Opisthorchiasis caused by food-borne trematode
Opisthorchis felineus
is a substantial public health problem, with 17 million persons infected worldwide. This chronic disease is associated with hepatobiliary inflammation, cholangiocyte dysplasia, cholangiofibrosis, intraepithelial neoplasia, and even cholangiocarcinoma among chronically infected individuals. To provide first insights into the mechanism by which
O
.
felineus
infection causes precancerous liver lesions, we investigated the level of oxidative stress (lipid peroxidation byproducts and 8-hydroxy-2′-deoxyguanosine) as well as the time course profiles of chronic inflammation and fibrogenesis markers in the dynamics of opisthorchiasis from 1 month to 1.5 years postinfection in an experimental model based on golden hamsters
Mesocricetus auratus
. For the first time, we showed that
O
.
felineus
infection provokes time-dependent accumulation of oxidative hepatobiliary lesions in the injured liver of hamsters. In particular, over the course of infection, lipid peroxidation byproducts 4-hydroxynonenal and malondialdehyde were upregulated; these changes in general correlate with the dynamics of hepatic histopathological changes. We detected macrophages with various immunophenotypes and elevated levels of CD68, COX2, and CD163 in the
O
.
felineus
–infected animals. Meanwhile, there was direct time-dependent elevation of TNF-α (R = 0.79; p < 0.001) and CD163 protein levels (R = 0.58; p = 0.022). We also provide quantitative data about epithelial hyperplasia marker CK7 and a marker of myofibroblast activation (α smooth muscle actin). Our present data provide first insights into the histopathological mechanism by which
O
.
felineus
infection causes liver injuries. These findings support the inclusion of
O
.
felineus
in Group 1 of biological carcinogens.
Chronic opisthorchiasis associated with Opisthorchis felineus infection is accompanied by severe fibrotic complications. It is of high practical significance to elucidate the mechanisms of hepatic fibrosis in chronic infection dynamics. The goal of the study is to investigate the temporal profile of key markers and the Jagged1/Notch signaling pathway in the implementation of fibrosis in a chronic O. felineus infection. For the first time, using histological methods and real-time PCR analysis, we demonstrated the activation of the Jagged1/Notch pathway in liver fibrogenesis, including the activation of the Hes1 and Hey1 target genes during experimental opisthorchiasis in Mesocricetus auratus. Cluster analysis followed by regression analysis of key markers during the infection showed that Jagged1 and Mmp9have the greatest contribution to the development of cholangiofibrosis and periductal fibrosis. Moreover, we detected a significant increase in the number of Jagged1-positive cells in the liver of chronic opisthorchiasis patients compared to that of the control group without infection. The results of the study are extremely informative both in terms of investigation both diverse fibrosis mechanisms as well as potential targets in complex antihelmintic therapy.
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