The Overactivation of NADPH Oxidase during Clonorchis sinensis Infection and the Exposure to N-Nitroso Compounds Promote Periductal Fibrosis

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.

Osteopontin (SPP1) expression on gallstone formation in rabbits fed with a lithogenic diet

“…Free radicals are usually known as any chemical species that exist independently and are usually unstable and highly reactive chemical species due to the presence of one or more unpaired electrons in the outer orbitals; therefore, they are characterized by high reactivity in chemical reactions for electron exchange [ 25 ]. There are two sorts of free radicals in the biological system, reactive oxygen species (ROS) and reactive nitrogen species [ 26 , 27 ], that are produced in the liver as a byproduct through the processes of metabolizing various compounds [ 28 , 29 ] and also through a mitochondrial electron chain reaction [ 30 ]. Hydrogen peroxide (H 2 O 2 ) is capable of causing significant cellular damage even at low concentrations [ 31 ].…”

Clonorchis sinensis infection modulates key cytokines for essential immune response impacted by sex

“…The adult worms of C. sinensis living in the biliary tree of the liver produce eggs which are passed in feces. C. sinensis infection predominantly leads to hepatobiliary abnormalities, such as periductal fibrosis, cholangitis, cholecystitis and cholelithiasis [12][13][14][15]. Moreover, it is classified as "carcinogenic to humans" (Group 1) by the International Agency for Research on Cancer, because of the carcinogenesis in fatal cholangiocarcinoma [16].…”