银屑病与角朊细胞凋亡关系初探
摘要
细胞凋亡规律失常很可能是银屑病发生和发展的一个重要因素，但迄今还有不少问题悬而未决。本论文分五个章节报告了我们有关银屑病与角朊细胞凋亡关系的研究结果。第一章报告了银屑病皮损中凋亡角朊细胞的检测结果；第二章着重阐述了凋亡相关基因与银屑病细胞凋亡异常的关系与作用；第三章介绍了有关银屑病皮损中总的基因转录的情况；第四章阐述了角朊细胞终末分化酶——Ⅰ型转谷氨酰胺酶(TG Ⅰ)在银屑病异常终末分化和细胞凋亡中的作用；第五章则介绍了有关钙泊三醇对细胞凋亡的影响的研究结果。
一．采用末端脱氧核苷酰转移酶介导的dUTP缺口末端标记[Terminal deoxynucleotidyl transferase(TdT)-mediated dUTP-biotin nick end-labeling，TUNEL]技术，对36份寻常型银屑病各期皮损标本、4份红皮病型银屑病标本进行了凋亡细胞的原位检测，并与HE染色进行了对比研究。发现多数银屑病皮损表皮的基底上各层，存在着凋亡角朊细胞，在寻常型银屑病的静止期皮损和红皮病型皮损中尤为多见，提示银屑病皮损中角朊细胞的凋亡增加与银屑病的发病和发展很可能有关。
二．采用免疫组化方法(ABC法和LSAB法)和非同位素核酸原位杂交技术从蛋白和mRNA二个水平检测了原癌基因c-myc、c-fos、抑癌基因P53和凋亡保护基因bcl-2在银屑病皮损中的表达状况。结果发现，寻常型银屑病和红皮病型银屑病表皮中的细胞增殖核抗原(PCNA)、c-myc和P53阳性细胞数较正常皮肤明显增加。阳性细胞主要分布于棘层下部和基底层，而bcl-2阳性细胞在表皮基底层中明显减少。在PCNA阳性细胞数＞30的银屑病皮损中，有更多的c-myc阳性细胞(p＜0.001)、更多的P53阳性细胞(p＜0.001)，bcl-2的表达明显下降(p＜0.02)及更多的凋亡诱导(p＜0.01)。这些结果表明，c-myc、P53和bcl-2在银屑病的角朊细胞过度增殖和凋亡中均起着重要作用，c-myc、P53的表达上调和bcl-2的表达下调可能共同激活了角朊细胞的凋亡通路。从细胞凋亡的角度提出了银屑病可能的发病机理设想，认为细胞凋亡可能是针对细胞过度增殖的一种稳态机制，在银屑病表皮良性增生中起了积极作用，但也造成了银屑病时特有的病理生理状态，并椐此提出了银屑
Defective regulation of apoptosis may play an important role in the development of psoriasis, but quiet a few doubtful points remain to be solved and elucidated This dissertation is divided into 5 chapters to present our research reports on the relationship between psoriasis and the apoptosis of keratinocytes. The first chapter displays the morphological and biochemical findings in the psoriatic epidermis. The second chapter elucidates the study on the action of apoptosis-relared genes in defective regulation of apoptosis of the psoriatic lesions. The third chapter introduces the study on the total RNA level in psoriatic lesions of different stages. The fourth chapter elaborates the investigation on the epidermal transglutaminase (TG I)- an important enzyme of the terminal differentiation of keratinocytes and its effect on the apoptosis of keratinocytes. The fifth chapter expounds the effect of topical treatment with calcipotriol ointment on the abnormal apoptosis of psoriasis.
1. The apoptotic cell was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) technique and HE staining in 36 lesional skin samples from patients with psoriasis vulgaris and 4 from psoriatic erythroderma. A large number of keratinocytes showing morphological and biochemical features of cells undergoing apoptosis were observed in all the suprabasal layers of the psoriatic epidermis, especially in the lesions of quiescent and erythrodermic stages. It was suggested that the increased apoptosis of keratinocytes in the lesions of psoriasis may be likely to play some parts in the pathogenesis and development of psoriasis.
2. A total of 36 lesional skin samples from patients with psoriasis vulgaris and 4 from psoriatic erythroderma were stained immunohistochemically with monoclonal antibodies to c-myc, P53(DO7), bcl-2 and PCNA and with polyclonal antibody to c-fos. At the same time the mRNA
一．采用末端脱氧核苷酰转移酶介导的dUTP缺口末端标记[Terminal deoxynucleotidyl transferase(TdT)-mediated dUTP-biotin nick end-labeling，TUNEL]技术，对36份寻常型银屑病各期皮损标本、4份红皮病型银屑病标本进行了凋亡细胞的原位检测，并与HE染色进行了对比研究。发现多数银屑病皮损表皮的基底上各层，存在着凋亡角朊细胞，在寻常型银屑病的静止期皮损和红皮病型皮损中尤为多见，提示银屑病皮损中角朊细胞的凋亡增加与银屑病的发病和发展很可能有关。
二．采用免疫组化方法(ABC法和LSAB法)和非同位素核酸原位杂交技术从蛋白和mRNA二个水平检测了原癌基因c-myc、c-fos、抑癌基因P53和凋亡保护基因bcl-2在银屑病皮损中的表达状况。结果发现，寻常型银屑病和红皮病型银屑病表皮中的细胞增殖核抗原(PCNA)、c-myc和P53阳性细胞数较正常皮肤明显增加。阳性细胞主要分布于棘层下部和基底层，而bcl-2阳性细胞在表皮基底层中明显减少。在PCNA阳性细胞数＞30的银屑病皮损中，有更多的c-myc阳性细胞(p＜0.001)、更多的P53阳性细胞(p＜0.001)，bcl-2的表达明显下降(p＜0.02)及更多的凋亡诱导(p＜0.01)。这些结果表明，c-myc、P53和bcl-2在银屑病的角朊细胞过度增殖和凋亡中均起着重要作用，c-myc、P53的表达上调和bcl-2的表达下调可能共同激活了角朊细胞的凋亡通路。从细胞凋亡的角度提出了银屑病可能的发病机理设想，认为细胞凋亡可能是针对细胞过度增殖的一种稳态机制，在银屑病表皮良性增生中起了积极作用，但也造成了银屑病时特有的病理生理状态，并椐此提出了银屑
Defective regulation of apoptosis may play an important role in the development of psoriasis, but quiet a few doubtful points remain to be solved and elucidated This dissertation is divided into 5 chapters to present our research reports on the relationship between psoriasis and the apoptosis of keratinocytes. The first chapter displays the morphological and biochemical findings in the psoriatic epidermis. The second chapter elucidates the study on the action of apoptosis-relared genes in defective regulation of apoptosis of the psoriatic lesions. The third chapter introduces the study on the total RNA level in psoriatic lesions of different stages. The fourth chapter elaborates the investigation on the epidermal transglutaminase (TG I)- an important enzyme of the terminal differentiation of keratinocytes and its effect on the apoptosis of keratinocytes. The fifth chapter expounds the effect of topical treatment with calcipotriol ointment on the abnormal apoptosis of psoriasis.
1. The apoptotic cell was detected with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) technique and HE staining in 36 lesional skin samples from patients with psoriasis vulgaris and 4 from psoriatic erythroderma. A large number of keratinocytes showing morphological and biochemical features of cells undergoing apoptosis were observed in all the suprabasal layers of the psoriatic epidermis, especially in the lesions of quiescent and erythrodermic stages. It was suggested that the increased apoptosis of keratinocytes in the lesions of psoriasis may be likely to play some parts in the pathogenesis and development of psoriasis.
2. A total of 36 lesional skin samples from patients with psoriasis vulgaris and 4 from psoriatic erythroderma were stained immunohistochemically with monoclonal antibodies to c-myc, P53(DO7), bcl-2 and PCNA and with polyclonal antibody to c-fos. At the same time the mRNA
引文
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