Nrf2 Is a Key Transcription Factor That Regulates Antioxidant Defense in Macrophages and Epithelial Cells: Protecting against the Proinflammatory and Oxidizing Effects of Diesel Exhaust Chemicals

Abstract

The proinflammatory effects of particulate pollutants, including diesel exhaust particles (DEP), are related to their content of redox cycling chemicals and their ability to generate oxidative stress in the respiratory tract. An antioxidant defense pathway, which involves phase II enzyme expression, protects against the pro-oxidative and proinflammatory effects of DEP. The expression of enzymes, including heme oxygenase-1 (HO-1) and GST, is dependent on the activity of a genetic antioxidant response element in their promoters. In this study we investigated the mechanism by which redox cycling organic chemicals, prepared from DEP, induce phase II enzyme expression as a protective response. We demonstrate that aromatic and polar DEP fractions, which are enriched in polycyclic aromatic hydrocarbons and quinones, respectively, induce the expression of HO-1, GST, and other phase II enzymes in macrophages and epithelial cells. We show that HO-1 expression is mediated through accumulation of the bZIP transcription factor, Nrf2, in the nucleus, and that Nrf2 gene targeting significantly weakens this response. Nrf2 accumulation and subsequent activation of the antioxidant response element is regulated by the proteasomal degradation of Nrf2. This pathway is sensitive to pro-oxidative and electrophilic DEP chemicals and is also activated by ambient ultrafine particles. We propose that Nrf2-mediated phase II enzyme expression protects against the proinflammatory effects of particulate pollutants in the setting of allergic inflammation and asthma.

Field Validation of the New Miniature Versatile Aerosol Concentration Enrichment System (mVACES)

“…Further, as performance validation of the mVACES is the principal focus of this work, discussion of the physical and chemical characteristics of the observed aerosol is subsequently limited. Our observations, however, are consistent with extensive measurements previously reported at the same site (Sardar et al 2005;Miguel et al 2004). …”

“…Given the complexity of the urban aerosol, achieving consistent concentration enrichment factors and performance by the mVACES provides a more comprehensive validation than can be achieved in the laboratory. Of particular interest in the present study was the ability of the mVACES to concentrate effectively species such as trace elements and metals as well as organic compounds, such as organic carbon (OC) and polycyclic aromatic hydrocarbons (PAH), all of which are associated with health effects attributable to PM (Pope et al 2002;Li et al 2003Li et al , 2004.…”

Enhancing Nrf2 Pathway by Disruption of Keap1 in Myeloid Leukocytes Protects against Sepsis

“…HMGB1, a well-characterized cytokine with pleiotropic function, is a crucial late mediator of mortality in sepsis (32). Secretory HMGB1 augments proinflammatory response and promotes inflammation and tissue injury (33).The level of HMGB-1, was also significantly higher in LysMNrf2 2/2 compared with LysM-Keap1 2/2 . Both mice and clinical studies have documented that the balance of proinflammatory and antiinflammatory cytokines is a better predictive marker of severity and mortality in sepsis rather than a single mediator (23,34).…”

Seasonal and spatial trends in particle number concentrations and size distributions at the children's health study sites in Southern California

“…To this date, however, there appears to be heterogeneity in particulate matter (PM) concentrations and PMassociated health effects between locations within an urban setting, which raises considerable uncertainties as to whether PM mass, number, size, bulk or surface chemistry are the appropriate metrics associated with PM toxicity. For example, recent studies have shown that atmospheric ultrafine particles (with physical diameter o100 nm) have the potential for eliciting adverse health effect (Oberdo¨rster and Utell, 2002;Li et al, 2003Li et al, , 2004Xia et al, 2004). Recent epidemiological studies by Peters et al (1997) have demonstrated a higher association between health effects and exposures to ultrafine particles compared to accumulation mode or coarse particles.…”