Pathogenesis of Opisthorchiasis induced persistent periductal fibrosis and CCA

在慢性尾棘皮病中，发病机制表现为一系列明确的阶段，胆管上皮的正常组织结构由胆管内吸虫的机械、毒性和免疫机制的组合所致的反复损伤的慢性炎症反应逐步重塑。当个体感染多年(通常是终生)时，肝内胆管会发生持续的组织损伤和修复循环，形成慢性炎症环境，刺激胆管周围纤维化的形成，并为胆管上皮细胞恶性转化为胆管癌(CCA)提供“阴燃和极化”的炎症基础。在项目1中，我们假设存在以炎性细胞因子失调为特征的促炎表型，即使在PZQ去除病原体后，具有促炎表型的个体仍会继续产生高水平的IL-6和不可逆转(即，持续性)的晚期管周纤维化(APF)。我们进一步假设，这种持续性的APF为CCA的恶变提供了基础。TMRC的项目1将专注于这种慢性炎症表型和从感染到持续性APF和最终恶性转化(CCA)的进展过程，具体目标如下：(1)继续我们的基于社区的队列研究，在泰国坤健池河流域高危传播的村庄中与晚期导管周围纤维化相关的危险因素，将感染者分成“已缓解”和“持续”晚期导管周围纤维化患者；(2)研究慢性华支睾吸虫感染过程中宿主炎性细胞因子信号转导途径，如IL-6信号转导通路在晚期胆管纤维化进展中的作用；(3)通过微卫星DNA分析检测华支睾吸虫寄生虫的遗传多样性及其与慢性和持续性晚期胆管周围纤维化的关系。。

During chronic opisthorchiasis, pathogenesis is manifested in a series of well-defined stages as the normal tissue architecture of the biliary epithelium is progressively remodeled by the chronic inflammatory response from repeated injury sustained by the biliary epithelium from a combination ofthe mechanical, toxic, and immune mechanisms of the fluke in the bile duct. As individuals are infected with O. viverrini for many years (often a lifetime), a persistent cycle of tissue damage and repair takes place in the intrahepatic biliary ducts, creating a chronic inflammatory milieu that stimulates periductal fibrogenesis and provides the "smoldering and polarized" inflammatory basis for malignant transformation of biliary epithelial cells to cholangiocarcinoma (CCA). In project 1, we hypothesize the existence of a pro-inflammatory phenotype which is characterized by a inflammatory cytokine dysregulation such that, even after removal ofthe pathogen by PZQ, individuals with the pro-inflammatory phenotype continue to produce high levels of IL-6 and an unreversed (i.e., persistent) form of Advanced Periductal Fibrosis (APF). We further hypothesize that this persistent APF provides the basis for malignant transformation to CCA. Project 1 ofthe TMRC will focus on the processes involved in this chronic inflammatory phenotype and the progression from infection to persistent APF and eventually to malignant transformation (CCA) by undertaking the following specific aims: (1) continuing our a community-based cohort study for the risk factors associated with Advanced Periductal Fibrosis in villages with high O. viverrini transmission along the Chi River basin in Khon Kaen, Thailand to stratify infected individuals into those with "resolved" and "persistent" Advanced Periductal Fibrosis; (2) to determine the host inflammatory cytokine signaling pathways, such as the IL-6 signaling pathways, induced during chronic O. viverrini infection on the risk of progressing either resolved or persistent advanced periductal fibrosis, and bile duct cancer; and (3) examine the genetic diversity ofthe O. viverrini parasite by microsatellite DNA analysis and its association with resolved and persistent forms advanced periductal fibrosis. .