006,174(1):58-66.
[49]Rodriguez AM,Elabd C,Delteil F,et al.Adipocyte differentiation of multipotent cells established from human adipose tissue[J].Biochem Biophys Res Commun,2004,315(2):255-263.
[50]Xinping J,Xin J,Chao Q,et al.Intravenous delivery of adiposederived mesenchymal stromal cells attenuates acute radiationinduced lung injury in rats[J].Cytotherapy,2015,17(5):560-570.
[51]Xiaohong W,Haitao G,Wei H,et al.Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice[J].Diabetes,2016,65(10):3111-3128.
[52]Hakulinen J,Sankkila L,Sugiyama N,et al.Secretion of active membrane type 1 matrix metalloproteinase(MMP-14)into extracellular space in microvesicular exosomes[J].J Cell Biochem,2008,105(5):1211-1218.
[2]Kubo H.Extracellular vesicles in lung disease[J].Chest,2018,153(1):210-216.
[3]Selmaj I,Mycko MP,Raine CS,et al.The role of exosomes in CNSinflammation and their involvement in multiple sclerosis[J].J Neuroimmunol,2017,306:1-10.
[4]Barile L,Moccetti T,Marban E,et al.Roles of exosomes in cardioprotection[J].Eur Heart J,2017,38(18):1372-1379.
[5]Terrasini N,Lionetti V.Exosomes in critical illness[J].Crit Care Med,2017,45(6):1054-1060.
[6]Vallabhaneni KC,Penfornis P,Dhule S,et al.Extracelluar versicles from bone marrow mesenchymal stem/stromal cells transport tumor regulatory microRNA,proteins,and metabolites[J].Oncotarget,2015,6(7):4953-4967.
[7]Batagov AO,Kurochkin IV.Exosomes secreted by human cells transport largely mRNA fragments that are enriched in the 3'-untranslated regions[J].Biol Direct,2013,8:12.
[8]Yuan Z,Bedi B,Sadikot RT.Bronchoalveolar lavage exosomes in lpopolysaccharide-induced septic lung injury[J].J Vis Exp,2018(135).
[9]Corrado C,Raimondo S,Chiesi A,et al.Exosomes as intercellular signaling organelles involved in health and disease:Basic science and clinical applications[J].Int J Mol Sci,2013,14(3):5338-5366.
[10]Zhenhua W,Xinyu W,Rong Y,et al.Effects of carbon ion beam irradiation on lung injury and pulmonary fibrosis in mice[J].Exp Ther Med,2013,5(3):771-776.
[11]Yu S,Yujun Du,Hui Z,et al.Protective effects of ulinastatin and methylprednisolone against radiation-induced lung injury in mice[J].J Radiat Res,2016,57(5):505-511.
[12]Deyun Z,Hongjin Q,Jiaming G,et al.Protective effects of myrtol standardized against radiation-induced lung injury[J].Cell Physiol Biochem,2016,38(2):619-634.
[13]Haiying Y,Rensheng W.放射性肺损伤机制研究进展[J].中华放射肿瘤学杂志,2014,5(23):230-233.
[14]Xuan L,Guoxiong X,Tiankui Q,et al.Effects of CpG oligodeoxynucleotide 1826 on acute radiation-induced lung injury in mice[J].Biol Res,2016,49:8.
[15]Mahmood J,Jelveh S,Zaidi A,et al.Mitigation of radiationinduced lung injury with EUK-207 and genistein:Effects in adolescent rats[J].Radiat Res,2013,179(2):125-134.
[16]Selman M,King T,Pardo A.Idiopathic pulmonary fibrosis:Prevailing and evolving hypotheses about its pathogenesis and implications for therapy[J].Ann Intern Med,2001,134(2):136-151.
[17]Tajima G,Delisle AJ,Hoang K,et al.Immune system phenotyping of radiation and radiation combined injury in outbred mice[J].Radiat Res,2013,179(1):101-112.
[18]Wynn TA.Integrating mechanisms of pulmonary fibrosis[J].J Exp Med,2011,208(7):1339-1350.
[19]Balli D,Ustiyan V,Zhang Y,et al.Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition[J].EMBO J,2013,32(2):231-244.
[20]Yijuan H,Weiqiang Z,Fangrong Y,et al.The cellular and molecular mechanism of radiation-induced lung injury[J].Med Sci Monit,2017,(23):3446-3450.
[21]Moon HG,Cao Y,Yang J,et al.Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway[J].Cell Death Dis,2015,6:e2016.
[22]Yan W,Xiwei W,Weiying Z,et al.Cancer-cell-secreted exosomal miR-105 promotes tumour growth through the MYC-dependent metabolic reprogramming of stromal cells[J].Nat Cell Biol,2018,20(5):597-609.
[23]Kortlever RM,Sodir NM,Wilson CH,et al.Myc cooperates with ras by programming inflammation and immune suppression[J].Cell,2017,171(6):1301-1315.
[24]Lianhong Y,Jianhua Y,Guoqian L,et al.Pathophysiological responses in rat and mouse models of radiation-induced brain injury[J].Mol Neurobiol,2017,54(2):1022-1032.
[25]Yumo D,Zhuansun YX,Rui C,et al.Mesenchymal stem cell exosomes promote immunosuppression of regulatory T cells in asthma[J].Exp Cell Res,2018,363(1):114-120.
[26]Shanshan X,Xiujie P,Long X,et al.Regulatory T Cells Promote beta-Catenin-Mediated Epithelium-to-Mesenchyme Transition During Radiation-Induced Pulmonary Fibrosis[J].Int J Radiat Oncol Biol Phys,2015,93(2):425-435.
[27]Lai RC,Tan SS,Teh BJ,et al.Proteolytic Potential of the MSCExosome Proteome:Implications for an Exosome-Mediated Delivery of Therapeutic Proteasome[J].Int J Proteomics,2012,2012:971907.
[28]Kojima M,Gimenes-Junior JA,Chan TW,et al.Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll-like receptor 4[J].FASEB J,2018,32(1):97-110.
[29]Kim JS,Son Y,Jung MG,et al.Geranylgeranylacetone alleviates radiation-induced lung injury by inhibiting epithelial-to-mesenchymal transition signaling[J].Mol Med Rep,2016,13(6):4666-4670.
[30]Eldh M,Ekstrom K,Valadi H,et al.Exosomes communicate protective messages during oxidative stress;possible role of exosomal shuttle RNA[J].PLo S One,2010,5(12):e15353..
[31]Arslan F,Lai RC,Smeets MB,et al.Mesenchymal stem cellderived exosomes increase ATP levels,decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury[J].Stem Cell Res,2013,10(3):301-312.
[32]Ezquer F,Quintanilla ME.Intranasal delivery of mesenchymal stem cell-derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post-deprivation relapse drinking[J/OL].Addict Biol,2018[2018-10-01].https://onlinelibrary.wiley.com/doi/abs/10.1111/adb.12675[publised online ahead of print Sep 21,2018].
[33]Yan W,Ranzun Z,Debin L,et al.Exosomes derived from miR-214-Enriched bone marrow-derived mesenchymal stem cells regulate oxidative damage in cardiac stem cells by targeting Ca MKⅡ[J].Oxid Med Cell Longev,2018,72(16):c94.
[34]Minna L,Limin L,Ming B,et al.Hypoxia-induced activation of Twist/miR-214/E-cadherin axis promotes renal tubular epithelial cell mesenchymal transition and renal fibrosis[J].Biochem Biophys Res Commun,2018,495(3):2324-2330.
[35]Tang MKS,Yue PYK,Ip PP.Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface[J].Nat Commun,2018,9(1):2270.
[36]MA X,Becker Buscaglia LE,Barker JR,et al.MicroRNAs in NF-kappaB signaling[J].J Mol Cell Biol,2011,3(3):159-166.
[37]Fujita Y,Kadota T,Araya J,et al.Extracellular Vesicles:New Players in Lung Immunity[J].Am J Respir Cell Mol Biol,2018,58(5):560-565.
[38]Doxaki C,Kampranis SC.Coordinated Regulation of miR-155 and miR-146a Genes during Induction of Endotoxin Tolerance in Macrophages[J].J Immunol,2015,195(12):5750-5761.
[39]Alexander M,Hu R,Runtsch MC,et al.Exosome-delivered microRNAs modulate the inflammatory response to endotoxin[J].Nat Commun,2015,6:7321.
[40]Sanchez-Vidaurre S,Eldh M,Larssen P,et al.RNA-containing exosomes in induced sputum of asthmatic patients[J].J Allergy Clin Immunol,2017,140(5):1459-1461.
[41]Njock MS,Guiot J,Henket MA,et al.Sputum exosomes:Promising biomarkers for idiopathic pulmonary fibrosis[J].Thorax,2018,74(3):309-312.
[42]Mariathasan S,Weiss DS,Newton K,et al.Cryopyrin activates the inflammasome in response to toxins and ATP[J].Nature,2006,440(7081):228-232.
[43]Qu Y,Franchi L,Nunez G,et al.Nonclassical IL-1 beta secretion stimulated by P2X7 receptors is dependent on inflammasome activation and correlated with exosome release in murine macrophages[J].J Immuno,2007,179(3):1913-1925.
[44]Chao Z,Wenfeng Z,Yi Y,et al.Naringenin ameliorates radiationinduced lung injury by lowering IL-1beta level[J].J Pharmacol Exp Ther,2018,366(2):341-348.
[45]Huaidong L,Qingxiao Z,Zhi M,et al.Exogenous interleukin-10attenuates hyperoxia-induced acute lung injury in mice[J].Exp Physiol,2015,100(3):331-340.
[46]Haiyang Z,Yi W.Exosomes serve as nanoparticles to suppress tumor growth and angiogenesis in gastric cancer by delivering hepatocyte growth factor siRNA[J].Cancer Sci,2018,109(3):629-641.
[47]Zhang B,Yeo RWY,Lai RC,et al.Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigenpresenting cell-mediated pathway[J].Cytotherapy,2018,20(5):687-696.
[48]Marchand-Adam S,Fabre A,Mailleux AA,et al.Defect of prohepatocyte growth factor activation by fibroblasts in idiopathic pulmonary fibrosis[J].Am J Respir Crit Care Med,2006,174(1):58-66.
[49]Rodriguez AM,Elabd C,Delteil F,et al.Adipocyte differentiation of multipotent cells established from human adipose tissue[J].Biochem Biophys Res Commun,2004,315(2):255-263.
[50]Xinping J,Xin J,Chao Q,et al.Intravenous delivery of adiposederived mesenchymal stromal cells attenuates acute radiationinduced lung injury in rats[J].Cytotherapy,2015,17(5):560-570.
[51]Xiaohong W,Haitao G,Wei H,et al.Hsp20-mediated activation of exosome biogenesis in cardiomyocytes improves cardiac function and angiogenesis in diabetic mice[J].Diabetes,2016,65(10):3111-3128.
[52]Hakulinen J,Sankkila L,Sugiyama N,et al.Secretion of active membrane type 1 matrix metalloproteinase(MMP-14)into extracellular space in microvesicular exosomes[J].J Cell Biochem,2008,105(5):1211-1218.