Pathogenesis of Opisthorchiasis induced persistent periductal fibrosis and CCA

后睾吸虫病引起的持续性导管周围纤维化和 CCA 的发病机制

• 批准号: 8919229
• 负责人: Banchob Sripa
• 金额: $ 15.66万
• 依托单位: KHON KAEN UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8919229
• 关键词: 19 year old; Aftercare; Architecture; Area; Bile duct carcinoma; Biliary; Biological; Cholangiocarcinoma; Chronic; Clinical; Cohort Studies; Communities; Cytokine Signaling; DNA; DNA analysis; Deposition; Diet; Disease; Duct (organ) structure; Ecology; Epithelial Cells; Epithelium; Excision; Faculty; Fasciola hepatica; Feces; Fibrosis; Fishes; Genetic Variation; Genotype; Hepatobiliary; Immune; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Life; Malignant - descriptor; Mechanics; Medicine; Microsatellite Repeats; Normal tissue morphology; Opisthorchiasis; Parasites; Pathogenesis; Pattern; Phenotype; Process; Production; Research; Risk; Risk Factors; Rivers; Role; Sampling Studies; Series; Serum; Signal Pathway; Southeastern Asia; Specimen; Staging; Structure; Thailand; Tissues; Trematoda; Universities; base; bile duct; biliary tract; carcinogenesis; cytokine; egg; fibrogenesis; follow-up; intrahepatic; pathogen; repaired; repository; response; tissue repair; transmission process; uncooked

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. .

在慢性后睾吸虫病中，发病机制表现为一系列明确的阶段，因为胆管上皮的正常组织结构被慢性炎症反应逐渐重塑，慢性炎症反应来自胆管内吸虫的机械、毒性和免疫机制的组合，由胆管上皮持续的反复损伤。当个体感染O.在肝内胆管中发生组织损伤和修复的持续循环多年（通常是一生），产生慢性炎性环境，其刺激管周纤维形成并为胆管上皮细胞向胆管癌（CCA）的恶性转化提供“阴燃和极化”炎性基础。在项目1中，我们假设存在促炎表型，其特征在于炎性细胞因子失调，使得即使在通过PZQ去除病原体之后，具有促炎表型的个体继续产生高水平的IL-6和未逆转的（即，晚期导管周围纤维化（APF）。我们进一步假设这种持续性APF为CCA恶性转化提供了基础。TMRC的项目1将重点关注这种慢性炎症表型的过程以及从感染到持续性APF和最终恶变（CCA）的进展，具体目标如下：（1）继续我们在高O.在泰国孔敬的志河流域进行沿着灵猫病毒的传播，以将感染的个体分为“消退的”和“持续的”晚期导管周围纤维化的个体;（2）确定在慢性O.（3）检测O.通过微卫星DNA分析探讨灵猫寄生虫与晚期导管周围纤维化的关系.