Allergic asthma (AA) is the most commonly encountered respiratory disease in the United States and is a leading cause of morbidity worldwide The goals of this project are to undertake phase IIa studies of a gamma tocopherol enriched mixed tocopherol (?T-mT) preparation on chronic eosinophilic inflammation and acute increases in neutrophilic inflammation in allergic asthmatics (AAs) associated with LPS and O3 challenge. Endotoxin (lipopolysaccharide or LPS) is a component of coarse and fine mode PM, bioaerosols, tobacco and biomass smoke. Ozone (O3) is the most commonly encountered ambient air pollutant in the US. Epidemiological studies have shown that both LPS and O3 are important asthma triggers. In challenge studies of AAs, we have shown that LPS and O3 induces influx of neutrophils (PMNs) and eosinophils in AAs as well as augmenting response to inhaled allergens. O3 is also an oxidant, and both O3 and LPS increase radical production by airway cells, with both nutritional and genetically defined antioxidant deficiencies (such as the GSTM1 null genotype) being associated with increased risk for pollutant-induced asthma exacerbation. In challenge studies, we have reported that LPS and O3 PMN responses are increased in GSTM1 null volunteers. Gamma tocopherol has known antioxidant and anti-inflammatory actions. We have shown that ?T prevents allergen, O3 and LPS-induced respiratory tract inflammation in rodents. Our phase I human studies with ?T-mT established a dose which maintains ?T and its anti-inflammatory metabolites, decreases monocyte responses to LPS and IgE-mediated basophil response to allergen. Data from our initial double-blinded, placebo controlled phase IIa study in healthy volunteers demonstrates that ?T-mT inhibits LPS-induced granulocyte influx. Successful completion of this phase IIa study in AAs will guide development of a phase III efficacy study of this low cost nutriceutical intervention for preventio of pollutant-induced asthma exacerbations.
Gamma tocopherol is a vitamin E isoform that has antioxidant and anti-inflammatory actions, and we have shown that it prevents acute inflammatory responses in animal and humans. We will test the ability of this agent to reduce chronic eosinophilic inflammation and prevent LPS and O3-induced inflammation in allergic asthmatics. Such actions would demonstrate feasibility of using this as an inexpensive asthma therapeutic.
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