Terao R, Honda K, Hatano E, Uehara T, Yamamoto M, Yamaoka Y
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Japan.
Hepatology. 1998 Sep;28(3):605-12. doi: 10.1002/hep.510280301.
Proliferative cholangitis (PC) associated with hepatolithiasis develops the stricture of main bile ducts, and is the main cause of residual and/or recurrent stones after repeated treatments for hepatolithiasis. The aim of this study was to inhibit PC using the cytostatic gene therapy with direct adenovirus-mediated retinoblastoma (Rb) gene transfer to the biliary tract. PC was induced by introducing a fine nylon thread into the bile duct in a rat model. The adenovirus vector encoding a nonphosphorylatable, constitutively active form of retinoblastoma gene product (AdRb) was administered directly into the biliary tract. The adenovirus vector encoding beta-galactosidase (AdlacZ) was also given as a control. The bile duct wall thickness and 5'-bromodeoxyuridine (BrdU) labeling index were compared among uninfected, AdlacZ-infected, and AdRb-infected PC rats. The Rb expression in the bile duct was detected using reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemical study. AdRb-infected bile ducts showed inhibition of the epithelial and fibrous tissue proliferation and the peribiliary gland hyperplasia, resulting in a significant reduction of wall thickness compared with uninfected and AdlacZ-infected ones. The BrdU labeling index was 4.87% +/- 3.06% in the AdRb-infected bile ducts, while those of uninfected and AdlacZ-infected ones were 15.48% +/- 4.61% and 11.72% +/- 1.23%, respectively (P < .05). In conclusion, our cytostatic gene therapy approach using direct Rb gene transfer into the biliary tract suppressed PC in a rat model and may offer an effective therapeutic option for reducing recurrences following treatments against hepatolithiasis.
与肝内胆管结石相关的增殖性胆管炎（PC）会导致肝内胆管狭窄，是肝内胆管结石反复治疗后结石残留和/或复发的主要原因。本研究的目的是通过直接腺病毒介导的视网膜母细胞瘤（Rb）基因转移至胆道的细胞生长抑制基因疗法来抑制PC。在大鼠模型中，通过将一根细尼龙线插入胆管来诱导PC。将编码视网膜母细胞瘤基因产物非磷酸化、组成型活性形式的腺病毒载体（AdRb）直接注入胆道。编码β-半乳糖苷酶的腺病毒载体（AdlacZ）也作为对照给予。比较未感染、AdlacZ感染和AdRb感染的PC大鼠的胆管壁厚度和5'-溴脱氧尿苷（BrdU）标记指数。使用逆转录聚合酶链反应（RT-PCR）和免疫组织化学研究检测胆管中的Rb表达。与未感染和AdlacZ感染的胆管相比，AdRb感染的胆管显示上皮和纤维组织增殖以及胆管周围腺体增生受到抑制，导致管壁厚度显著降低。AdRb感染的胆管中BrdU标记指数为4.87%±3.06%，而未感染和AdlacZ感染的胆管中分别为15.48%±4.61%和11.72%±1.23%（P<0.05）。总之，我们将Rb基因直接转移至胆道的细胞生长抑制基因疗法在大鼠模型中抑制了PC，可能为减少肝内胆管结石治疗后的复发提供一种有效的治疗选择。
