Therapeutic anti-inflammatory phase II "anti-oxidant"

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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.