不同持续时间低氧后运动对大鼠胸腺组织细胞凋亡的影响
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摘要
目的：本研究采用不同持续时间低氧暴露后大鼠进行常氧下中等强度运动模型(模拟高住低练),探讨不同持续时间低氧暴露后运动条件下,观察大鼠胸腺组织细胞形态变化、细胞凋亡小体数目、胸腺组织分泌的胸腺素及CD30含量的变化、凋亡通路及相关因子蛋白及mRNA表达的影响,揭示不同持续时间低氧后运动对胸腺细胞凋亡的影响及其可能作用机制。
方法：60只SD大鼠按体重随机分为6组(10只／组),即：正常对照组(A)、低氧暴露8h组(B)、低氧暴露12h组(C)、常氧运动组(D)、低氧8h暴露后运动组(E)和低氧12h暴露后运动组(F)。D、E、F组大鼠在坡度为0,速度为25m/min的PT动物跑台上每天运动1h。运动完后,将B、E组和C、F组依次放入氧浓度为12.5%(相当于海拔4000m)的低氧舱内8h和12h,共持续4周(5天／周)。最后一次实验结束后24小时,大鼠腹腔麻醉断头处死,取胸腺组织液氮保存,胸腺组织匀浆后酶联免疫(ELISA)法检测胸腺组织胸腺素、CD30的水平；制备胸腺组织石蜡切片,常规HE染色检测胸腺组织细胞形态学的变化；TUNEL标记法在光镜下观察胸腺组织凋亡；免疫组化法检测大鼠胸腺组织细胞HIF-la、B细胞淋巴瘤/白血病癌基因-2(B cell lymphoma/leukemia 2,Bcl-2)、Bax(Bel-2 associated x,Bax)因子的蛋白水平；RT-PCR法检测大鼠胸腺细胞HIF-la、Bcl-2、Bax的mRNA水平。
结果：(1)组织匀浆胸腺素、CD30含量变化：胸腺素、CD30含量A组、B组、C组三组之间比较均显示,具有显著性差异(p<0.05),两两比较A组胸腺素、CD30的含量达均低于B组和C组,C组高于B组,具有显著性差异(p<0.05)；E组、F组、D组三组比较,胸腺素与CD30均无显著性差异(p>0.05),但E组和F组较D组有上升的趋势；D组、E组、F组胸腺素、CD30含量分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(2)HE染色显示：A组胸腺组织细胞结构完整,胞核较大,核膜完整。髓质与皮质部未见特殊改变；B组胸腺细胞较A组胸腺细胞无明显的变化,在皮质部分出现少量的脱落细胞；C组胸腺小体部分细胞肿胀,核膜部分边缘脱落,在皮质可见较多的脱落细胞；D组胸腺小体部分扩大,细胞呈扁平,细胞间隙增大；E组胸腺小体扩大,胸腺小体细胞轻度肿胀,少量核膜有轻度损坏未见脱落；F组胸腺细胞水肿,以皮质部：最为严重,在皮质部可见到细胞核损坏的脱落细胞。
(3)TUNEL染色显示：胸腺细胞凋亡阳性颗粒多发生在皮质和髓质,少发生在胸腺小体部分。图像分析表明E组、F组、D组三组凋亡指数之间比较,呈显著性差异(p<0.05),两两比较F组阳性凋亡均高于D组和E组,E组高于D组,具有显著性差异(p<0.05)；D组、E组、F组凋亡指数分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(4)免疫组织化学染色石蜡切片观察大鼠胸腺组织HIF-la的蛋白表达显示：HIF-la免疫组织化学阳性物质定位于胞浆内,细胞核内偶见,核膜阴性,呈弥散或颗粒状主要分布于胸腺组织皮质部分。统计学分析结果显示：A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较B组和C组表达均高于A组比较,均具有显著性差异(p<0.05)；E组、F组、D组三组比较,具有显著性差异(p<0.05)；两两比较F组均高于D组和E组,E组低于D组,均具有显著性差异(p<0.05)；D组、E组、F组阳性表达分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(5)免疫组化染色石蜡切片观察大鼠胸腺组织Bcl-2、Bax的阳性表达显示：bcl-2、Bax免疫组织化学阳性物质定位于胞浆内,偶见细胞核内,核膜阴性,呈弥散或颗粒状主要分布于胸腺组织皮质部分。统计学分析结果：Bcl-2、bax的阳性表达均显示A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较A组阳性表达均低于B组和C组,C组高于B组,具有显著性差异(p<0.05)；D组、E组、F组阳性表达分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(6)大鼠胸腺组织细胞凋亡与Bax、Bax/bcl-2比值的相关性以及HIF-la与Bax表达的相关性显示：大鼠胸腺组织细胞凋亡指数与Bax、Bax/Bcl-2比值之间存在正相关(p<0.05)；胸腺组织细胞HIF-la的蛋白表达与Bax之间存在正相关(P<0.05)。
(7)RT-PCR检测mRNA的表达：Bcl-2、bax mRNA表达A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较A组mRNA表达均低于B组和C组,C组高于B组,具有显著性差异(p<0.05)；D组、E组、F组mRNA表达分别高于A组、B组、C组,具有显著性差异(P<0.05);HIF-la mRNA表达A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较B组和C组表达均高于A组比较,均具有显著性差异(p<0.05)；D组、E组、F组mRNA表达分别高于A组、B组、C组,具有显著性差异(P<0.05)。
结论：1.低氧暴露或运动促进胸腺组织浆液胸腺素和CD30的含量升高,但低氧暴露后运动双重刺激下其含量没有变化。
2.低氧暴露或低氧暴露后运动诱导胸腺组织凋亡,凋亡多发生在皮质和髓质,胸腺小体少见,且低氧暴露8h作为应激原作用强度较缓和。
3.低氧暴露后运动诱导胸腺凋亡因子Bax、bcl-2蛋白表达以及Bax/bcl-2比值均升高,且mRNA与蛋白的表达一致。
4.低氧暴露后运动诱导HIF-la的蛋白表达升高,但mRNA的表达与蛋白表达不一致。
5.Bax与bcl-2参与胸腺细胞凋亡的调控,且HIF-la可能协同bcl-2家族参与凋亡调控。随着低氧时间的延长,促凋亡因子Bax的表达加速,加快胸腺细胞凋亡。
Objective:By using of different duration of hypoxia training model,Effect of the different duration exercise under the condition to hypoxia of rat thymus cells in morphology, the number of apoptotic cells, thymus cells hypoxia inducible factor (Hypoxia Induced Factor-la, HIF-la) changes in apoptosis pathway-related factor bcl-2, Bax protein and mRNA expression, hypoxia of different duration exercise on thymocyte apoptosis and its mechanism.
Methods:60 SD rats were randomly divided into 6 groups of 10 each, namely:control group (A), hypoxia 8h group (B), hypoxic 12h group (C), regular aerobic exercise group (D), hypoxia 8h exercise group (E) and 12h hypoxia exercise group (F).D, E, F group every day in the animal gradient of 0 to 25m/min speed treadmill exercise 1h. After exercise, the B, E group and C,F group in turn into the oxygen concentration of 12.5%(equivalent to an altitude 4000 m) in the hypoxic chamber 8h and 12h. Lasted 4 weeks,5 days a week. The last 24 hours after the end of the experiment, rats were anesthetized intraperitoneally implementation, the ideal of whole blood taken after the eyeball were executed, and thymus tissue preparation of paraffin sections of thymus tissue, HE staining of thymus cell morphological changes; TUNEL labeling of thymus tissue were observed in the light of apoptosis index; immune staining of rat thymus cells HIF-la, B-cell lymphoma/ leukemia oncogene-2 (B cell lymphoma/leukemia 2,Bcl-2),Bax (Bel-2 associated x,Bax) factors of the protein;RT-PCR detection of rat thymus cells in HIF-la, Bcl-2, Bax in the mRNA level.
Results:(1)Tissue thymosin, CD30 content:thymosin, CD30 content of A,B group,C group were compared among the three groups showed significant differences (p<0.05),group A pairwise comparison of thymus.
(2) Thymus tissue in the HE staining:A group of thymus tissue structural integrity, membrane integrity, the nucleus is relatively large. Medulla and the cortex and there were no specific changes;B group than the A group of thymus cells in the thymus cells had no significant changes in the cortex when a small number of exfoliated cells;C group thymic corpuscles swelling, some edge off, shedding more visible in the cortex cells;D group significantly expanded thymic corpuscles, flat cells, cell gap increases;E group than the D group of thymic corpuscles scope and extent of degeneration were significantly smaller than and light in the D group, thymic corpuscles mild swelling; F Thymus edema and degeneration of cells to the cortex serious, can be seen in the cortex of the small number of exfoliated cells.
(3) TUNEL staining:positive granules in apoptosis of thymocytes in medulla more, few parts of the cortex.Image analysis showed that the E group, F group, D group compared among the three groups, showing significant difference (p<0.05), the expression of any two F groups were higher than D group and E group, E group was higher than D group, with significant difference (p<0.05);D group, E group, F group were higher than the positive group A,B group,C group,with significant difference (P<0.05).
(4)Immunohistochemical staining of rat thymus tissue HIF-la protein expression displayed:HIF-la immunohistochemical positive signal in the cytoplasm, which showed diffuse or granular distribution in the cortical part of the nucleus occasionally. Statistical analysis showed that:A group,B group,C group compared among the three groups, with significant difference (p<0.05),22 compared the expression of B group and C group were higher than A group were significant difference (p<0.05);E group,F group,D group compared three groups with significant difference (p<0.05);22 more F group was higher than D group and E group,E group than in D group,were significant differences (p<0.05);D group,E group,F group were higher than the positive group A, B group, C group, with significant difference (P<0.05).
(5)Immunohistochemical staining of rat thymus tissue Bcl-2, Bax expression showed positive, bcl-2, Bax immunohistochemistry positive signal in the cytoplasm,occasionally in the nucleus. Statistical analysis: Bcl-2, bax expression showed positive group A,B group,C group compared among the three groups,with significant difference (p<0.05), Comparison of expression were lower than the B group group and C group,C group was higher than B group,with significant difference (p<0.05);D group,E group,F group were higher than the positive group A,B group,C group,with significant difference (P<0.05).
(6)Thymus tissue apoptosis of rat and Bax,Bax/bcl-2 the correlation ratio and the HIF-1a and Bax expression show:rat thymus tissue cell apoptosis and Bax,Bax/Bcl-2 There was a positive correlation between the ratio (p<0.05);thymus cells HIF-1a protein expression and positive correlation between Bax (P<0.05).
(7) RT-PCR detection of mRNA expression:Bcl-2,bax mRNA expression of A group, B group, C group compared among the three groups,with significant difference (p<0.05),A group of mRNA expression compared lower than the B group and C group, C group was higher than B group,with significant difference (p<0.05);D group, E group, F group mRNA expression were higher than A,B group, C group,significant differences (P<0.05);HIF-la mRNA expression of A group, B group, C group compared among the three groups, with significant difference (p<0.05), compared the expression of B group and C group were higher than group A comparison, there were significant differences (p<0.05);D group, E group, F group were higher than the mRNA expression of A group, B group, C group, with significant difference (P<0.05).
Conclusion:
1.Hypoxic exposure on exercise for thymosin thymus size and CD30 levels increased, but when the duration of hypoxia, the content does not rise instead of decrease.
2.Hypoxic and/or exercise induced thymus apoptosis, more than in medulla, cortex rare, and the original role of hypoxia as a stress intensity 8h modest.
3.Hypoxic and/or exercise induced thymic apoptosis factor Bax, bcl-2 protein expression, and mRNA and protein expression of the same.
4. Hypoxic and/or exercise induced HIF-la protein expression increased, but mRNA and protein expression of inconsistency.
5.Bax and bcl-2 apoptosis of thymus cells, and HIF-la may be synergistic bcl-2 family involved in apoptosis regulation. As the hypoxia time,the expression of pro-apoptotic factor Bax to accelerate, accelerate thymocyte apoptosis.
方法：60只SD大鼠按体重随机分为6组(10只／组),即：正常对照组(A)、低氧暴露8h组(B)、低氧暴露12h组(C)、常氧运动组(D)、低氧8h暴露后运动组(E)和低氧12h暴露后运动组(F)。D、E、F组大鼠在坡度为0,速度为25m/min的PT动物跑台上每天运动1h。运动完后,将B、E组和C、F组依次放入氧浓度为12.5%(相当于海拔4000m)的低氧舱内8h和12h,共持续4周(5天／周)。最后一次实验结束后24小时,大鼠腹腔麻醉断头处死,取胸腺组织液氮保存,胸腺组织匀浆后酶联免疫(ELISA)法检测胸腺组织胸腺素、CD30的水平；制备胸腺组织石蜡切片,常规HE染色检测胸腺组织细胞形态学的变化；TUNEL标记法在光镜下观察胸腺组织凋亡；免疫组化法检测大鼠胸腺组织细胞HIF-la、B细胞淋巴瘤/白血病癌基因-2(B cell lymphoma/leukemia 2,Bcl-2)、Bax(Bel-2 associated x,Bax)因子的蛋白水平；RT-PCR法检测大鼠胸腺细胞HIF-la、Bcl-2、Bax的mRNA水平。
结果：(1)组织匀浆胸腺素、CD30含量变化：胸腺素、CD30含量A组、B组、C组三组之间比较均显示,具有显著性差异(p<0.05),两两比较A组胸腺素、CD30的含量达均低于B组和C组,C组高于B组,具有显著性差异(p<0.05)；E组、F组、D组三组比较,胸腺素与CD30均无显著性差异(p>0.05),但E组和F组较D组有上升的趋势；D组、E组、F组胸腺素、CD30含量分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(2)HE染色显示：A组胸腺组织细胞结构完整,胞核较大,核膜完整。髓质与皮质部未见特殊改变；B组胸腺细胞较A组胸腺细胞无明显的变化,在皮质部分出现少量的脱落细胞；C组胸腺小体部分细胞肿胀,核膜部分边缘脱落,在皮质可见较多的脱落细胞；D组胸腺小体部分扩大,细胞呈扁平,细胞间隙增大；E组胸腺小体扩大,胸腺小体细胞轻度肿胀,少量核膜有轻度损坏未见脱落；F组胸腺细胞水肿,以皮质部：最为严重,在皮质部可见到细胞核损坏的脱落细胞。
(3)TUNEL染色显示：胸腺细胞凋亡阳性颗粒多发生在皮质和髓质,少发生在胸腺小体部分。图像分析表明E组、F组、D组三组凋亡指数之间比较,呈显著性差异(p<0.05),两两比较F组阳性凋亡均高于D组和E组,E组高于D组,具有显著性差异(p<0.05)；D组、E组、F组凋亡指数分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(4)免疫组织化学染色石蜡切片观察大鼠胸腺组织HIF-la的蛋白表达显示：HIF-la免疫组织化学阳性物质定位于胞浆内,细胞核内偶见,核膜阴性,呈弥散或颗粒状主要分布于胸腺组织皮质部分。统计学分析结果显示：A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较B组和C组表达均高于A组比较,均具有显著性差异(p<0.05)；E组、F组、D组三组比较,具有显著性差异(p<0.05)；两两比较F组均高于D组和E组,E组低于D组,均具有显著性差异(p<0.05)；D组、E组、F组阳性表达分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(5)免疫组化染色石蜡切片观察大鼠胸腺组织Bcl-2、Bax的阳性表达显示：bcl-2、Bax免疫组织化学阳性物质定位于胞浆内,偶见细胞核内,核膜阴性,呈弥散或颗粒状主要分布于胸腺组织皮质部分。统计学分析结果：Bcl-2、bax的阳性表达均显示A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较A组阳性表达均低于B组和C组,C组高于B组,具有显著性差异(p<0.05)；D组、E组、F组阳性表达分别高于A组、B组、C组,具有显著性差异(P<0.05)。
(6)大鼠胸腺组织细胞凋亡与Bax、Bax/bcl-2比值的相关性以及HIF-la与Bax表达的相关性显示：大鼠胸腺组织细胞凋亡指数与Bax、Bax/Bcl-2比值之间存在正相关(p<0.05)；胸腺组织细胞HIF-la的蛋白表达与Bax之间存在正相关(P<0.05)。
(7)RT-PCR检测mRNA的表达：Bcl-2、bax mRNA表达A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较A组mRNA表达均低于B组和C组,C组高于B组,具有显著性差异(p<0.05)；D组、E组、F组mRNA表达分别高于A组、B组、C组,具有显著性差异(P<0.05);HIF-la mRNA表达A组、B组、C组三组之间比较,具有显著性差异(p<0.05),两两比较B组和C组表达均高于A组比较,均具有显著性差异(p<0.05)；D组、E组、F组mRNA表达分别高于A组、B组、C组,具有显著性差异(P<0.05)。
结论：1.低氧暴露或运动促进胸腺组织浆液胸腺素和CD30的含量升高,但低氧暴露后运动双重刺激下其含量没有变化。
2.低氧暴露或低氧暴露后运动诱导胸腺组织凋亡,凋亡多发生在皮质和髓质,胸腺小体少见,且低氧暴露8h作为应激原作用强度较缓和。
3.低氧暴露后运动诱导胸腺凋亡因子Bax、bcl-2蛋白表达以及Bax/bcl-2比值均升高,且mRNA与蛋白的表达一致。
4.低氧暴露后运动诱导HIF-la的蛋白表达升高,但mRNA的表达与蛋白表达不一致。
5.Bax与bcl-2参与胸腺细胞凋亡的调控,且HIF-la可能协同bcl-2家族参与凋亡调控。随着低氧时间的延长,促凋亡因子Bax的表达加速,加快胸腺细胞凋亡。
Objective:By using of different duration of hypoxia training model,Effect of the different duration exercise under the condition to hypoxia of rat thymus cells in morphology, the number of apoptotic cells, thymus cells hypoxia inducible factor (Hypoxia Induced Factor-la, HIF-la) changes in apoptosis pathway-related factor bcl-2, Bax protein and mRNA expression, hypoxia of different duration exercise on thymocyte apoptosis and its mechanism.
Methods:60 SD rats were randomly divided into 6 groups of 10 each, namely:control group (A), hypoxia 8h group (B), hypoxic 12h group (C), regular aerobic exercise group (D), hypoxia 8h exercise group (E) and 12h hypoxia exercise group (F).D, E, F group every day in the animal gradient of 0 to 25m/min speed treadmill exercise 1h. After exercise, the B, E group and C,F group in turn into the oxygen concentration of 12.5%(equivalent to an altitude 4000 m) in the hypoxic chamber 8h and 12h. Lasted 4 weeks,5 days a week. The last 24 hours after the end of the experiment, rats were anesthetized intraperitoneally implementation, the ideal of whole blood taken after the eyeball were executed, and thymus tissue preparation of paraffin sections of thymus tissue, HE staining of thymus cell morphological changes; TUNEL labeling of thymus tissue were observed in the light of apoptosis index; immune staining of rat thymus cells HIF-la, B-cell lymphoma/ leukemia oncogene-2 (B cell lymphoma/leukemia 2,Bcl-2),Bax (Bel-2 associated x,Bax) factors of the protein;RT-PCR detection of rat thymus cells in HIF-la, Bcl-2, Bax in the mRNA level.
Results:(1)Tissue thymosin, CD30 content:thymosin, CD30 content of A,B group,C group were compared among the three groups showed significant differences (p<0.05),group A pairwise comparison of thymus.
(2) Thymus tissue in the HE staining:A group of thymus tissue structural integrity, membrane integrity, the nucleus is relatively large. Medulla and the cortex and there were no specific changes;B group than the A group of thymus cells in the thymus cells had no significant changes in the cortex when a small number of exfoliated cells;C group thymic corpuscles swelling, some edge off, shedding more visible in the cortex cells;D group significantly expanded thymic corpuscles, flat cells, cell gap increases;E group than the D group of thymic corpuscles scope and extent of degeneration were significantly smaller than and light in the D group, thymic corpuscles mild swelling; F Thymus edema and degeneration of cells to the cortex serious, can be seen in the cortex of the small number of exfoliated cells.
(3) TUNEL staining:positive granules in apoptosis of thymocytes in medulla more, few parts of the cortex.Image analysis showed that the E group, F group, D group compared among the three groups, showing significant difference (p<0.05), the expression of any two F groups were higher than D group and E group, E group was higher than D group, with significant difference (p<0.05);D group, E group, F group were higher than the positive group A,B group,C group,with significant difference (P<0.05).
(4)Immunohistochemical staining of rat thymus tissue HIF-la protein expression displayed:HIF-la immunohistochemical positive signal in the cytoplasm, which showed diffuse or granular distribution in the cortical part of the nucleus occasionally. Statistical analysis showed that:A group,B group,C group compared among the three groups, with significant difference (p<0.05),22 compared the expression of B group and C group were higher than A group were significant difference (p<0.05);E group,F group,D group compared three groups with significant difference (p<0.05);22 more F group was higher than D group and E group,E group than in D group,were significant differences (p<0.05);D group,E group,F group were higher than the positive group A, B group, C group, with significant difference (P<0.05).
(5)Immunohistochemical staining of rat thymus tissue Bcl-2, Bax expression showed positive, bcl-2, Bax immunohistochemistry positive signal in the cytoplasm,occasionally in the nucleus. Statistical analysis: Bcl-2, bax expression showed positive group A,B group,C group compared among the three groups,with significant difference (p<0.05), Comparison of expression were lower than the B group group and C group,C group was higher than B group,with significant difference (p<0.05);D group,E group,F group were higher than the positive group A,B group,C group,with significant difference (P<0.05).
(6)Thymus tissue apoptosis of rat and Bax,Bax/bcl-2 the correlation ratio and the HIF-1a and Bax expression show:rat thymus tissue cell apoptosis and Bax,Bax/Bcl-2 There was a positive correlation between the ratio (p<0.05);thymus cells HIF-1a protein expression and positive correlation between Bax (P<0.05).
(7) RT-PCR detection of mRNA expression:Bcl-2,bax mRNA expression of A group, B group, C group compared among the three groups,with significant difference (p<0.05),A group of mRNA expression compared lower than the B group and C group, C group was higher than B group,with significant difference (p<0.05);D group, E group, F group mRNA expression were higher than A,B group, C group,significant differences (P<0.05);HIF-la mRNA expression of A group, B group, C group compared among the three groups, with significant difference (p<0.05), compared the expression of B group and C group were higher than group A comparison, there were significant differences (p<0.05);D group, E group, F group were higher than the mRNA expression of A group, B group, C group, with significant difference (P<0.05).
Conclusion:
1.Hypoxic exposure on exercise for thymosin thymus size and CD30 levels increased, but when the duration of hypoxia, the content does not rise instead of decrease.
2.Hypoxic and/or exercise induced thymus apoptosis, more than in medulla, cortex rare, and the original role of hypoxia as a stress intensity 8h modest.
3.Hypoxic and/or exercise induced thymic apoptosis factor Bax, bcl-2 protein expression, and mRNA and protein expression of the same.
4. Hypoxic and/or exercise induced HIF-la protein expression increased, but mRNA and protein expression of inconsistency.
5.Bax and bcl-2 apoptosis of thymus cells, and HIF-la may be synergistic bcl-2 family involved in apoptosis regulation. As the hypoxia time,the expression of pro-apoptotic factor Bax to accelerate, accelerate thymocyte apoptosis.
引文
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