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

• Published in: Antioxidants & redox signaling Vol. 9; no. 11; p. 1963
• Main Authors: Thimmulappa, Rajesh K, Fuchs, Ralph J, Malhotra, Deepti, Scollick, Catherine, Traore, Kassim, Bream, Jay H, Trush, Michael A, Liby, Karen T, Sporn, Michael B, Kensler, Thomas W, Biswal, Shyam
• Format: Journal Article
• Language: English
• Published: United States 01.11.2007
• Subjects: 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; Neutrophils - drug effects; Neutrophils - immunology; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - physiology; Oleanolic Acid - analogs & derivatives; Oleanolic Acid - pharmacology; Reactive Oxygen Species - metabolism; Receptors, Formyl Peptide - metabolism; RNA, Messenger - metabolism; Time Factors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1523-0864
• DOI: 10.1089/ars.2007.1745

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.