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National Institute of Environmental Health Sciences

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Publication Detail

Title: The effect of ex vivo CDDO-Me activation on nuclear factor erythroid 2-related factor 2 pathway in white blood cells from patients with septic shock.

Authors: Noel, Sanjeev; Zheng, Laura; Navas-Acien, Ana; Fuchs, Ralph J

Published In Shock, (2014 Nov)

Abstract: Nuclear factor erythroid 2-related factor 2 (NRF2) has been shown to protect against experimental sepsis in mice and lipopolysaccharide (LPS)-induced inflammation in ex vivo white blood cells from healthy subjects by upregulating cellular antioxidant genes. The objective of this study was to test the hypothesis that ex vivo methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate (CDDO-Me) activates NRF2-regulated antioxidant genes in white blood cells from patients with septic shock and protects against LPS-induced inflammation and reactive oxidative species production. Peripheral blood was collected from 18 patients with septic shock who were being treated in medical and surgical intensive care units. Real-time polymerase chain reaction was used to quantify the expression of NRF2 target genes (NQO1, HO-1, GCLM, and FTL) and IL-6 in peripheral blood mononuclear cells (PBMCs), monocytes, and neutrophils after CDDO-Me treatment alone or after subsequent LPS exposure. Superoxide anion (O2) was measured to assess the effect of CDDO-Me pretreatment on subsequent LPS exposure. Treatment with CDDO-Me increased the gene expression of NQO1 (P = 0.04) and decreased the expression of HO-1 (P = 0.03) in PBMCs from patients with septic shock. Purified monocytes exhibited significant increases in the expression of NQO1 (P = 0.01) and GCLM (P = 0.003) after CDDO-Me treatment. Levels of other NRF2 target genes (HO-1 and FTL) remained similar to those of vehicle-treated cells. Peripheral blood mononuclear cells showed a trend toward increased IL-6 gene expression after CDDO-Me treatment, whereas purified monocytes showed a trend toward decreased IL-6. There was no discernible trend in the IL-6 expression subsequent to LPS treatment in either vehicle-treated or CDDO-Me-treated PBMCs and monocytes. Treatment with CDDO-Me significantly increased O2 production in PBMCs (P = 0.04). Although CDDO-Me pretreatment significantly attenuated O2 production to subsequent LPS exposure (P = 0.03), the change was comparable to that observed in vehicle-treated PBMCs. Pretreatment with CDDO-Me followed by LPS exposure had no significant effect on O2 levels in purified monocytes. These data suggest that the NRF2 pathway is differentially responsive to CDDO-Me activation in peripheral blood cells from patients with septic shock and results in increased O2 production. The data may also suggest a suppressed NRF2 pathway in white blood cells from critically ill patients.

PubMed ID: 25105464 Exiting the NIEHS site

MeSH Terms: Adult; Aged; Aged, 80 and over; Antioxidants/pharmacology*; Cells, Cultured; Female; Gene Expression Regulation/drug effects; Humans; Interleukin-6/biosynthesis; Interleukin-6/genetics; Leukocytes, Mononuclear/drug effects*; Leukocytes, Mononuclear/metabolism; Male; Middle Aged; NF-E2-Related Factor 2/genetics; NF-E2-Related Factor 2/physiology*; Oleanolic Acid/analogs & derivatives*; Oleanolic Acid/pharmacology; RNA, Messenger/genetics; Reactive Oxygen Species/blood; Shock, Septic/blood*; Shock, Septic/genetics; Signal Transduction/drug effects; Signal Transduction/physiology; Young Adult

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