Therapeutic anti-inflammatory phase II "anti-oxidant"

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications & trials

Abstract

Relevance: The goal of this project is to define a novel therapeutic approach to an unaddressed aspect of[unreadable] allergic airways disease, the component driven by participate pollution. No current anti-allergic or antiinflammatory[unreadable] treatment is designed to address this important health issue.[unreadable] We will test the hypothesis that induction of phase II "anti-oxidant" enzymes will mitigate the inflammatory[unreadable] effects of particulate air pollution, i.e. diesel exhaust particles (DEP) in human airway challenge models.[unreadable] Treatment will be oral sulforaphane (SFN), in a broccoli sprout homogenate, as a nutraceutical that is a[unreadable] potent inducer of phase II enzymes via activation of the transcription factor Nrf-2 that drives these phase II[unreadable] genes as they contain an anti-oxidant response motif. Our approach is based on studies showing that a)[unreadable] oxidative stress responses participate in the observed effects of DEP in humans and animal, b) induction of[unreadable] a phase II enzymes can protect against development of an inflammatory response, and c) that anti-oxidants[unreadable] can block the proinflammatory effects of DEP. Furthermore, we have completed human dosing studies with[unreadable] the SFN nutraceutical that show robust induction of phase II enzymes in the blood and importantly in the[unreadable] airways of human subjects. Benefit from phase II cytoprotective "anti-oxidant" enzymes via SFN will be[unreadable] experimentally tested in three distinct human challenge models defining effects of DEP on 1) induction of[unreadable] local inflammation, 2) enhancement of established allergic-lgE responses and 3) enhancement of primary[unreadable] sensitization to a neoallergen. These studies will be carried out using in a population of subjects selected for[unreadable] their susceptibility to DEP driven inflammation. In Aim 1, we will test the ability of oral SFN to inhibit the local[unreadable] inflammatory effects of nasal DEP challenge alone using cellular infiltration as the primary endpoint. Aim 2[unreadable] will test whether SFN treatment can blunt DEP driven secondary allergic airway inflammation following[unreadable] challenge with DEP plus cat allergen inhibition of DEP driven enhancement of IgE antibody to cat. Aim 3 will[unreadable] determine whether induction of an anti-oxidant response via SFN can prevent DEP dependent primary[unreadable] mucosal allergic sensitization to the neoantigen KLH. Dr. Diaz-Sanchez (Project 3) will assist in the[unreadable] laboratory studies. We will also work with Dr. Nel (Project 1) and Core C using proteomics with informative[unreadable] subjects' nasal samples to investigate novel aspects of the human in vivo response to DEP plus allergen.