X线全身照射对2型糖尿病KKAy小鼠造血免疫系统功能的影响
|
摘要
目的观察X线全身照射对2型糖尿病模型KKAy小鼠的造血免疫系统功能的损伤作用,并与对照C57小鼠进行比较。方法 KKAy小鼠,分为对照组和照射组,照射组小鼠经X线全身照射,剂量4 Gy,C57小鼠作为对照。照射后15 d检测小鼠的外周血常规,流式细胞术检测骨髓中造血祖细胞、造血干细胞和长期造血干细胞的比例,脾中B细胞和T细胞的比例,胸腺中CD4CD8双阳性T细胞、CD4单阳性T细胞和CD8单阳性T细胞的比例。通过粒细胞集落形成能力实验评价小鼠造血祖细胞的功能。结果照射前KKAy小鼠的HSC和LT-HSC的比例低于C57小鼠。4 Gy全身照射后,KKAy小鼠的外周血WBC、RBC、PLT、HGB和LYM%分别下降了68. 42%、12. 17%、8. 78%、30. 12%、70. 84%;骨髓中HPC、HSC和LT-HSC的比例分别下降了34. 02%、29. 49%、35. 74%;脾B细胞和T细胞的比例分别下降了57. 85%、58. 81%;胸腺CD4CD8双阳性细胞的比例下降了51. 70%。KKAy小鼠的骨髓HSC、LT-HSC、外周血RBC和HGB的降低幅度显著低于C57小鼠。结论 4 Gy全身照射损伤KKAy小鼠的造血免疫系统功能,KKAy小鼠可能比C57小鼠表现出对电离辐射较强的耐受性。
Objective To explore the damaging effect of X-ray whole body irradiation on hematopoiesis and immune functions in KKAy mice with type 2 diabetes mellitus. Methods KKAy mice were exposed to 4 Gy total body irradiation( TBI),and compared with C57 BL/6 J mice. All mice were euthanized for routine analysis of peripheral blood,hematopoietic progenitor cells( HPC),hematopoietic stem cells( HSC),and long-term hematopoietic stem cells( LTHSC) frequencies and the percentages of splenic lymphocytes and thymic lymphocytes. The function of HPCs was measured by colony-forming unit-granulocyte and macrophage( CFU-GM) assay. Results The frequency of HSCs and LT-HSCs in KKAy mice was lower than that in C57 mice. After 4 Gy whole body irradiation,the percentages of WBCs,RBCs,PLTs,HG B and LYM% in peripheral blood of KKAy mice were decreased by 68. 42%,12. 17%,8. 78%,30. 12%,and70. 84%,respectively. The percentages of HPCs,HSCs and LT-HSCs in bone marrow were decreased by 34. 02%,29. 49%,35. 74%,respectively. The proportions of splenic B and T cells were decreased by 57. 85% and 58. 81%,respectively. The proportion of thymic CD4+/CD8+cells was decreased by 51. 7%. The HPC function( CFU-GM) was also impaired. The decrease levels of bone marrow HSC,LT-HSC,peripheral blood RBC and HGB in KKAy mice were significantly lower than those in C57 mice.Conclusions Whole body irradiation by 4 Gy X-rays impairs the hematopoiesis and immune functions,and KKAy mice might show a greater tolerance to ionizing radiation than C57 mice.
Objective To explore the damaging effect of X-ray whole body irradiation on hematopoiesis and immune functions in KKAy mice with type 2 diabetes mellitus. Methods KKAy mice were exposed to 4 Gy total body irradiation( TBI),and compared with C57 BL/6 J mice. All mice were euthanized for routine analysis of peripheral blood,hematopoietic progenitor cells( HPC),hematopoietic stem cells( HSC),and long-term hematopoietic stem cells( LTHSC) frequencies and the percentages of splenic lymphocytes and thymic lymphocytes. The function of HPCs was measured by colony-forming unit-granulocyte and macrophage( CFU-GM) assay. Results The frequency of HSCs and LT-HSCs in KKAy mice was lower than that in C57 mice. After 4 Gy whole body irradiation,the percentages of WBCs,RBCs,PLTs,HG B and LYM% in peripheral blood of KKAy mice were decreased by 68. 42%,12. 17%,8. 78%,30. 12%,and70. 84%,respectively. The percentages of HPCs,HSCs and LT-HSCs in bone marrow were decreased by 34. 02%,29. 49%,35. 74%,respectively. The proportions of splenic B and T cells were decreased by 57. 85% and 58. 81%,respectively. The proportion of thymic CD4+/CD8+cells was decreased by 51. 7%. The HPC function( CFU-GM) was also impaired. The decrease levels of bone marrow HSC,LT-HSC,peripheral blood RBC and HGB in KKAy mice were significantly lower than those in C57 mice.Conclusions Whole body irradiation by 4 Gy X-rays impairs the hematopoiesis and immune functions,and KKAy mice might show a greater tolerance to ionizing radiation than C57 mice.
引文
[1] Xu Y,Wang L,He J,et al. Prevalence and control of diabetes in Chinese adults[J]. JAMA,2013,310(9):948-959.
[2] Giovannucci E,Harlan DM,Archer MC,et al. Diabetes and cancer:a consensus report[J]. Diabetes Care,2010,33(7):1674-1685.
[3] Tsilidis KK,Kasimis JC,Lopez DS,et al. Type 2 diabetes and cancer:umbrella review of meta-analyses of observational studies[J]. BMJ,2015,350:g7607.
[4] Citrin DE. Recent developments in radiotherapy[J]. N Engl J Med,2017,377(11):1065-1075.
[5] Oikawa A,Siragusa M,Quaini F,et al. Diabetes mellitus induces bone marrow microangiopathy[J]. Arterioscler Thromb Vasc Biol,2010,30(3):498-508.
[6] Fadini GP, Ferraro F, Quaini F, et al. Concise review:diabetes, the bone marrow niche, and impaired vascular regeneration[J]. Stem Cells Transl Med,2014,3(8):949-957.
[7] Esser N,Legrand-Poels S,Piette J,et al. Inflammation as a link between obesity,metabolic syndrome and type 2 diabetes[J].Diabetes Res Clin Pract,2014,105(2):141-150.
[8] Zhu X,Zhang C,Fan Q,et al. Inhibiting microRNA-503 and microRNA-181d with losartan ameliorates diabetic nephropathy in KKAy mice[J]. Med Sci Monit,2016,22:3902-3909.
[9]陈其明,史顺娣,申竹芳,等.糖尿病KK小鼠生物特性的研究[J].中国医学科学院学报,1988,10(6):416-420.Chen QM, Shi SD, Shen ZF, et al.,Study on biological characteristics of spontaneous diabetic KK mice[J]. J Chin Acad Med Sci,1988,10(6):416-420.
[10] Li C,Lu L,Zhang J,et al. Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation[J]. Cell Biosci,2015,5:65.
[11] Zhang H, Zhai Z, Wang Y, et al. Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice[J]. Free Radic Biol Med,2013,54:40-50.
[12] Chiba H, Ataka K, Iba K, et al. Diabetes impairs the interactions between long-term hematopoietic stem cells and osteopontin-positive cells in the endosteal niche of mouse bone marrow[J]. Am J Physiol Cell Physiol,2013,305(7):C693-703.
[13] Ferraro F,Lymperi S,Mendez-Ferrer S,et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function[J]. Sci Transl Med,2011,3(104):104ra101.
[14] Bannon P,Wood S,Restivo T,et al. Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice[J]. Dis Model Mech,2013,6(6):1434-1447.
[15] Ishii K,Misonoh J. Induction of radio-adaptive response by lowdose X-irradiation on chromosome aberrations in human embryonic fibroblasts[J]. Physiol Chem Phys Med NMR,1996,28(2):83-90.
[16] Chang J,Wang Y,Shao L,et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice[J].Nat Med,2016,22(1):78-83.
[17] Shao L,Wang Y,Chang J,et al. Hematopoietic stem cell senescence and cancer therapy-induced long-term bone marrow injury[J]. Transl Cancer Res,2013,2(5):397-411.
[18] Palmer AK, Tchkonia T, Le Brasseur NK, et al. Cellular senescence in type 2 diabetes:a therapeutic opportunity[J].Diabetes,2015,64(7):2289-2298.
[2] Giovannucci E,Harlan DM,Archer MC,et al. Diabetes and cancer:a consensus report[J]. Diabetes Care,2010,33(7):1674-1685.
[3] Tsilidis KK,Kasimis JC,Lopez DS,et al. Type 2 diabetes and cancer:umbrella review of meta-analyses of observational studies[J]. BMJ,2015,350:g7607.
[4] Citrin DE. Recent developments in radiotherapy[J]. N Engl J Med,2017,377(11):1065-1075.
[5] Oikawa A,Siragusa M,Quaini F,et al. Diabetes mellitus induces bone marrow microangiopathy[J]. Arterioscler Thromb Vasc Biol,2010,30(3):498-508.
[6] Fadini GP, Ferraro F, Quaini F, et al. Concise review:diabetes, the bone marrow niche, and impaired vascular regeneration[J]. Stem Cells Transl Med,2014,3(8):949-957.
[7] Esser N,Legrand-Poels S,Piette J,et al. Inflammation as a link between obesity,metabolic syndrome and type 2 diabetes[J].Diabetes Res Clin Pract,2014,105(2):141-150.
[8] Zhu X,Zhang C,Fan Q,et al. Inhibiting microRNA-503 and microRNA-181d with losartan ameliorates diabetic nephropathy in KKAy mice[J]. Med Sci Monit,2016,22:3902-3909.
[9]陈其明,史顺娣,申竹芳,等.糖尿病KK小鼠生物特性的研究[J].中国医学科学院学报,1988,10(6):416-420.Chen QM, Shi SD, Shen ZF, et al.,Study on biological characteristics of spontaneous diabetic KK mice[J]. J Chin Acad Med Sci,1988,10(6):416-420.
[10] Li C,Lu L,Zhang J,et al. Granulocyte colony-stimulating factor exacerbates hematopoietic stem cell injury after irradiation[J]. Cell Biosci,2015,5:65.
[11] Zhang H, Zhai Z, Wang Y, et al. Resveratrol ameliorates ionizing irradiation-induced long-term hematopoietic stem cell injury in mice[J]. Free Radic Biol Med,2013,54:40-50.
[12] Chiba H, Ataka K, Iba K, et al. Diabetes impairs the interactions between long-term hematopoietic stem cells and osteopontin-positive cells in the endosteal niche of mouse bone marrow[J]. Am J Physiol Cell Physiol,2013,305(7):C693-703.
[13] Ferraro F,Lymperi S,Mendez-Ferrer S,et al. Diabetes impairs hematopoietic stem cell mobilization by altering niche function[J]. Sci Transl Med,2011,3(104):104ra101.
[14] Bannon P,Wood S,Restivo T,et al. Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice[J]. Dis Model Mech,2013,6(6):1434-1447.
[15] Ishii K,Misonoh J. Induction of radio-adaptive response by lowdose X-irradiation on chromosome aberrations in human embryonic fibroblasts[J]. Physiol Chem Phys Med NMR,1996,28(2):83-90.
[16] Chang J,Wang Y,Shao L,et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice[J].Nat Med,2016,22(1):78-83.
[17] Shao L,Wang Y,Chang J,et al. Hematopoietic stem cell senescence and cancer therapy-induced long-term bone marrow injury[J]. Transl Cancer Res,2013,2(5):397-411.
[18] Palmer AK, Tchkonia T, Le Brasseur NK, et al. Cellular senescence in type 2 diabetes:a therapeutic opportunity[J].Diabetes,2015,64(7):2289-2298.