靶向PCNA的反义基因治疗对慢性增生性胆管炎的实验疗效

Therapeutic effects of antisense gene targeting at PCNA on proliferative cholangitis

目的 近年的研究证实胆结石的术后高复发率和胆道再狭窄率均与术后遗留的慢性增生性胆管炎（PC）密切相关,鉴于PC是一种过度增殖疾病,本研究拟探讨应用PCNA shRNA抑制PC的过度增殖行为和成石潜力的可行性和疗效,以期为预防结石的术后复发和胆道再狭窄探讨新的治疗途径.方法 建立慢性增生性胆管炎的实验动物模型,胆总管内注入0.5 ml的PCNA shRNA,探讨其对PC的过度增殖行为和成石潜力的影响.结果 PCNA shRNA可通过抑制PCNA和Procollagen Ⅲ mRNA和蛋白的表达,有效抑制胆道黏膜上皮、黏膜下腺体和胶原纤维的过度增殖,有望达到控制或逆转慢性增生性胆管炎及其所继发的胆道狭窄的目的 .此外,该治疗还可抑制黏蛋白基因Mucin 5AC的激活和表达,有助于降低PC的成石潜力.结论 PCNA shRNA治疗可能在达到控制或逆转慢性增生性胆管炎及其所继发的胆道狭窄的目的 同时,亦有助于降低病变胆管的成石潜力.

Objective In recent years, high stone recurrence and biliary restenosis rates in hepatolithiasis patients have been confirmed to be closely related to chronic proliferative cholangitis（PC）.Since PC is a kind of chronic proliferative disease, we designed this study to investigate the feasibility and effectiveness of applying PCNA shRNA to inhibit the hyperplasia and lithogenic potentiality of PC and to explore a new treatment approach for the prevention of stone recurrence and biliary restenosis.Methods The common bile duct of a PC animal model was given an intralumenal administration of 0.5 ml of PCNA shRNA to investigate its influence on PC.Results The PCNA shRNA could efficiently inhibit the hyperplasia of the biliary epithelium, submucosal gland, and collagen fiber by inhibiting mRNA or protein expressions of PCNA and Procollagen Ⅲ, thus showing promise to control or reverse PC and its secondary biliary stricture.In addition, it could inhibit the lithogenic potentiality of PC by inhibiting the expression of mucin 5AC.Conclusion PCNA shRNA treatment might achieve the effect of controlling or reversing the PC and its subsequent biliary stricture and concurrently assist in preventing the recurrence of intrahepatic stone.