Relevance: The goal of this project is to define a novel therapeutic approach to an unaddressed aspect of allergic airways disease, the component driven by participate pollution. No current anti-allergic or antiinflammatory treatment is designed to address this important health issue. We will test the hypothesis that induction of phase II """"""""anti-oxidant"""""""" enzymes will mitigate the inflammatory effects of particulate air pollution, i.e. diesel exhaust particles (DEP) in human airway challenge models. Treatment will be oral sulforaphane (SFN), in a broccoli sprout homogenate, as a nutraceutical that is a potent inducer of phase II enzymes via activation of the transcription factor Nrf-2 that drives these phase II genes as they contain an anti-oxidant response motif. Our approach is based on studies showing that a) oxidative stress responses participate in the observed effects of DEP in humans and animal, b) induction of a phase II enzymes can protect against development of an inflammatory response, and c) that anti-oxidants can block the proinflammatory effects of DEP. Furthermore, we have completed human dosing studies with the SFN nutraceutical that show robust induction of phase II enzymes in the blood and importantly in the airways of human subjects. Benefit from phase II cytoprotective """"""""anti-oxidant"""""""" enzymes via SFN will be experimentally tested in three distinct human challenge models defining effects of DEP on 1) induction of local inflammation, 2) enhancement of established allergic-lgE responses and 3) enhancement of primary sensitization to a neoallergen. These studies will be carried out using in a population of subjects selected for their susceptibility to DEP driven inflammation.
In Aim 1, we will test the ability of oral SFN to inhibit the local inflammatory effects of nasal DEP challenge alone using cellular infiltration as the primary endpoint.
Aim 2 will test whether SFN treatment can blunt DEP driven secondary allergic airway inflammation following challenge with DEP plus cat allergen inhibition of DEP driven enhancement of IgE antibody to cat.
Aim 3 will determine whether induction of an anti-oxidant response via SFN can prevent DEP dependent primary mucosal allergic sensitization to the neoantigen KLH. Dr. Diaz-Sanchez (Project 3) will assist in the laboratory studies. We will also work with Dr. Nel (Project 1) and Core C using proteomics with informative subjects'nasal samples to investigate novel aspects of the human in vivo response to DEP plus allergen.
|Heber, David; Li, Zhaoping; Garcia-Lloret, Maria et al. (2014) Sulforaphane-rich broccoli sprout extract attenuates nasal allergic response to diesel exhaust particles. Food Funct 5:35-41|
|Li, Ning; Wang, Meiying; Barajas, Berenice et al. (2013) Nrf2 deficiency in dendritic cells enhances the adjuvant effect of ambient ultrafine particles on allergic sensitization. J Innate Immun 5:543-54|
|Ooi, Aik T; Ram, Sonal; Kuo, Alan et al. (2012) Identification of an interleukin 13-induced epigenetic signature in allergic airway inflammation. Am J Transl Res 4:219-28|
|Li, Ning; Nel, Andre E (2011) Feasibility of biomarker studies for engineered nanoparticles: what can be learned from air pollution research. J Occup Environ Med 53:S74-9|
|Li, Ning; Harkema, Jack R; Lewandowski, Ryan P et al. (2010) Ambient ultrafine particles provide a strong adjuvant effect in the secondary immune response: implication for traffic-related asthma flares. Am J Physiol Lung Cell Mol Physiol 299:L374-83|
|Kang, Xuedong; Li, Ning; Wang, Meiying et al. (2010) Adjuvant effects of ambient particulate matter monitored by proteomics of bronchoalveolar lavage fluid. Proteomics 10:520-31|
|George, Saji; Pokhrel, Suman; Xia, Tian et al. (2010) Use of a rapid cytotoxicity screening approach to engineer a safer zinc oxide nanoparticle through iron doping. ACS Nano 4:15-29|
|Tachdjian, Raffi; Al Khatib, Shadi; Schwinglshackl, Andreas et al. (2010) In vivo regulation of the allergic response by the IL-4 receptor alpha chain immunoreceptor tyrosine-based inhibitory motif. J Allergy Clin Immunol 125:1128-1136.e8|
|Kovochich, Michael; Espinasse, Benjamin; Auffan, Melanie et al. (2009) Comparative toxicity of C60 aggregates toward mammalian cells: role of tetrahydrofuran (THF) decomposition. Environ Sci Technol 43:6378-84|
|Nel, Andre E; Mädler, Lutz; Velegol, Darrell et al. (2009) Understanding biophysicochemical interactions at the nano-bio interface. Nat Mater 8:543-57|
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