The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal Fibrosis
<i>Clonorchis sinensis</i>, 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 (...
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MDPI AG
2021-05-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/10/6/869 |
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| author | Ji Hoon Jeong Junyeong Yi Myung Ki Hwang Sung-Jong Hong Woon-Mok Sohn Tong-Soo Kim Jhang Ho Pak |
| author_facet | Ji Hoon Jeong Junyeong Yi Myung Ki Hwang Sung-Jong Hong Woon-Mok Sohn Tong-Soo Kim Jhang Ho Pak |
| author_sort | Ji Hoon Jeong |
| collection | DOAJ |
| description | <i>Clonorchis sinensis</i>, 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 <i>C. sinensis</i> infection- and/or carcinogen <i>N</i>-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 (<i>N</i>-acetylcysteine), indicating the involvement of excessive NOX-dependent ROS formation in periductal fibrosis. The immunoreactive NOX subunits, p47<sup>phox</sup> and p67<sup>phox</sup>, were observed in the livers of mice infected with <i>C. sinensis</i> 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. |
| first_indexed | 2024-03-10T10:56:28Z |
| format | Article |
| id | doaj.art-48f3ab0d2ec44b7fb717ba4147ec482d |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T10:56:28Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-48f3ab0d2ec44b7fb717ba4147ec482d2023-11-21T21:51:11ZengMDPI AGAntioxidants2076-39212021-05-0110686910.3390/antiox10060869The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal FibrosisJi Hoon Jeong0Junyeong Yi1Myung Ki Hwang2Sung-Jong Hong3Woon-Mok Sohn4Tong-Soo Kim5Jhang Ho Pak6Department of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, KoreaDepartment of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, KoreaDepartment of Tropical Medicine and Parasitology, School of Medicine, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, KoreaDepartment of Medical Environmental Biology, College of Medicine, Chung-Ang University, 84 Heuksuk-ro, Dongjak-gu, Seoul 06974, KoreaDepartment of Parasitology and Tropical Medicine, Institute of Health Sciences, College of Medicine, Gyeongsang National University, 79 Gangnam-ro, Jinju 52727, KoreaDepartment of Tropical Medicine and Parasitology, School of Medicine, Inha University, 100 Inha-ro, Michuhol-gu, Incheon 22212, KoreaDepartment of Convergence Medicine, University of Ulsan College of Medicine and Asan Institute for Life Sciences, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea<i>Clonorchis sinensis</i>, 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 <i>C. sinensis</i> infection- and/or carcinogen <i>N</i>-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 (<i>N</i>-acetylcysteine), indicating the involvement of excessive NOX-dependent ROS formation in periductal fibrosis. The immunoreactive NOX subunits, p47<sup>phox</sup> and p67<sup>phox</sup>, were observed in the livers of mice infected with <i>C. sinensis</i> 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.https://www.mdpi.com/2076-3921/10/6/869<i>Clonorchis sinensis</i> infectionexcretory-secretory products<i>N</i>-nitrosodimethylaminecholangiocytesoxidative stressNADPH oxidases |
| spellingShingle | Ji Hoon Jeong Junyeong Yi Myung Ki Hwang Sung-Jong Hong Woon-Mok Sohn Tong-Soo Kim Jhang Ho Pak The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal Fibrosis Antioxidants <i>Clonorchis sinensis</i> infection excretory-secretory products <i>N</i>-nitrosodimethylamine cholangiocytes oxidative stress NADPH oxidases |
| title | The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal Fibrosis |
| title_full | The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal Fibrosis |
| title_fullStr | The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal Fibrosis |
| title_full_unstemmed | The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal Fibrosis |
| title_short | The Overactivation of NADPH Oxidase during <i>Clonorchis sinensis</i> Infection and the Exposure to <i>N</i>-Nitroso Compounds Promote Periductal Fibrosis |
| title_sort | overactivation of nadph oxidase during i clonorchis sinensis i infection and the exposure to i n i nitroso compounds promote periductal fibrosis |
| topic | <i>Clonorchis sinensis</i> infection excretory-secretory products <i>N</i>-nitrosodimethylamine cholangiocytes oxidative stress NADPH oxidases |
| url | https://www.mdpi.com/2076-3921/10/6/869 |
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