大黄素对人增生性瘢痕成纤维细胞作用的实验研究
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摘要
增生性瘢痕(hypertrophic scar,HS)是医学界尚未解决的难题之一,其本质是成纤维细胞的异常增殖和细胞外基质的过度沉积,是一种常见的病理性愈合现象。增生性瘢痕往往破坏了组织器官的正常解剖结构,给创伤后的功能恢复和重建带来很大障碍。尽管对增生性瘢痕的发病机制和治疗手段进行了大量的研究,但目前目前仍没有理想的结果。增生性瘢痕成纤维细胞(hypertrophic scar fibroblasts,HSFb)是产生瘢痕的主要细胞。大黄素(Emodin)具有广泛的药理作用,包括抑制器官纤维化、抗肿瘤、抗炎等。本实验对体外培养的HSFb进行了以下实验内容,深入研究Emodin对HSFb的抑制作用,以探讨Emodin对HS的作用方式和机制,为临床治疗HS提供理论依据。
方法:
分离培养HSFb,取4～6代细胞,实验组Emodin终浓度为20μg/ml、40μg/ml、60μg/ml,对照组选择完全培养基处理,观察药物对细胞的影响。
检测指标:
1.MTT法检测细胞增殖活力的变化;
2.流式细胞仪检测细胞周期的变化及各时相所占的比例;
3.流式细胞仪检测细胞凋亡情况;
4.激光共聚焦法检测细胞内[Ca~(2+)]浓度的变化及释放情况;
5.~3H-脯氨酸掺入法检测细胞胶原蛋白的合成;
6.RT-PCR方法检测Ⅰ型胶原mRNA的表达水平;
7.免疫细胞化学方法检测转化生长因子-β1(transforming growth factor-β1,TGF-β1)的表达;
8.免疫细胞化学方法检测α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)的表达。
结果:
1.MTT比色结果显示Emodin作用后HSFb的增殖呈现出明显的抑制趋势,且和药物浓度呈相关性。
2.Emodin作用后,HSFb细胞G0/G1期百分比增加,而S期和G2/M期百分比则减少,从而阻滞细胞进入S期,使DNA合成受阻。
3.Emodin处理后细胞凋亡率增加,和对照组相比有统计学差异。
4.Emodin作用后,HSFb胞内钙库大量释放[Ca~(2+)],形成胞浆钙超载现象,从而抑制HSFb的增殖并促进细胞凋亡。
5.Emodin作用后HSFb的胶原合成率减少,并且呈现出明显的时间-效应依赖性。
6.Emodin降低HSFb中的Ⅰ型胶原mRNA的转录水平。
7.Emodin抑制HSFb中TGF-β_1的表达:图形分析软件分析结果表明,和对照组相比,干预组TGF-β_1表达下降。
8.Emodin抑制HSF b中α-SMA的表达:图形分析软件分析结果表明,和对照组相比,干预组α-SMA表达下降。
结论:
1.Emodin阻滞细胞周期与G0/G1期,抑制细胞增殖,并且促进细胞凋亡,这种改变细胞增殖/凋亡的机制可能与细胞内[Ca~(2+)]超载有关;
2.Emodin可以改变细胞外胶原合成/降解功能的比例,减少细胞外胶原的堆积,并可以在mRNA转录水平抑制Ⅰ型胶原的表达;
3.Emodin下调细胞中TGF-β1和α-SMA的表达。
Hypertrophic scar(HS) is one of the major unsettled clinical problems that due to abnormal proliferation of fibroblast and excessive deposition of extracellular matrix.The scars most commonly occur when epithelialization has been delayed during,foe example, the healing of deep dermal burn wounds.The HS are thick and raised and often darker in color than surrounding skin,moreover,that are frequently associated with pruritus and pain. Therefore,it is significant that exploring the mechanism of HS formation to look for effective prevention and treatment.Many published reports documented the mechanism and advocated a variety of therapies;however,few studies provide a coherent therapeutic plan. Applying traditional Chinese physician to occur the HS is the idea treatment method because of lots of advantages,e.g.extensive resources,cheap price,widely clinical application and light adverse effect.Emodin(3-methyl-1,6,8-carboxyl-anthraquinone) is derivate of hydroxyanthraquinone and an effective component isolated from many kinds of herbs.Generous studies prove that emodin has various biological effects in inhibiting tumor cells and smoothing muscle cells proliferation,influencing the infammatory cytokines secretion of monocyte.Thus,we design the experiment to observe effect of emodin on HS to exploring the effective treatment method of HS and provide the theoretical foundation of clinical medicine.
Method:HS fibroblasts were isolated and cultured by routine method.The 4-6 generation cells could be used.The final concentrations of emodin for experimental group were:20ug/ml,40 ug/ml and 60 ug/ml.
Detecting indexes:
1.Detecting the improves of cell proliferation using the method of MTT.
2.FACS detecting the changes of cell cycle.
3.FACS checked the condition of apoptosis.
4.Laser focusing detected the ion concentration of intracellular Ca~(2+) and the liberation.
5.~3 H-TdR detected the synthesis of collagen protein.
6.RT-PCR to checked the transcription of mRNA ofⅠtype collagen.
7.Immunohistochemistry detected TGF-β_1
8.Immunohistochemistry detectedα-smooth muscle actin.
Result:
1.The result of MTT showed that the proliferative tendency of experimental HSFb presented inhibited correlating with does of medicine
2.By administration of emodin,the detection of cell cycle showed that:the percentage of G0/G1 was increased while the percentage of S phase and G2/M was decreased.The result demonstrated that emodin could block the cells enter into phase S and hindered the DNA synthesis.
3.By administration of emodin,the percentage of apoptosis was increased in dose of emodin dependent way.
4.By administration of emodin,The intracellular Ca~(2+) of HSFb were released from the calcium library to inhibit HSFb proliferation.
5.The decreased collagen synthesis of experimental HSFb with the relationship with the time.
6.Emodin could inhibit the transcription of mRNA ofⅠtype collagen.
7.Emodin could inhibit the TGF-β1 expression of HSFb.
8.Emodin could inhibit theα-SMA expression of HSFb.
Conclusion:
To detect different indexes of HSFb by administration of emodin,we proved that emodin could significantly inhibit HSFb proliferation.The mechanism maybe including: changing the morphous of cells,blocking of DNA synthesize,enhancing release of intracellular Ca~(2+),inhibiting synthesis of collagen protein,promoting HSFb apoptosis and inhibiting the expression of TGF-β1,α-SMA.
方法:
分离培养HSFb,取4～6代细胞,实验组Emodin终浓度为20μg/ml、40μg/ml、60μg/ml,对照组选择完全培养基处理,观察药物对细胞的影响。
检测指标:
1.MTT法检测细胞增殖活力的变化;
2.流式细胞仪检测细胞周期的变化及各时相所占的比例;
3.流式细胞仪检测细胞凋亡情况;
4.激光共聚焦法检测细胞内[Ca~(2+)]浓度的变化及释放情况;
5.~3H-脯氨酸掺入法检测细胞胶原蛋白的合成;
6.RT-PCR方法检测Ⅰ型胶原mRNA的表达水平;
7.免疫细胞化学方法检测转化生长因子-β1(transforming growth factor-β1,TGF-β1)的表达;
8.免疫细胞化学方法检测α-平滑肌肌动蛋白(α-smooth muscle actin,α-SMA)的表达。
结果:
1.MTT比色结果显示Emodin作用后HSFb的增殖呈现出明显的抑制趋势,且和药物浓度呈相关性。
2.Emodin作用后,HSFb细胞G0/G1期百分比增加,而S期和G2/M期百分比则减少,从而阻滞细胞进入S期,使DNA合成受阻。
3.Emodin处理后细胞凋亡率增加,和对照组相比有统计学差异。
4.Emodin作用后,HSFb胞内钙库大量释放[Ca~(2+)],形成胞浆钙超载现象,从而抑制HSFb的增殖并促进细胞凋亡。
5.Emodin作用后HSFb的胶原合成率减少,并且呈现出明显的时间-效应依赖性。
6.Emodin降低HSFb中的Ⅰ型胶原mRNA的转录水平。
7.Emodin抑制HSFb中TGF-β_1的表达:图形分析软件分析结果表明,和对照组相比,干预组TGF-β_1表达下降。
8.Emodin抑制HSF b中α-SMA的表达:图形分析软件分析结果表明,和对照组相比,干预组α-SMA表达下降。
结论:
1.Emodin阻滞细胞周期与G0/G1期,抑制细胞增殖,并且促进细胞凋亡,这种改变细胞增殖/凋亡的机制可能与细胞内[Ca~(2+)]超载有关;
2.Emodin可以改变细胞外胶原合成/降解功能的比例,减少细胞外胶原的堆积,并可以在mRNA转录水平抑制Ⅰ型胶原的表达;
3.Emodin下调细胞中TGF-β1和α-SMA的表达。
Hypertrophic scar(HS) is one of the major unsettled clinical problems that due to abnormal proliferation of fibroblast and excessive deposition of extracellular matrix.The scars most commonly occur when epithelialization has been delayed during,foe example, the healing of deep dermal burn wounds.The HS are thick and raised and often darker in color than surrounding skin,moreover,that are frequently associated with pruritus and pain. Therefore,it is significant that exploring the mechanism of HS formation to look for effective prevention and treatment.Many published reports documented the mechanism and advocated a variety of therapies;however,few studies provide a coherent therapeutic plan. Applying traditional Chinese physician to occur the HS is the idea treatment method because of lots of advantages,e.g.extensive resources,cheap price,widely clinical application and light adverse effect.Emodin(3-methyl-1,6,8-carboxyl-anthraquinone) is derivate of hydroxyanthraquinone and an effective component isolated from many kinds of herbs.Generous studies prove that emodin has various biological effects in inhibiting tumor cells and smoothing muscle cells proliferation,influencing the infammatory cytokines secretion of monocyte.Thus,we design the experiment to observe effect of emodin on HS to exploring the effective treatment method of HS and provide the theoretical foundation of clinical medicine.
Method:HS fibroblasts were isolated and cultured by routine method.The 4-6 generation cells could be used.The final concentrations of emodin for experimental group were:20ug/ml,40 ug/ml and 60 ug/ml.
Detecting indexes:
1.Detecting the improves of cell proliferation using the method of MTT.
2.FACS detecting the changes of cell cycle.
3.FACS checked the condition of apoptosis.
4.Laser focusing detected the ion concentration of intracellular Ca~(2+) and the liberation.
5.~3 H-TdR detected the synthesis of collagen protein.
6.RT-PCR to checked the transcription of mRNA ofⅠtype collagen.
7.Immunohistochemistry detected TGF-β_1
8.Immunohistochemistry detectedα-smooth muscle actin.
Result:
1.The result of MTT showed that the proliferative tendency of experimental HSFb presented inhibited correlating with does of medicine
2.By administration of emodin,the detection of cell cycle showed that:the percentage of G0/G1 was increased while the percentage of S phase and G2/M was decreased.The result demonstrated that emodin could block the cells enter into phase S and hindered the DNA synthesis.
3.By administration of emodin,the percentage of apoptosis was increased in dose of emodin dependent way.
4.By administration of emodin,The intracellular Ca~(2+) of HSFb were released from the calcium library to inhibit HSFb proliferation.
5.The decreased collagen synthesis of experimental HSFb with the relationship with the time.
6.Emodin could inhibit the transcription of mRNA ofⅠtype collagen.
7.Emodin could inhibit the TGF-β1 expression of HSFb.
8.Emodin could inhibit theα-SMA expression of HSFb.
Conclusion:
To detect different indexes of HSFb by administration of emodin,we proved that emodin could significantly inhibit HSFb proliferation.The mechanism maybe including: changing the morphous of cells,blocking of DNA synthesize,enhancing release of intracellular Ca~(2+),inhibiting synthesis of collagen protein,promoting HSFb apoptosis and inhibiting the expression of TGF-β1,α-SMA.
引文
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