The dietary antioxidant quercetin reduces hallmarks of bleomycin-induced lung fibrogenesis in mice

Agnes W. Boots*, Carmen Veith, Catrin Albrecht, Roger Bartholome, Marie-Jose Drittij, Sandra M. H. Claessen, Aalt Bast, Martin Rosenbruch, Leonie Jonkers, Frederik-Jan van Schooten, Roel P. F. Schins

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

Background Idiopathic pulmonary fibrosis (IPF) is a chronic, lethal disease of which the etiology is still not fully understood. Current treatment comprises two FDA-approved drugs that can slow down yet not stop or reverse the disease. As IPF pathology is associated with an altered redox balance, adding a redox modulating component to current therapy might exert beneficial effects. Quercetin is a dietary antioxidant with strong redox modulating capacities that is suggested to exert part of its antioxidative effects via activation of the redox-sensitive transcription factor Nrf2 that regulates endogenous antioxidant levels. Therefore, the aim of the present study was to investigate if the dietary antioxidant quercetin can exert anti-fibrotic effects in a mouse model of bleomycin-induced pulmonary fibrogenesis through Nrf2-dependent restoration of redox imbalance. Methods Homozygous Nrf2 deficient mice and their wildtype littermates were fed a control diet without or with 800 mg quercetin per kg diet from 7 days prior to a single 1 mu g/2 mu l per g BW bleomycin challenge until they were sacrificed 14 days afterwards. Lung tissue and plasma were collected to determine markers of fibrosis (expression of extracellular matrix genes and histopathology), inflammation (pulmonary gene expression and plasma levels of tumor necrosis factor-alpha (TNF alpha) and keratinocyte chemoattrachtant (KC)), and redox balance (pulmonary gene expression of antioxidants and malondialdehyde-dG (MDA)- DNA adducts). Results Mice fed the enriched diet for 7 days prior to the bleomycin challenge had significantly enhanced plasma and pulmonary quercetin levels (11.08 +/- 0.73 mu M versus 7.05 +/- 0.2 mu M) combined with increased expression of Nrf2 and Nrf2-responsive genes compared to mice fed the control diet in lung tissue. Upon bleomycin treatment, quercetin-fed mice displayed reduced expression of collagen (COL1A2) and fibronectin (FN1) and a tendency of reduced inflammatory lesions (2.8 +/- 0.7 versus 1.9 +/- 0.8). These beneficial effects were accompanied by reduced pulmonary gene expression of TNF alpha and KC, but not their plasma levels, and enhanced Nrf2-induced pulmonary antioxidant defences. In Nrf2 deficient mice, no effect of the dietary antioxidant on either histology or inflammatory lesions was observed. Conclusion Quercetin exerts anti-fibrogenic and anti-inflammatory effects on bleomycin-induced pulmonary damage in mice possibly through modulation of the redox balance by inducing Nrf2. However, quercetin could not rescue the bleomycin-induced pulmonary damage indicating that quercetin alone cannot ameliorate the progression of IPF.

Original languageEnglish
Article number112
Number of pages16
JournalBMC Pulmonary Medicine
Volume20
Issue number1
DOIs
Publication statusPublished - 29 Apr 2020

Keywords

  • Bleomycin
  • Dietary supplementation
  • Inflammation
  • Mice
  • Oxidative stress
  • Quercetin
  • IDIOPATHIC PULMONARY-FIBROSIS
  • OXIDATIVE STRESS
  • DNA-ADDUCTS
  • NRF2
  • PATHOGENESIS
  • EXPRESSION
  • INJURY
  • ACETYLCYSTEINE
  • INFLAMMASOME
  • MODULATION

Cite this