PM Adjuvant Effects, Dendritic Cells and Hierarchical, Oxidative Stress Response

University Of California Los Angeles, Los Angeles CA

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Linked publications & trials

Abstract

Relevance: The goal of this application is to understand the pathway by which participate air pollutants[unreadable] (a.k.a. particulate matter or PM) lead to worsening of allergic asthma by impacting dendritic cells (DC) in the[unreadable] immune system (IS). This research is relevant to understanding how air pollutants contribute to the[unreadable] development of asthma, and proposes rational therapy to block the impact of of PM on asthma through the[unreadable] use of a novel class of antioxidants.[unreadable] The principal hypothesis is that PM and adsorbed redox cycling organic chemicals alter DC function to favor[unreadable] Th2 skewing of the IR. The proposal is that oxidative stress perturbs DC activities such as antigen[unreadable] presentation, cellular maturation, cytokine production and/or co-stimulatory activity that are key for T-cell[unreadable] activation and Th2 differentiation. A pathway that is regulated by the transcription factor, Nrf2, protects[unreadable] against the pro-inflammatory and adjuvant effects of PM. Nrf2 accomplishes this by inducing the expression[unreadable] of a battery of phase II antioxidant enzymes that exert anti-inflammatory effects. Aim 1 will determine in a DC[unreadable] adoptive transfer model the mechanism(s) by which oxidative stress promotes Th2 skewing in vitro and in[unreadable] vivo. Diesel exhaust particles, ambient ultrafine particles and pro-oxidative PM chemical fractions will be[unreadable] used to determine their effect on DC immunoregulatory properties, including antigen uptake, antigen[unreadable] presentation, maturation, cytokine/chemokine production, transgenic T-cell activation, and co-stimulatory[unreadable] activity. In vivo skewing of the IR will be further expored in transgenic mice that express a nlL-4-GFP[unreadable] transgene knocked into the IL-4 promoter. Aim 2 will determine whether the Nrf2-mediated antioxidant[unreadable] defense pathway, by modification of DC function, regulates PM-induced oxidative stress and asthma. This[unreadable] will be accomplished by comparing wild type with Nrf2-deficient animals. This study will determine whether[unreadable] interference in phase II enzyme expression leads to exaggerated PM effects on DC antigen presenting[unreadable] activity and whether Nrf2 deficiency promotes Th2 skewing and allergic inflammation in vivo. Proteome[unreadable] analysis will be conducted to reveal in vivo oxidative stress markers in the BAL fluid that can used to study[unreadable] PM oxidative stress effects. In collaboration with Projects 2 & 3, proteome analysis will also be conducted on[unreadable] human nasal lavage fluid to develop a comprehensive understanding of the allergic inflammatory effects of[unreadable] DEP in the nose, including the dynamic equilibrium between pro-and antioxidant pathways. Aim 3 will[unreadable] determine whether Nrf2-mediated phase II enzyme expression during treatment with alpha-lipoic acid and[unreadable] sulfurophane protects against PM oxidative stress effects and asthma exacerbation in vivo and modulation of[unreadable] DC function in vitro.