The primary goal of this project is to determine if CAM agents (either as monotherapy or as adjunctive agents to established asthma & allergy therapies) minimize airway responses to common inducers of asthma and allergy exacerbation. Ozone and endotoxin are common and important causes of asthma exacerbation which initially induce innate, non-lgE mediated inflammation in asthmatics. Allergen challenge induces IgE mediated airway inflammation. We will employ established, IRB approved, O3, endotoxin and allergen challenge protocols which mimic inflammatory events associated with asthma exacerbation in allergic asthmatic volunteers to determine if CAM therapies inhibit Innate or IgE mediated exacerbation of airway inflammation in vivo. Our collaborators at CHORI (Jiang, Illek & Ames) have employed biochemical and cellular methods to provide mechanistic rationale for using gamma tocopherol (gammaT) as a CAM therapy directed against inflammatory processes in the airway, due to its action as an antioxidant, sparing consumption of other antioxidants, including ascorbate, inhibiting production of inflammatory cytokines such as TNF, and inhibiting production of both CO and LO-pathway derived eicosanoids (prostaglandins & leukotrienes). They have also provided evidence that gammaT is superior to other tocopherol forms in these actions. As gammaT is available as a health supplement with established toxicity profiles indicating safe use in humans, we can immediately commence with Phase I proof of concept testing of the action of gammaT against innate and IgE mediated exacerbation of airway inflammation in allergic asthmatics. We will assess airway inflammation via examination of induced sputum for cell content, monocyte, macrophage and granulocyte function, and immunophenotyping using flow cytometry. Dr. Ames (Core B) will assess serum levels of tocopherols, tocopherol metabolites, oxidative stress products and eicosanoids in these samples. Dr. Patel, (Core C) will oversee assessment of protein mediator levels in sputum samples obtained from these volunteers, assist in assessment of macrophage immunobiology characterization, and using proteomic techniques screen samples for multiple agents for hypothesis generation regarding mechanisms of asthma exacerbation and CAM actions which can subsequently be tested.
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