低强度脉冲超声对阿霉素联合环磷酰胺化疗后大鼠造血功能的影响
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摘要
目的探讨低强度脉冲超声(LIPUS)对阿霉素联合环磷酰胺化疗后大鼠造血功能的影响。方法将80只大鼠根据性别和体质量进行随机分层分组,对照组和LIPUS组各40只。对照组用阿霉素(2 mg/kg)+环磷酰胺(20 mg/kg)先后腹腔注射,连续给药4 d;LIPUS组在相同剂量给药后LIPUS连续辐照7 d。于开始给药第0、4、7、9、11、14、18天测定各组大鼠白细胞、红细胞、血小板计数;于第0、4、11天做骨髓组织病理切片、流式细胞术检测凋亡、qPCR(SCF、ICAM-1、VCAM-1)检测、ELISA检测IL-3和GM-CSF。结果血常规结果显示,LIPUS组白细胞较对照组明显提高(P<0.05),骨髓组织病理切片结果显示LIPUS组造血组织的增加显著(P<0.05),流式细胞术结果显示LIPUS组骨髓细胞凋亡低于对照组(P<0.05),qPCR结果显示LIPUS组ICAM-1和VCAM-1的水平明显高于对照组(P<0.05),ELISA检测结果显示,LIPUS组IL-3和GM-CSF均显著高于对照组(P<0.05)。结论LIPUS可改善阿霉素联合环磷酰胺化疗后的造血损伤,可能是因为其能提升ICAM-1、VCAM-1水平和IL-3、GM-CSF水平所致。
Objective To investigate the effect of low-intensity pulsed ultrasound(LIPUS) on hematopoietic function in rats after combined chemotherapy with doxorubicin and cyclophosphamide. Methods Eighty rats were randomized into control group and LIPUS group(n=40) for treatment with intraperitoneal injection of doxorubicin(2 mg/kg)+cyclophosphamide(20 mg/kg)for 4 consecutive days and continuous irradiation with LIPUS for 7 days following the injections, respectively. The white blood cells, red blood cells and platelets counts in each group were measured at 0, 4, 7, 9, 11, 14 and 18 days after the start of drug administration. The pathological sections of the bone marrow were examined at 0, 4 and 11 days, and the flow cytometry was performed for detecting the cell apoptosis; qPCR was performed for detecting the expressions of SCF, ICAM-1, and VCAM-1 mRNAs, and ELISA was used to detect the expressions of IL-3 and GM-CSF. Results The white blood cell count was significantly higher in LIPUS group than in the control group(P<0.05). Histopathological examination of the bone marrow revealed significantly increased hematopoietic tissue in LIPUS group(P<0.05). Flow cytometry demonstrated an obviously lower cell apoptosis rate in the bone marrow in LIPUS group than in the control group(P<0.05). Compared with those in the control group, the mRNA expression levels of ICAM-1 and VCAM-1 as well as the protein levels of IL-3 and GM-CSF were significantly increased in LIPUS group(P<0.05). Conclusion LIPUS can alleviate the hematopoietic damage after combined chemotherapy with doxorubicin with cyclophosphamide probably by increasing the expressions of ICAM-1, VCAM-1, IL-3,and GM-CSF.
Objective To investigate the effect of low-intensity pulsed ultrasound(LIPUS) on hematopoietic function in rats after combined chemotherapy with doxorubicin and cyclophosphamide. Methods Eighty rats were randomized into control group and LIPUS group(n=40) for treatment with intraperitoneal injection of doxorubicin(2 mg/kg)+cyclophosphamide(20 mg/kg)for 4 consecutive days and continuous irradiation with LIPUS for 7 days following the injections, respectively. The white blood cells, red blood cells and platelets counts in each group were measured at 0, 4, 7, 9, 11, 14 and 18 days after the start of drug administration. The pathological sections of the bone marrow were examined at 0, 4 and 11 days, and the flow cytometry was performed for detecting the cell apoptosis; qPCR was performed for detecting the expressions of SCF, ICAM-1, and VCAM-1 mRNAs, and ELISA was used to detect the expressions of IL-3 and GM-CSF. Results The white blood cell count was significantly higher in LIPUS group than in the control group(P<0.05). Histopathological examination of the bone marrow revealed significantly increased hematopoietic tissue in LIPUS group(P<0.05). Flow cytometry demonstrated an obviously lower cell apoptosis rate in the bone marrow in LIPUS group than in the control group(P<0.05). Compared with those in the control group, the mRNA expression levels of ICAM-1 and VCAM-1 as well as the protein levels of IL-3 and GM-CSF were significantly increased in LIPUS group(P<0.05). Conclusion LIPUS can alleviate the hematopoietic damage after combined chemotherapy with doxorubicin with cyclophosphamide probably by increasing the expressions of ICAM-1, VCAM-1, IL-3,and GM-CSF.
引文
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[23]赵静,张晓彤,胡克,等.紫杉醇联合卡铂三周方案同步胸部放疗治疗不宜手术的局部晚期非小细胞肺癌疗效和安全性研究:一项来自单中心的回顾性研究[J].中国肺癌杂志,2016,19(11):731-7.
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[32]Zhao LR,Singhal S,Duan WM,et al.Brain repair by hematopoietic growth factors in a rat model of stroke[J].Stroke,2007,38(9):2584-91.
[33]王改琴,吴宏.VCAM-1、ICAM-1与造血干细胞的动员、归巢及作用机制[J].国际检验医学杂志,2007,28(12):1114-6.
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[36]Hubbard AK,Rothlein R.Intercellular adhesion molecule-1(ICAM-1)expression and cell signaling cascades[J].Free Radical Bio Med,2000,28(9):1379-86.
[37]Goldar S,Khaniani MS,Derakhshan SM,et al.Molecular mechanisms of apoptosis and roles in cancer development and treatment[J].Asian Pac J Cancer Prev,2015,16(6):2129-44.
[2]Staff NP,Grisold A,Grisold W,et al.Chemotherapy-induced peripheral neuropathy:A current review[J].Ann Neurol,2017,81(6):772-81.
[3]Yoshimura A,Noro R,Miyanaga A,et al.Combination chemotherapy of alternating etoposide and carboplatin with weekly administration of irinotecan and cisplatin in extensive-stage smallcell lung cancer[J].Anticancer Res,2012,32(10):4473-8.
[4]Varricchi G,Marone G,Mercurio V,et al.Immune checkpoint inhibitors and cardiac toxicity:an emerging issue[J].Curr Med Chem,2018,25(11):1327-39.
[5]Glass CK,Mitchell RN.Winning the battle,but losing the war:mechanisms and morphology of cancer-therapy-associated cardiovascular toxicity[J].Cardiovasc Pathol,2017,30:55-63.
[6]胡红,王利.抗肿瘤药物所致不良反应调查与分析[J].中医临床研究,2017,9(35):51-3.
[7]Barreto JN,Mccullough KB,Ice LL,et al.Antineoplastic agents and the associated myelosuppressive effects:a review[J].J Pharm Pract,2014,27(5):440-6.
[8]Lalami Y,Klastersky J.Impact of chemotherapy-induced neutropenia(CIN)and febrile neutropenia(FN)on cancer treatment outcomes:An overview about well-established and recently emerging clinical data[J].Crit Rev Oncol Hematol,2017,120:163-79.
[9]Chen W,Rizzieri D,Drago S.Safety of growth factor administration for leukapheresis in those with WBC counts greater than 60 000/μL[J].J ClinApher,2015,30(1):28-31.
[10]Chen SH,Yang SH,Chu SC,et al.The role of donor characteristics and post-granulocyte colony-stimulating factor white blood cell counts in predicting the adverse events and yields of stem cell mobilization[J].Int J Hematol,2011,93(5):652-9.
[11]Uddin SM,Qin YX.Enhancement of osteogenic differentiation and proliferation in human mesenchymal stem cells by a modified low intensity ultrasound stimulation under simulated microgravity[J].PLoS One,2013,8(9):e73914.
[12]Jia L,Chen J,Wang Y,et al.Focused low-intensity pulsed ultrasound affects extracellular matrix degradation via decreasing chondrocyte apoptosis and inflammatory mediators in a surgically induced osteoarthritic rabbitmodel[J].UltrasoundMed Biol,2016,42(1):208-19.
[13]Fung CH,CheungWH,Pounder NM,et al.Osteocytes exposed to far field of therapeutic ultrasound promotes osteogenic cellular activities in pre-osteoblasts through soluble factors[J].Ultrasonics,2014,54(5):1358-65.
[14]杜登悝,陈世荣,易刚,等.低强度脉冲超声促进人骨性关节炎软骨细胞合成细胞外基质[J].细胞与分子免疫学杂志,2016,32(11):1536-40.
[15]于海生.低强度脉冲超声促进骨髓来源细胞增殖的研究[D].[重庆]:重庆医科大学,2012.
[16]于海生,陈文直,王嫣,等.低强度脉冲超声对体外培养的骨髓间充质干细胞增殖效应的研究[J].中国医科大学学报,2011,11:971-4.
[17]Liu B,Luo Y,Luo D,et al.Treatment effect of low intensity pulsed ultrasound on leukopenia induced by cyclophosphamide in rabbits[J].Am J Transl Res,2017,9(7):3315-25.
[18]张愉,何瑞欣,周微尘,等.低强度脉冲超声对阿糖胞苷所致新西兰兔白细胞、血小板减少的影响[J].重庆医科大学学报,2015,12:1503-9.
[19]Singh JC,Mamtani A,Barrio A,et al.Pathologic complete response with neoadjuvant doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab and pertuzumab in patients with HER2-Positive early stage breast cancer:a single center experience[J].Oncologist,2017,22(2):139-43.
[20]Que L,He L,Yu CS,et al.Activation of Nrf2-ARE signaling mitigates cyclophosphamide-induced myelosuppression[J].Toxicol Lett,2016,262:17-26.
[21]于冬冬,牛云云,路玫,等.针灸对CTX小鼠骨髓细胞DNA修复基因XRCC1和ADPRT的调控作用[J].中国中医基础医学杂志,2018(9):1270-2.
[22]凌兰兴,吴桂甫,杨小叶,等.针刺对阿霉素所致大鼠骨髓抑制的保护作用[J].中国医药指南,2013,12:467-8.
[23]赵静,张晓彤,胡克,等.紫杉醇联合卡铂三周方案同步胸部放疗治疗不宜手术的局部晚期非小细胞肺癌疗效和安全性研究:一项来自单中心的回顾性研究[J].中国肺癌杂志,2016,19(11):731-7.
[24]颜虹.医学统计学[M]2版.北京:人民卫生出版社,2010.
[25]Siegel RL,Miller KD,Jemal A.Cancer statistics,2018[J].CACancer J Clin,2018,68(1):7-30.
[26]Jia XL,Chen WZ,Zhou K,et al.Effects of low-intensity pulsed ultrasound in repairing injured articular cartilage[J].Chin JTraumatol,2005,8(3):175-8.
[27]Lu HB,Liu FF,Chen HB,et al.The effect of low-intensity pulsed ultrasound on bone-tendon junction healing:Initiating after inflammation stage[J].J Orthop Res,2016,34(10):1697-706.
[28]Yang PF,Li D,Zhang SM,et al.Efficacy of ultrasound in the treatment of osteoarthritis of the knee[J].Orthop Surg,2011,3(3):181-7.
[29]Mourad PD,Lazar DA,Curra FP,et al.Ultrasound accelerates functional recovery after peripheral nerve damage[J].Neurosurgery,2001,48(5):1136-40;discussion 1140-1.
[30]Nesser HJ,Karia DH,Tkalec W,et al.Therapeutic ultrasound in cardiology[J].Herz,2002,27(3):269-78.
[31]Akiyama M,Ishibashi T,Yamada T,et al.Low-frequency ultrasound penetrates the cranium and enhances thrombolysis in vitro[J].Neurosurgery,1998,43(4):828-32.
[32]Zhao LR,Singhal S,Duan WM,et al.Brain repair by hematopoietic growth factors in a rat model of stroke[J].Stroke,2007,38(9):2584-91.
[33]王改琴,吴宏.VCAM-1、ICAM-1与造血干细胞的动员、归巢及作用机制[J].国际检验医学杂志,2007,28(12):1114-6.
[34]Schlesinger M,Bendas G.Vascular cell adhesion molecule-1(VCAM-1)--an increasing insight into its role in tumorigenicity and metastasis[J].Int J Cancer,2015,136(11):2504-14.
[35]Sarecka-Hujar B,Zak I,Krauze J.Interactions between rs5498polymorphism in the ICAM1 gene and traditional risk factors influence susceptibility to coronary artery disease[J].Clin Exp Med,2009,9(2):117-24.
[36]Hubbard AK,Rothlein R.Intercellular adhesion molecule-1(ICAM-1)expression and cell signaling cascades[J].Free Radical Bio Med,2000,28(9):1379-86.
[37]Goldar S,Khaniani MS,Derakhshan SM,et al.Molecular mechanisms of apoptosis and roles in cancer development and treatment[J].Asian Pac J Cancer Prev,2015,16(6):2129-44.