摘要
目的:探讨磷脂酰肌醇3激酶/蛋白激酶B(PI3K/PKB或PI3K/AKT)信号通路抑制剂对前列腺增生的影响及机制。方法:选用鼠龄12周的雄性SD大鼠48只,随机分为4组:假手术对照组;BPH模型组;LY294002 50 mg组和LY294002 100 mg组,每组12只。大鼠去势后肌注丙酸睾酮10 mg/(kg.d)连续30 d建模,LY294002 50 mg组和100 mg组同时肌注LY294002 50 mg/kg和100 mg/kg,隔日1次。给药30 d后,切除各组大鼠前列腺组织,称取前列腺重量,切片观察前列腺组织细胞结构变化。免疫组化法检测K i-67、凋亡相关蛋白Bc l-2与Bax的表达情况;核酸末端原位标记法(TUNEL)检测细胞凋亡情况。结果:各组大鼠前列腺湿重(mg)和前列腺指数:假手术对照组:551±10.8,1.61±0.05;模型组:687±13.8,2.15±0.12;LY294002 50 mg组:623±23.5,1.95±0.11,与模型组相比,差异有显著性(P<0.05);LY294002 100 mg组:561±12.6,1.71±0.18,与模型组相比,差异具有极显著性(P<0.01)。凋亡相关蛋白Bax与Bc l-2的表达:假手术对照组:16.7%,16.7%;模型组:16.7%,58.3%;LY294002 50 mg组:33.3%,33.3%,与模型组相比,差异有显著性(P<0.05);LY294002 100 mg组:50.0%,25.0%,与模型组相比,差异极有显著性(P<0.01)。增殖和凋亡指数(%):假手术对照组:上皮组织14.2±6.4,6.5±1.8,间质组织7.6±2.6,2.5±0.3;模型组:上皮组织50.9±12.8,2.7±1.4,间质组织16.5±5.7,1.3±0.8;LY294002 50 mg组:上皮组织32.0±13.8,6.2±2.5,间质组织12.1±3.8,1.6±1.1;与模型组相比,差异有显著性(P<0.05);LY294002 100 mg组:上皮组织17.8±14.7,7.4±3.6,间质组织9.5±3.4,2.2±1.3;与模型组相比,差异有显著性(P<0.05)或极显著性(P<0.01)。结论:前列腺增生动物模型前列腺细胞增殖增加和凋亡的相对减少参与了BPH的发生发展过程。PI3K/AKT介导的信号通路在前列腺增生的发生发展过程中起重要作用,阻断PI3K/AKT信号通路具有抑制前列腺增生的作用。
Objective：To explore the effect of the phosphoinositide 3-kinase/protein kinase B（PI3K/PKB or PI3K/AKT） signaling pathway inhibitor on benign prostate hyperplasia（BPH） and its mechanism.Methods：Forty-eight SD male adult rats aged 12 weeks were equally randomized to 4 groups：sham operation control,BPH model,50 mg LY294002 and 100 mg LY294002.The BPH models were made by muscular injection of testosterone propionate at 10 mg/kg/d for 30 days following castration.The LY294002 groups were treated with the PI3K/AKT signaling pathway inhibitor LY294002 at 50 and 100 mg/kg every other day for 30 days.The prostates of the rats were weighed and the structural changes of the prostatic histocytes observed under the light microscope.The expressions of Ki-67,anti-apoptotic Bcl-2 and apoptotic Bax were detected by immunohistochemistry,and the apoptosis of prostatic cells determined by terminal de-oxynucleotidyl transferase-mediated dUTP nick end labeling.Results：The prostate wet weight and prostatic index were（551±10.8） mg and 1.61±0.05 in the sham operation group,（687±13.8） mg and 2.15±0.12 in the BPH model group,（623±23.5） mg and 1.95±0.11 in the LY294002 50 mg group（P〈0.05 versus the BPH models） and（561±12.6） mg and 1.71±0.18 in the LY294002 100 mg group（P〈0.01 versus the BPH models）.The expressions of apoptotic Bax and anti-apoptotic Bcl-2 were 16.7% and 16.7% in the sham operation group,16.7% and 58.3% in the BPH model group,33.3% and 33.3% in the LY294002 50 mg group（P〈0.05 versus the BPH models）,and 50.0% and 25.0% in the LY294002 100 mg group（P〈0.01 versus the BPH models）.The proliferative and apoptotic indexes were 14.2±6.4 and 6.5±1.8 in the epithelial and 7.6±2.6 and 2.5±0.3 in the interstitial tissue of the sham operation group,50.9±12.8 and 2.7±1.4 in the epithelial and 16.5±5.7 and 1.3±0.8 in the interstitial tissue of the BPH models,32.0±13.8 and 6.2±2.5 in the epithelial and 12.1±3.8 and 1.6±1.1 in the interstitial tissue of the LY294002 50 mg group（P〈0.05 versus the BPH models）,and 17.8±14.7 and 7.4±3.6 in the epithelial and 9.5±3.4 and 2.2±1.3 in the interstitial tissue of the LY294002 100 mg group（P〈0.01 versus the BPH models）.Conclusion：The increased proliferation and decreased apoptosis of prostatic cells in the BPH animal models might be involved in the development and progression of BPH.The PI3K/AKT signaling pathway plays an important role in the development of BPH,which could be inhibited by blocking the PI3K/AKT signaling pathway.
出处
《中华男科学杂志》
CAS
CSCD
北大核心
2010年第12期1068-1075,共8页
National Journal of Andrology
基金
湖南省自然科学基金(09JJ3038)~~
