Maeng Sejung, Lee Hye Won, Bashir Qudsia, Kim Tae Im, Hong Sung-Jong, Lee Tae Jin, Sohn Woon-Mok, Na Byoung-Kuk, Kim Tong-Soo, Pak Jhang Ho
Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
Department of Medical Environmental Biology and Research Center for Biomolecules and Biosystems, Chung-Ang University College of Medicine, Seoul 156-756, Republic of Korea.
Int J Parasitol. 2016 Mar;46(3):195-204. doi: 10.1016/j.ijpara.2015.11.003. Epub 2015 Dec 21.
Clonorchis sinensis is a high-risk pathogenic helminth that strongly provokes inflammation, epithelial hyperplasia, periductal fibrosis, and even cholangiocarcinoma in chronically infected individuals. Chronic inflammation is associated with an increased risk of various cancers due to the disruption of redox homeostasis. Accordingly, the present study was conducted to examine the time course relationship between histopathological changes and the appearance of oxidative stress markers, including lipid peroxidation, enzymes involved in lipid peroxidation, and mutagenic DNA adducts in the livers of mice infected with C. sinensis, as well as proinflammatory cytokines in infected mouse sera. Histopathological phenotypes such as bile duct epithelial hyperplasia, periductal fibrosis, edema and inflammatory infiltration increased in infected livers in a time-dependent manner. Intense immunoreactivity of lipid peroxidation products (4-hydroxy-2-nonenal; malondialdehyde), cyclooxygenase-2, 5-lipoxygenase and 8-oxo-7,8-dihydro-2'-deoxyguanosine were concomitantly observed in these injured regions. We also found elevated expressions of cyclooxygenase-2 and 5-lipoxygenase in C. sinensis excretory-secretory product-treated cholangiocarcinoma cells. Moreover, the levels of proinflammatory cytokines such as TNF-α, ILβ-1 and IL-6 were differentially upregulated in infected sera. With regard to oxidative stress-mediated carcinogenesis, our findings suggest that C. sinensis infestation may disrupt host redox homeostasis, creating a damaging environment that favors the development of advanced hepatobiliary diseases such as clonorchiasis-associated cholangiocarcinoma.
华支睾吸虫是一种高风险的致病性蠕虫，在慢性感染个体中会强烈引发炎症、上皮增生、胆管周围纤维化，甚至胆管癌。由于氧化还原稳态的破坏，慢性炎症与各种癌症风险的增加有关。因此，本研究旨在探讨感染华支睾吸虫的小鼠肝脏中组织病理学变化与氧化应激标志物（包括脂质过氧化、参与脂质过氧化的酶和诱变性DNA加合物）的出现之间的时间进程关系，以及感染小鼠血清中的促炎细胞因子。胆管上皮增生、胆管周围纤维化、水肿和炎症浸润等组织病理学表型在受感染的肝脏中呈时间依赖性增加。在这些受损区域同时观察到脂质过氧化产物（4-羟基-2-壬烯醛；丙二醛）、环氧化酶-2、5-脂氧合酶和8-氧代-7,8-二氢-2'-脱氧鸟苷的强烈免疫反应性。我们还发现华支睾吸虫排泄-分泌产物处理的胆管癌细胞中环氧化酶-2和5-脂氧合酶的表达升高。此外，感染血清中促炎细胞因子如TNF-α、ILβ-1和IL-6的水平也有不同程度的上调。关于氧化应激介导的致癌作用，我们的研究结果表明，华支睾吸虫感染可能会破坏宿主的氧化还原稳态，创造一个有利于发展如华支睾吸虫病相关胆管癌等晚期肝胆疾病的有害环境。
