Abstract
Clonorchis sinensis, a high-risk pathogenic human liver fluke, provokes various hepatobiliary complications, including epithelial hyperplasia, inflammation, periductal fibrosis, and even cholangiocarcinogenesis via direct contact with worms and their excretory–secretory products (ESPs). These pathological changes are strongly associated with persistent increases in free radical accumulation, leading to oxidative stress-mediated lesions. The present study investigated C. sinensis infection- and/or carcinogen N-nitrosodimethylamine (NDMA)-associated fibrosis in cell culture and animal models. The treatment of human cholangiocytes (H69 cells) with ESPs or/and NDMA increased reactive oxidative species (ROS) generation via the activation of NADPH oxidase (NOX), resulting in augmented expression of fibrosis-related proteins. These increased expressions were markedly attenuated by preincubation with a NOX inhibitor (diphenyleneiodonium chloride) or an antioxidant (N-acetylcysteine), indicating the involvement of excessive NOX-dependent ROS formation in periductal fibrosis. The immunoreactive NOX subunits, p47phox and p67phox, were observed in the livers of mice infected with C. sinensis and both infection plus NDMA, concomitant with collagen deposition and immunoreactive fibronectin elevation. Staining intensities are proportional to lesion severity and infection duration or/and NDMA administration. Thus, excessive ROS formation via NOX overactivation is a detrimental factor for fibrogenesis during liver fluke infection and exposure to N-nitroso compounds.
Highlights
These prompted the examination of NADPH oxidase (NOX) activation in normal human cholangiocytes, which was one of the major reactive oxidative species (ROS)-producing enzymes in response to excretory–secretory products (ESPs), along with the NDMA
The present study showed that the pretreatment of H69 cells with NAC reduced the levels of fibronectin and collagen type I expression induced by ESPs or/and NDMA without significantly affecting the translocation of NOX subunits to the plasma membrane (Figure 3), implying that NAC may not participate in NOX activity inhibition
This study showed that treatment of H69 cells with C. sinensis ESPs or/and NDMA triggers NOX-mediated oxidative insult and subsequent increases in collagen type I and fibronectin expression
Summary
Oxidative stress results from an excessive pro-oxidant formation to antioxidant detoxifying capacity, exerting oxidative damages in tissues and organs. Free radicals (reactive oxygen and nitrogen species; ROS/RNS) are generated in the liver as byproducts during the metabolizing processes of various compounds as well as a mitochondrial electron chain reaction. Their levels are increased by ischemia/reperfusion; alcohol overconsumption; xenobiotics or heavy metals intoxications; and bacterial, viral, and parasitic infections [1,2]. Aberrant accumulations of these free radicals contribute to the initiation 4.0/).
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