外源性糖皮质激素诱导的大鼠垂体前叶细胞凋亡和中药干预作用的实验研究
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摘要
一、背景和目的
糖皮质激素(Glucocorticoid, GC)是肾上腺皮质激素的一种,由束状带合成和分泌,具有重要的生理学意义。目前,GC已经成为临床各科室广泛应用的药物,具有抗炎、抗过敏、抗休克、免疫抑制等药理作用。但长期大量系统应用GC会产生严重的不良反应,诸如感染(病毒、细菌、真菌等)、消化道溃疡或穿孔、皮质功能亢进或减退、电解质紊乱、骨质疏松或缺血性骨坏死、以及对神经精神的影响等,还可加重原有的糖尿病、高血压等,不适当的停药或减量还可引起病情反跳。近年来,在深入研究GC作用机理的同时对减轻其副作用的措施也进行了一系列卓有成效的研究。目前的共识：GC的释放受到下丘脑-垂体-肾上腺轴(Hypothalamic-Pituitary-Adrenal axis, HPAA)的调控,它又对此神经内分泌环施行强烈的负反馈作用。GC负反馈作用基本位点除了下丘脑和海马结构外,主要就是垂体前叶的促肾上腺皮质激素(Adrenocorticotrophic Hormone, ACTH)细胞。用下丘脑室旁核分泌的促肾上腺皮质激素释放激素(Corticotropin Release Hormone,CRH)刺激这些细胞导致ACTH的释放,ACTH是肾上腺皮质合成和释放GC的主要刺激物。GC对于ACTH细胞功能的负反馈作用发生在几个水平上,最具特征性的是对ACTH的合成和释放以及CRH受体的表达。任何剂量的GC如果抑制了CRH和ACTH的分泌,且在用药期内这种抑制没有被恢复,均会产生中心性肾上腺分泌不足,久而久之会引起外周肾上腺的萎缩。GC长期治疗后的停药,无论在人还是鼠上均出现了HPAA对内源性或者外源性刺激的反应功能降低,这种功能变化反映在HPAA的各层次器官上。有人将鼠肾上腺切除后2周,给予持续的地塞米松导致了鼠垂体前叶细胞非常显著的凋亡活动,同时有丝分裂活动被抑制。尽管不可能知道是垂体的哪一类细胞减少,但已经提示总的垂体细胞减少到2周前基础水平以下。LA Nolan等人认为,GC停药伴随着短时或长时的HPAA的分泌能力的损伤。这种垂体前叶对GC的反应在鼠上包括了凋亡介导的细胞数量减少、被损伤细胞的恢复、未定型的前体细胞分化及其他类型分泌细胞的转化。这预示着,如果有足够的时间垂体前叶细胞完全恢复是可能的。
中医认为,“肾”的功能涉及到垂体-肾上腺皮质系统,HPAA是中西医结合肾本质研究的一个焦点。近年来国内外对肾虚本质和补肾药作用机理的探讨取得了多方面的进展。广泛涉及内分泌系统、免疫系统和基础代谢等方面。临床上用补肾方药治疗肾虚病人长能调节阴阳、改善症状恢复健康。补肾中药与GC合用,可减轻或消除长期应用GC所致的脑垂体前叶细胞的形态改变。中医辨证论治的目的在于肾阴阳平衡上着手调整,使HPAA功能得以恢复。张景岳创制的右归丸常被作为“阴中求阳”的代表方,它选用大量补阴药填补命门真阴,以治命门火衰,用少量补阳药温阳化气、直接温补肾阳。罗汉文等报道,右归丸可以提高血中可的松浓度,使垂体ACTH细胞数高于对照组。
基于上述的理论依据,本实验选用右归丸作为GC导致HPAA功能抑制的保护性药物,探讨其作用机理可能与减轻GC诱导的垂体前叶细胞凋亡有关。
二、方法
通过外源性给予糖皮质激素建立大鼠肾阳虚模型,即糖皮质激素副作用动物模型,进行体内实验；利用原代培养的垂体前叶细胞进行体外实验；按照随机对照的原则分组；应用免疫组织化学染色、TUNEL染色、Real-Time qPCR及流式细胞技术检测各组垂体前叶细胞的凋亡量、凋亡相关蛋白的表达以及线粒体膜电位的变化；方差分析比较各组的差异,得出结论。
三、结果
体内实验和体外实验均得出地塞米松加右归丸组的凋亡细胞数明显少于地塞米松组(P<0.05)；凋亡促进蛋白及其mRNA的表达在地塞米松加右归丸组明显少于地塞米松组(P<0.05),而抗凋亡蛋白及其mRNA在地塞米松组的表达高于地塞米松组(P<0.05)；线粒体膜电位下降的细胞数在地塞米松加右归丸组明显少于地塞米松组(P<0.05)。
四、结论
本实验通过大鼠体内和体外两方面的研究,结合当前的理论基础我们可以得出结论：中药右归丸可以减轻糖皮质激素诱导的大鼠垂体前叶细胞的凋亡；其机制可能是参与了凋亡的线粒体途径,正向调节凋亡抑制蛋白而反向作用于促凋亡蛋白。本研究为中药右归丸治疗糖皮质激素所导致的HPAA抑制提供了理论基础。
Background and Object
Glucocorticoids (GC) is a kind of adrenal cortex hormones synthesized and secreted by fascicular zone, and it has physiological significance. At present, GC has been widely used clinically, and has anti-inflammatory, anti-allergic, anti-shock, immune suppression and other pharmacological effects. But long-term GC systemic application will cause a large number of serious adverse reactions, such as infection (viruses, bacteria, fungi, etc.), gastrointestinal ulceration or perforation, adrenocortical hyperfunction or insufficiency, electrolyte disturbance, osteoporosis or ischemic bone necrosis, as well as neuropsychiatric impact, but also aggravate the existing diabetes, high blood pressure. Inappropriate withdrawal or reduction of GC can also cause disease to rebound. The current consensus:release of GC regulated by the hypothalamus-pituitary-adrenal axis (HPAA), it has a strong negative feedback action on the neuroendocrine loop, mainly on anterior pituitary adrenocorticotropic hormone (ACTH) cell except for the hypothalamus and hippocampus structures. The corticotrophin releasing hormone (CRH) secreted by hypothalamic paraventricular nucleus can stimulate this cells to release ACTH, which is the main stimulus for GC. If any dose of GC inhibited the secretion of CRH and ACTH, and such a suppression has not been restored in the period of treatment, it will cause lack of central adrenal gland hormone and shrinkage of the peripheral adrenal. GC withdrawal after long-term treatment can reduce the HPAA reaction to endogenous or exogenous stimuli both in people and mice. This functional change reflects in the various levels of organs on the HPAA. Some people given rats dexamethasone sustainedly on 2 weeks after adrenalectomy, which resulted in very significant apoptotic activity in anterior pituitary cells, meanwhile mitotic activity was inhibited. While it is impossible to know what kind of pituitary cells decreased. but the total pituitary cells has been suggested that reduced to a level below the base at two weeks ago. LA Nolan believed GC withdrawal is accompanied by short-or long-term secretion damage of HPAA capacity. This anterior pituitary reaction maybe caused by cell-mediated apoptosis, damaged cells restoration, undifferentiated precursor cell differentiation and transformation of other types of secretory cells. This indicated that if there is sufficient time, full restoration of anterior pituitary cells is possible.
Traditional Chinese medicine (TCM) believes that "kidney" function related to the pituitary-adrenal cortex system. HPAA is a research focus on the nature of kidney of combination of Chinese and Western medicine. Clinical use of TCM of tonifying kidney to treat kidney deficiency can regulate yin and yang, improve the symptoms and return to be healthy. TCM of tonifying kidney combined with the GC can reduce or eliminate the morphological changes of the brain anterior pituitary cells induced by long-term application of GC. At home and abroad, the nature of kidney deficiency and mechanism of TCM of tonifying have been made progress in many aspects in recent years, which concerned extensively the endocrine system, immune system, basic metabolism and so on. The purpose of TCM treatment based on syndrome differentiation is to begin to adjust the balance of kidney yin and yang, so that the HPAA function can be resumed. The Yougui Pill created by Zhang Jingyue is a typical "nourishing yin and tonifying yang" representative, which use a large number of tonifying yang tonic drugs to cure decline of vital gate fire, and use a small amount of warm yang and promote qi transformation drugs directly to warm and supplement kidney yang. Luo Hanwen et al. reported, Yougui Pill can increase the blood concentrations of cortisone, and the number of pituitary ACTH cells were more than control group.
Therefore, based on the above theories, we choice Yougui Pill as protective drugs to cure HPAA disfunction experiment induced by GC, and explore its mechanism that may be related to reducing apoptosis of anterior pituitary cells.
Methods
Given rat exogenous glucocorticoid to build deficiency of kidney yang model, that is, animal model of glucocorticoid side effects, used as experiments in vivo, and primary cultured anterior pituitary cells used as experiments in vitro; in accordance with the principles of randomized controlled to group; application of Immunohistochemistry staining, TUNEL staining, Real-Time qPCR and flow cytometry to detect apoptosis in anterior pituitary cells in each group and the expression of apoptosis-related proteins, as well as changes in mitochondrial membrane potential; variance analysis to compare the differences in each group and draw the conclusion.
Results
In vivo and in vitro experiments, the number of apoptotic cells in dexamethasone plus Yougui pill group was less than that in dexamethasone group (P＜0.05); apoptosis promoting protein and its mRNA expressions in dexamethasone plus Yougui pill group were significantly less than dexamethasone group (P＜0.05), while the anti-apoptotic protein and its mRNA expressions in dexamethasone plus Yougui pill group were significantly hihger than dexamethasone group(P＜0.05); the number of mitochondrial membrane potential decline cells in dexamethasone plus Yougui pill group was significantly less than dexamethasone group (P＜0.05).
Conclusion
Through the results of this study combined with the current theoretical basis, we can conclude:Traditional Chinese medicine Yougui pill can reduce the glucocorticoid-induced apoptosis in rat anterior pituitary cells. Its mechanism may be involved in the mitochondrial pathway of apoptosis, positive regulation of apoptosis inhibitory protein and reverse effect on pro-apoptotic protein. This study provides a theoretical basis for using Yougui pill to treat the suppression of HPAA caused by exogenous glucocorticoid.
糖皮质激素(Glucocorticoid, GC)是肾上腺皮质激素的一种,由束状带合成和分泌,具有重要的生理学意义。目前,GC已经成为临床各科室广泛应用的药物,具有抗炎、抗过敏、抗休克、免疫抑制等药理作用。但长期大量系统应用GC会产生严重的不良反应,诸如感染(病毒、细菌、真菌等)、消化道溃疡或穿孔、皮质功能亢进或减退、电解质紊乱、骨质疏松或缺血性骨坏死、以及对神经精神的影响等,还可加重原有的糖尿病、高血压等,不适当的停药或减量还可引起病情反跳。近年来,在深入研究GC作用机理的同时对减轻其副作用的措施也进行了一系列卓有成效的研究。目前的共识：GC的释放受到下丘脑-垂体-肾上腺轴(Hypothalamic-Pituitary-Adrenal axis, HPAA)的调控,它又对此神经内分泌环施行强烈的负反馈作用。GC负反馈作用基本位点除了下丘脑和海马结构外,主要就是垂体前叶的促肾上腺皮质激素(Adrenocorticotrophic Hormone, ACTH)细胞。用下丘脑室旁核分泌的促肾上腺皮质激素释放激素(Corticotropin Release Hormone,CRH)刺激这些细胞导致ACTH的释放,ACTH是肾上腺皮质合成和释放GC的主要刺激物。GC对于ACTH细胞功能的负反馈作用发生在几个水平上,最具特征性的是对ACTH的合成和释放以及CRH受体的表达。任何剂量的GC如果抑制了CRH和ACTH的分泌,且在用药期内这种抑制没有被恢复,均会产生中心性肾上腺分泌不足,久而久之会引起外周肾上腺的萎缩。GC长期治疗后的停药,无论在人还是鼠上均出现了HPAA对内源性或者外源性刺激的反应功能降低,这种功能变化反映在HPAA的各层次器官上。有人将鼠肾上腺切除后2周,给予持续的地塞米松导致了鼠垂体前叶细胞非常显著的凋亡活动,同时有丝分裂活动被抑制。尽管不可能知道是垂体的哪一类细胞减少,但已经提示总的垂体细胞减少到2周前基础水平以下。LA Nolan等人认为,GC停药伴随着短时或长时的HPAA的分泌能力的损伤。这种垂体前叶对GC的反应在鼠上包括了凋亡介导的细胞数量减少、被损伤细胞的恢复、未定型的前体细胞分化及其他类型分泌细胞的转化。这预示着,如果有足够的时间垂体前叶细胞完全恢复是可能的。
中医认为,“肾”的功能涉及到垂体-肾上腺皮质系统,HPAA是中西医结合肾本质研究的一个焦点。近年来国内外对肾虚本质和补肾药作用机理的探讨取得了多方面的进展。广泛涉及内分泌系统、免疫系统和基础代谢等方面。临床上用补肾方药治疗肾虚病人长能调节阴阳、改善症状恢复健康。补肾中药与GC合用,可减轻或消除长期应用GC所致的脑垂体前叶细胞的形态改变。中医辨证论治的目的在于肾阴阳平衡上着手调整,使HPAA功能得以恢复。张景岳创制的右归丸常被作为“阴中求阳”的代表方,它选用大量补阴药填补命门真阴,以治命门火衰,用少量补阳药温阳化气、直接温补肾阳。罗汉文等报道,右归丸可以提高血中可的松浓度,使垂体ACTH细胞数高于对照组。
基于上述的理论依据,本实验选用右归丸作为GC导致HPAA功能抑制的保护性药物,探讨其作用机理可能与减轻GC诱导的垂体前叶细胞凋亡有关。
二、方法
通过外源性给予糖皮质激素建立大鼠肾阳虚模型,即糖皮质激素副作用动物模型,进行体内实验；利用原代培养的垂体前叶细胞进行体外实验；按照随机对照的原则分组；应用免疫组织化学染色、TUNEL染色、Real-Time qPCR及流式细胞技术检测各组垂体前叶细胞的凋亡量、凋亡相关蛋白的表达以及线粒体膜电位的变化；方差分析比较各组的差异,得出结论。
三、结果
体内实验和体外实验均得出地塞米松加右归丸组的凋亡细胞数明显少于地塞米松组(P<0.05)；凋亡促进蛋白及其mRNA的表达在地塞米松加右归丸组明显少于地塞米松组(P<0.05),而抗凋亡蛋白及其mRNA在地塞米松组的表达高于地塞米松组(P<0.05)；线粒体膜电位下降的细胞数在地塞米松加右归丸组明显少于地塞米松组(P<0.05)。
四、结论
本实验通过大鼠体内和体外两方面的研究,结合当前的理论基础我们可以得出结论：中药右归丸可以减轻糖皮质激素诱导的大鼠垂体前叶细胞的凋亡；其机制可能是参与了凋亡的线粒体途径,正向调节凋亡抑制蛋白而反向作用于促凋亡蛋白。本研究为中药右归丸治疗糖皮质激素所导致的HPAA抑制提供了理论基础。
Background and Object
Glucocorticoids (GC) is a kind of adrenal cortex hormones synthesized and secreted by fascicular zone, and it has physiological significance. At present, GC has been widely used clinically, and has anti-inflammatory, anti-allergic, anti-shock, immune suppression and other pharmacological effects. But long-term GC systemic application will cause a large number of serious adverse reactions, such as infection (viruses, bacteria, fungi, etc.), gastrointestinal ulceration or perforation, adrenocortical hyperfunction or insufficiency, electrolyte disturbance, osteoporosis or ischemic bone necrosis, as well as neuropsychiatric impact, but also aggravate the existing diabetes, high blood pressure. Inappropriate withdrawal or reduction of GC can also cause disease to rebound. The current consensus:release of GC regulated by the hypothalamus-pituitary-adrenal axis (HPAA), it has a strong negative feedback action on the neuroendocrine loop, mainly on anterior pituitary adrenocorticotropic hormone (ACTH) cell except for the hypothalamus and hippocampus structures. The corticotrophin releasing hormone (CRH) secreted by hypothalamic paraventricular nucleus can stimulate this cells to release ACTH, which is the main stimulus for GC. If any dose of GC inhibited the secretion of CRH and ACTH, and such a suppression has not been restored in the period of treatment, it will cause lack of central adrenal gland hormone and shrinkage of the peripheral adrenal. GC withdrawal after long-term treatment can reduce the HPAA reaction to endogenous or exogenous stimuli both in people and mice. This functional change reflects in the various levels of organs on the HPAA. Some people given rats dexamethasone sustainedly on 2 weeks after adrenalectomy, which resulted in very significant apoptotic activity in anterior pituitary cells, meanwhile mitotic activity was inhibited. While it is impossible to know what kind of pituitary cells decreased. but the total pituitary cells has been suggested that reduced to a level below the base at two weeks ago. LA Nolan believed GC withdrawal is accompanied by short-or long-term secretion damage of HPAA capacity. This anterior pituitary reaction maybe caused by cell-mediated apoptosis, damaged cells restoration, undifferentiated precursor cell differentiation and transformation of other types of secretory cells. This indicated that if there is sufficient time, full restoration of anterior pituitary cells is possible.
Traditional Chinese medicine (TCM) believes that "kidney" function related to the pituitary-adrenal cortex system. HPAA is a research focus on the nature of kidney of combination of Chinese and Western medicine. Clinical use of TCM of tonifying kidney to treat kidney deficiency can regulate yin and yang, improve the symptoms and return to be healthy. TCM of tonifying kidney combined with the GC can reduce or eliminate the morphological changes of the brain anterior pituitary cells induced by long-term application of GC. At home and abroad, the nature of kidney deficiency and mechanism of TCM of tonifying have been made progress in many aspects in recent years, which concerned extensively the endocrine system, immune system, basic metabolism and so on. The purpose of TCM treatment based on syndrome differentiation is to begin to adjust the balance of kidney yin and yang, so that the HPAA function can be resumed. The Yougui Pill created by Zhang Jingyue is a typical "nourishing yin and tonifying yang" representative, which use a large number of tonifying yang tonic drugs to cure decline of vital gate fire, and use a small amount of warm yang and promote qi transformation drugs directly to warm and supplement kidney yang. Luo Hanwen et al. reported, Yougui Pill can increase the blood concentrations of cortisone, and the number of pituitary ACTH cells were more than control group.
Therefore, based on the above theories, we choice Yougui Pill as protective drugs to cure HPAA disfunction experiment induced by GC, and explore its mechanism that may be related to reducing apoptosis of anterior pituitary cells.
Methods
Given rat exogenous glucocorticoid to build deficiency of kidney yang model, that is, animal model of glucocorticoid side effects, used as experiments in vivo, and primary cultured anterior pituitary cells used as experiments in vitro; in accordance with the principles of randomized controlled to group; application of Immunohistochemistry staining, TUNEL staining, Real-Time qPCR and flow cytometry to detect apoptosis in anterior pituitary cells in each group and the expression of apoptosis-related proteins, as well as changes in mitochondrial membrane potential; variance analysis to compare the differences in each group and draw the conclusion.
Results
In vivo and in vitro experiments, the number of apoptotic cells in dexamethasone plus Yougui pill group was less than that in dexamethasone group (P＜0.05); apoptosis promoting protein and its mRNA expressions in dexamethasone plus Yougui pill group were significantly less than dexamethasone group (P＜0.05), while the anti-apoptotic protein and its mRNA expressions in dexamethasone plus Yougui pill group were significantly hihger than dexamethasone group(P＜0.05); the number of mitochondrial membrane potential decline cells in dexamethasone plus Yougui pill group was significantly less than dexamethasone group (P＜0.05).
Conclusion
Through the results of this study combined with the current theoretical basis, we can conclude:Traditional Chinese medicine Yougui pill can reduce the glucocorticoid-induced apoptosis in rat anterior pituitary cells. Its mechanism may be involved in the mitochondrial pathway of apoptosis, positive regulation of apoptosis inhibitory protein and reverse effect on pro-apoptotic protein. This study provides a theoretical basis for using Yougui pill to treat the suppression of HPAA caused by exogenous glucocorticoid.
引文
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