Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils

Antioxid Redox Signal. 2007 Nov;9(11):1963-70. doi: 10.1089/ars.2007.1745.

Abstract

Sepsis is characterized by an inappropriate host immune-inflammatory response and sustained oxidative damage. Nrf2, a bZIP oxidant-responsive transcription factor, regulates a battery of cytoprotective genes including antioxidants and maintains cellular redox homeostasis. Mouse studies have demonstrated a critical role of Nrf2 in improving survival during sepsis. This preclinical ex vivo study using neutrophils and peripheral blood mononuclear cells (PBMCs) as a surrogate cells evaluates the efficacy of CDDO-Im and CDDO-Me [imidazole and methyl ester derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] to activate the Nrf2 pathway and protect from lipopolysaccharide (LPS)-induced inflammatory response in humans. CDDO-Im treatment significantly induced Nrf2-dependent antioxidative genes (HO-1, GCLC, GCLM, and NQO1) in PBMCs isolated from six normal subjects. CDDO-Im increased nuclear accumulation of Nrf2 protein. Pretreatment of PBMC by CDDO-Im significantly attenuated LPS-induced cytokine expression. Similar increases in levels of antioxidant genes and suppression of LPS-induced cytokine expression was observed after CDDO-Me pretreatment. CDDO-Im also greatly inhibited LPS, fMLP, TNF-alpha, and TPA-induced ROS generation in neutrophils. In conclusion, these results demonstrate that activation of the Nrf2-dependent antioxidative pathway by CDDO-Im or CDDO-Me protects against the LPS-induced inflammatory response and suggest that they can be potential therapeutic candidates for intervening sepsis syndrome.

Publication types

  • Evaluation Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / metabolism*
  • Drug Evaluation, Preclinical
  • Gene Expression Regulation / drug effects
  • Humans
  • Imidazoles / pharmacology*
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / immunology
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / immunology*
  • Lipopolysaccharides / toxicity
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / physiology*
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / pharmacology
  • RNA, Messenger / metabolism
  • Reactive Oxygen Species / metabolism
  • Receptors, Formyl Peptide / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • 1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole
  • Cytokines
  • Imidazoles
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • RNA, Messenger
  • Reactive Oxygen Species
  • Receptors, Formyl Peptide
  • Tumor Necrosis Factor-alpha
  • Oleanolic Acid
  • methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate