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Analyzing Oxidative Stress in Murine Intestinal Organoids using Reactive Oxygen Species-Sensitive Fluorogenic Probe
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NADPH oxidase 4 is protective and not fibrogenic in intestinal inflammation

Emily Stenke1, Gabriella Aviello1, Ashish Singh1

  • 1Conway Institute, School of Medicine, University College Dublin, Dublin, Ireland.

Redox Biology
|October 15, 2020
PubMed

Insights

NOX4 upregulation is observed in inflammatory bowel diseases like Crohn's disease (CD). However, Nox4 deficiency exacerbates acute intestinal injury, suggesting a tissue-protective role, cautioning against NOX4 inhibitors for fibrosis.

Area of Science:

  • Gastroenterology
  • Cellular Biology
  • Pathology

Background:

  • Dysregulated redox signaling and oxidative stress contribute to inflammation and fibrosis.
  • NOX4-generated hydrogen peroxide (H2O2) is implicated in fibrosis development.
  • Fibrosis leading to strictures affects 35-40% of Crohn's disease (CD) patients, necessitating surgical intervention.

Purpose of the Study:

  • To investigate NOX4 expression in CD patients with inflammatory or stricturing disease.
  • To determine the role of NOX4 in acute and fibrotic intestinal disease models.

Main Methods:

  • Assessment of NOX4 expression in human inflamed mucosal tissue (CD, UC) and CD ileal strictures.
  • Evaluation of intestinal disease in Nox4-deficient (Nox4-/-) mice compared to wildtype mice under acute (bacterial, chemical colitis) and chronic injury conditions.

Main Results:

  • NOX4 was upregulated in inflamed tissues of CD and UC patients, and in CD ileal strictures.
  • Nox4 deficiency aggravated tissue injury and pathogen colonization in acute colitis models.
  • In chronic injury models, Nox4-/- mice showed no significant difference in tissue remodeling or fibrosis gene expression compared to wildtype mice.

Conclusions:

  • NOX4 exhibits a tissue-protective role in acute intestinal injury, contrary to its proposed role in fibrosis.
  • Nox4 appears dispensable in TGF-β1-driven intestinal fibrogenesis.
  • The findings suggest a cautious approach to pharmacological NOX4 inhibition for treating CD fibrosis, given its protective function in acute inflammation.
Keywords:
Crohn's diseaseFibrosisIntestinal inflammationNADPH oxidaseNOX4

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