Oxidative stress-mediated mouse liver lesions caused by Clonorchis sinensis infestation

초록

Clonorchis sinensis is a high-risk pathogenic helminth that strongly provokes inflammation, epithelial hyperplasia, periductal fibrosis, and even cholangiocarcinoma (CCA) 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 histopathologic changes and the appearance of oxidative stress markers, including lipid peroxidation (LPO), enzymes involved in LPO, and mutagenic DNA adducts in the livers of mice infected with C. sinensis, as well as proinflammatory cytokines in infected mouse sera. Histopathologic phenotypes, such as bile duct epithelial hyperplasia, periductal fibrosis, edema, and inflammatory infiltration, increased in infected livers in a time-dependent manner. Intense immunoreactivities of LPO products (4-hydroxy-2-nonenal [HNE]; malondialdehyde [MDA]), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) were concomitantly observed in these injured regions. We also found elevated expressions of COX-2 and 5-LOX in C. sinensis excretory-secretory product-treated CCA 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 CCA.