Am J Pathol 2011 Dec;179 (6): 2845-54. [IF:5.224]
Biliary Infection May Exacerbate Biliary Cystogenesis Through the Induction of VEGF in Cholangiocytes of the Polycystic Kidney (PCK) Rat.
Ren XS , Sato Y , Harada K , Sasaki M , Yoneda N , Lin ZH , Nakanuma Y .
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan; Department of Pathology, Yanbian University College of Medicine, Yanji-City, China.
吉林延边大学医学院，日本金泽市金泽大学医学研究生院
Abstract
Cholangitis arising from biliary infection dominates the prognosis in Caroli's disease. To clarify the influences of bacterial infection on the biliary cystogenesis, in vivo and in vitro studies were performed using the polycystic kidney (PCK) rat as an animal model of Caroli's disease. Cholangitis became a frequent histological finding in aged PCK rats, and neovascularization around the bile ducts also increased in aged PCK rats. Immunohistochemistry revealed that expression of vascular endothelial growth factor (VEGF) was increased in PCK rat biliary epithelium. In vitro, PCK cholangiocytes overexpressed VEGF, and the supernatant of cultured PCK cholangiocytes significantly increased the proliferative activity, migration, and tube formation of cultured rat vascular endothelial cells. Stimulation with lipopolysaccharide (LPS) further induced VEGF expression in PCK cholangiocytes, which might be mediated by signaling pathways involving phosphatidylinositol 3-kinase (PI3K)-Akt and c-Jun N-terminal kinase (JNK). Both LPS and VEGF increased cell proliferative activity in PCK cholangiocytes, and siRNA against VEGF significantly reduced LPS-induced cell proliferation. Thus, LPS-induced overexpression of VEGF in the biliary epithelium may lead to hypervascularity around the bile ducts; concurrently, LPS and VEGF act as cell proliferation factors for cholangiocytes. Biliary infection may thus exacerbate biliary cystogenesis in PCK rats.
摘要：
由胆道感染引起的胆管炎是Caroli's病的主要预后因素。
为了阐明细菌感染对胆管囊肿形成的影响，使用多囊肾（PCK）大鼠作为Caroli's病的动物模型进行了体内、体外实验研究。
在老年PCK大鼠中胆管炎是非常常见的组织学变化，并且胆管周围血管新生现象也逐渐增加。免疫组化发现在多囊肾大鼠胆管细胞中VEGF的表达增加。在体外，多囊肾大鼠胆管细胞过表达VEGF，悬浮培养的胆管细胞繁殖能力、迁移能力增强，血管内皮细胞成管能力也增加。
脂多糖可以诱导PCK大鼠胆管细胞中VEGF的表达增加，这可能是通过PI3K-Akt 和JNK信号通路介导的。LPS和VEGF都能增强PCK胆管细胞的繁殖能力，靶向VEGF的siRNA能明显抑制LPS诱导的细胞增殖。因此，LPS诱导的胆管上皮细胞中过表达VEGF可能会导致胆道周围血管生成增加，同时，LPS和VEGF可以充当胆管细胞的增殖因子。胆道感染可能就是这样使PCK大鼠胆管囊肿形成加剧。
