NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation
Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. H2O2 generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-10-01
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| Series: | Redox Biology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231720309575 |
| _version_ | 1818391772716335104 |
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| author | Emily Stenke Gabriella Aviello Ashish Singh Sean Martin Des Winter Brian Sweeney Michael McDermott Billy Bourke Seamus Hussey Ulla G. Knaus |
| author_facet | Emily Stenke Gabriella Aviello Ashish Singh Sean Martin Des Winter Brian Sweeney Michael McDermott Billy Bourke Seamus Hussey Ulla G. Knaus |
| author_sort | Emily Stenke |
| collection | DOAJ |
| description | Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. H2O2 generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and primary biliary cholangitis. Fibrosis is a common complication in Crohn's disease (CD) leading to stricture formation in 35–40% of patients, who require surgical interventions in the absence of therapeutic options. Here we assess NOX4 expression in CD patients with inflammatory or stricturing disease and examine whether loss of NOX4 is beneficial in acute and fibrotic intestinal disease. NOX4 was upregulated in inflamed mucosal tissue of CD and ulcerative colitis (UC) patients, in CD ileal strictures, and in mice with intestinal inflammation. Nox4 deficiency in mice promoted pathogen colonization and exacerbated tissue injury in acute bacterial and chemical colitis. In contrast, in two chronic injury models aberrant tissue remodeling and fibrosis-related gene expression did not differ substantially between Nox4−/− mice and wildtype mice, suggesting that Nox4 is dispensable in TGF-β1-driven intestinal fibrogenesis. While animal models do not recapitulate all the hallmarks of CD fibrosis, the tissue-protective role of Nox4 warrants a cautious approach to pharmacological inhibitors. |
| first_indexed | 2024-12-14T05:18:50Z |
| format | Article |
| id | doaj.art-c9f11835f8b841bb9cc8c75918643375 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-12-14T05:18:50Z |
| publishDate | 2020-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-c9f11835f8b841bb9cc8c759186433752022-12-21T23:15:43ZengElsevierRedox Biology2213-23172020-10-0137101752NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammationEmily Stenke0Gabriella Aviello1Ashish Singh2Sean Martin3Des Winter4Brian Sweeney5Michael McDermott6Billy Bourke7Seamus Hussey8Ulla G. Knaus9Conway Institute, School of Medicine, University College Dublin, Dublin, IrelandConway Institute, School of Medicine, University College Dublin, Dublin, IrelandConway Institute, School of Medicine, University College Dublin, Dublin, IrelandSt. Vincent's University Hospital, Dublin, IrelandSt. Vincent's University Hospital, Dublin, IrelandNational Children's Research Centre, Children's Health Ireland, Dublin, IrelandNational Children's Research Centre, Children's Health Ireland, Dublin, IrelandConway Institute, School of Medicine, University College Dublin, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland, Dublin, IrelandNational Children's Research Centre, Children's Health Ireland, Dublin, Ireland; RCSI University of Medicine and Health Sciences, Dublin, IrelandConway Institute, School of Medicine, University College Dublin, Dublin, Ireland; National Children's Research Centre, Children's Health Ireland, Dublin, Ireland; Corresponding author. Conway Institute, University College Dublin, Belfield, Dublin, Ireland.Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. H2O2 generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and primary biliary cholangitis. Fibrosis is a common complication in Crohn's disease (CD) leading to stricture formation in 35–40% of patients, who require surgical interventions in the absence of therapeutic options. Here we assess NOX4 expression in CD patients with inflammatory or stricturing disease and examine whether loss of NOX4 is beneficial in acute and fibrotic intestinal disease. NOX4 was upregulated in inflamed mucosal tissue of CD and ulcerative colitis (UC) patients, in CD ileal strictures, and in mice with intestinal inflammation. Nox4 deficiency in mice promoted pathogen colonization and exacerbated tissue injury in acute bacterial and chemical colitis. In contrast, in two chronic injury models aberrant tissue remodeling and fibrosis-related gene expression did not differ substantially between Nox4−/− mice and wildtype mice, suggesting that Nox4 is dispensable in TGF-β1-driven intestinal fibrogenesis. While animal models do not recapitulate all the hallmarks of CD fibrosis, the tissue-protective role of Nox4 warrants a cautious approach to pharmacological inhibitors.http://www.sciencedirect.com/science/article/pii/S2213231720309575Intestinal inflammationFibrosisCrohn's diseaseNADPH oxidaseNOX4 |
| spellingShingle | Emily Stenke Gabriella Aviello Ashish Singh Sean Martin Des Winter Brian Sweeney Michael McDermott Billy Bourke Seamus Hussey Ulla G. Knaus NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation Redox Biology Intestinal inflammation Fibrosis Crohn's disease NADPH oxidase NOX4 |
| title | NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation |
| title_full | NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation |
| title_fullStr | NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation |
| title_full_unstemmed | NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation |
| title_short | NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation |
| title_sort | nadph oxidase 4 is protective and not fibrogenic in intestinal inflammation |
| topic | Intestinal inflammation Fibrosis Crohn's disease NADPH oxidase NOX4 |
| url | http://www.sciencedirect.com/science/article/pii/S2213231720309575 |
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