摘要
目的探讨平阳霉素对婴幼儿血管瘤的作用机制。方法取24只裸鼠建立婴幼儿血管瘤模型，将裸鼠分为实验组和空白对照组，各12只。将平阳霉素注入实验组血管瘤内，观察其形态变化，采用普通光学和电子显微镜观察血管瘤组织结构的变化，然后利用cDNA基因芯片检测血管瘤组织基因表达谱的变化。结果血管瘤注药后体积逐渐缩小变硬，充血程度减轻，1个月后血管瘤体基本消失。光镜下观察见血管瘤失去组织结构，大部分细胞溶解坏死，大片的胶原纤维取而代之。电镜下观察见细胞大片溶解，未见完整的细胞结构及血管，可见凋亡细胞和凋亡小体。基因芯片研究结果表明，与空白对照组比较共有33个基因表达差异在2倍以上，其中9个与凋亡有关的基因，分别是鼠双微体2（murine doubleminute2，MDM2）、不耐热肠毒素B亚单位（heat—labile enterotoxin Bsubunit，LTB）、淋巴毒素B受体（1ymphotoxin B receptorLTBR）、肿瘤坏死因子超家族7（tumor necrosisfactor ligand superfamily7，TNFSF7）、肿瘤坏死因子受体超家族2l（tumornecrosis factor receptor superfamily21，TNFRSF21）、TNFRSFlA、人髓细胞白血病基因1（myeloidcellleukemia-1，MCLl）和半胱天冬酶3（caspase3，CASP3）。13个与细胞增殖和细胞周期相关基因，分别是细胞分裂周期蛋白27（celldivisioncycle27，CDC27）、CDC37、CDC28蛋白激酶1B（CDC28proteinkinase1B，CKSlB）、细胞周期蛋白B1（cyclingB1，CCNBl）、CUL2（cullin2）、CUL3（cullin3）、CUL4A（cullin4A）、生长抑制和DNA损伤诱导基因45A（growtharrestandDNAdamage—inducible45A，Gadd45A）、减数分裂重组11同源体B（meioticrecombination11homologB，MREllB）、叉头框M1（forkheadboxM1，FOXMl）、微型染色体7（minichromosomemaintenance7，MCM7）、单克隆抗体Ki一67抗原（antigenidentifiedbymonoclonalantibodyKi67，MKl67）和细胞增殖核抗原（proliferatingcellnuclearantigen，PCNA）。11个与细胞应激和毒性反应有关的基因分别是谷胱甘肽过氧化物酶1（glutathioneperoxidase1，GPXl）、金属硫蛋白1A（metallothionein，MTlA）、超氧化物歧化酶1（superoxidedismutase一1，SODl）、热休克蛋白A1A（heatshockproteinA1A，HSPAlA）、HSPA2、HSPA4、HSPA5、HSP9B、HSPCA、巨噬细胞游走抑制因子（macrophagemigrationinhibitoryfactor，MIF）和纤溶酶原激活物抑制因子1（plasnfinogenactivatorinhibitor，PAll）。结论平阳霉素治疗婴幼儿血管瘤是多因素、多水平综合作用的结果，平阳霉素能够作用于细胞DNA的多个片段，既能诱发细胞凋亡，抑制细胞的增殖，还能直接使细胞的应激与毒性反应能力降低，细胞毒性作用和诱导细胞凋亡是同一作用机制的两种表现形式，并非两种作用机制。
Objective To investigate the therapeutic mechanism of Bleomycin A 5 on infancy hemangioma. Methods After intralesional injection of Bleomycin A5 into the tumor of animal model of infancy hemangioma, the variation of tumor form was and the variation of tumor structure were observed using light microscope and electron microscope, the variation of tumoF gene expression spectrtt was also tested by DNA microarray technique. Results After treatment, the tumor gradually shrunk, hardened, disappeared one month later. The tumor lost appearance of infancy hemangioma and replaced by lamellar collagen fibers and cellular nucleus scattered in the fibers, and almost all cells were necrotic and dissolved. Under electron microscope, only large stretches of dissolved cell could be seen without intact cells and blood vessels, but apoptotie cells and bodies could also be found. The results of DNA microarray analysis showed that 9 genes associated with apoptosis （murine double minute 2, heat-labile enterotoxin B subunit, lymphotoxin B receptor, tumor necrosis factor ligand superfamily 7, tumor necrosis factor receptor superfamily 21, tumor necrosis factor receptor superfamily 1A, myeloid cell leukemia-l, caspase3 ）, 13 genes associated with cell proliferation and cell cycle（ cell division cycle27, cell division cycle37, CDC28 protein kinase 1B, cycling B1, cullin 2, eullin 3, cullin 4A, growth arrest and DNA damage- inducible 45A, meiotic recombination 11 homolog B, forkhead box M1, minichromosome maintenance7, antigen identified by monoclonal antibody ki 67, proliferating cell nuclear antigen ）, and 11 genes associated with cellular stress and toxic reaction （glutathione peroxidase 1, metallothioneins, uperoxide dismutase-1, heat shock protein A1A, heat shock protein A2, heat shock protein A4, heat shock protein A5, heat shock protein 9B, heat shock protein CA, maerophage migration inhibitory factor, plasminogen activator inhibitor）were up or down regulated more than 2 folds in tumors treated with Bleomcyin A5 compared with controls. Conclusions The therapeutic effect of Bleomycin A5 on infancy hemangioma is the synthetic results of multiple factors. Bleomycin A5 could not only induce apoptosis and inhibit cell proliferation, but also depressed the ability of cell stress and toxic reaction.
出处
《中华口腔医学杂志》
CAS
CSCD
北大核心
2013年第1期18-22,共5页
Chinese Journal of Stomatology
基金
国家自然科学基金（81172589）
陕西省自然科学基金（2006c255）
关键词
血管瘤
血管畸形
平阳霉素
Hemangioma
Vascular Malformations
Bleomycin A5
