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NF-E2-Related Factor 2 Suppresses Intestinal Fibrosis by Inhibiting Reactive Oxygen Species-Dependent TGF-β1/SMADs

Yadi Guan1, Yue Tan1, Weiyu Liu2

  • 1Department of Gastroenterology, Shengjing Hospital of China Medical University, 39 Huaxiang Road, Tiexi District, Shenyang, 110022, Liaoning Province, China.

Digestive Diseases and Sciences
|August 18, 2017
PubMed
Abstract

Insights

NF-E2-Related Factor 2 (Nrf2) suppresses intestinal fibrosis by inhibiting the ROS/TGF-β1/SMADs pathway. This study clarifies Nrf2's antifibrotic role in intestinal fibrosis, offering therapeutic insights.

Area of Science:

  • Gastroenterology
  • Molecular Biology
  • Cell Biology

Background:

  • Intestinal fibrosis is a common complication of Crohn's disease.
  • The precise mechanisms underlying intestinal fibrosis remain largely unclear.
  • NF-E2-Related Factor 2 (Nrf2) has potential antifibrotic effects.

Purpose of the Study:

  • To evaluate the antifibrotic effects of Nrf2 in intestinal fibrosis.
  • To elucidate the molecular mechanisms by which Nrf2 influences intestinal fibrosis.
  • To investigate the role of reactive oxygen species (ROS) and TGF-β1/SMADs signaling in Nrf2-mediated antifibrotic activity.

Main Methods:

  • Induction of chronic fibrotic colitis in BALB/c mice using TNBS.
  • Administration of tert-butylhydroquinone (tBHQ), an Nrf2 agonist, to mice.
  • In vitro studies using human intestinal fibroblasts (CCD-18Co cells) treated with tBHQ or Nrf2 siRNA (si-Nrf2) followed by TGF-β1 stimulation.
  • Analysis of fibrosis markers (α-smooth muscle actin, collagen I, TIMP-1) and TGF-β1/SMADs pathway components via RT-PCR, immunohistochemistry, and Western blot.
  • Measurement of cellular ROS levels.

Main Results:

  • tBHQ treatment suppressed intestinal fibrosis in vivo and in vitro by inhibiting the TGF-β1/SMADs signaling pathway.
  • Nrf2 knockdown exacerbated TGF-β1-induced myofibroblast differentiation.
  • TGF-β1 stimulation increased ROS levels in intestinal fibroblasts.
  • ROS, particularly H2O2, interfered with tBHQ's ability to reduce TGF-β1 expression.
  • Scavenging ROS with N-acetyl cysteine inhibited TGF-β1 upregulation induced by Nrf2 knockdown.

Conclusions:

  • Nrf2 exerts antifibrotic effects in intestinal fibrosis.
  • Nrf2 suppresses intestinal fibrosis by inhibiting the ROS/TGF-β1/SMADs pathway.
  • Targeting Nrf2 and managing ROS may represent a therapeutic strategy for intestinal fibrosis.
Keywords:
ColitisFibrosisNF-E2-Related Factor 2Reactive oxygen speciesTGF-β1/SMADs signaling pathway

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