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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
1R01ES023349-01
Application #
8598698
Study Section
Special Emphasis Panel (ZRG1-CVRS-H (02))
Program Officer
Nadadur, Srikanth
Project Start
2013-09-12
Project End
2018-04-30
Budget Start
2013-09-12
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$526,078
Indirect Cost
$177,798
Name
University of North Carolina Chapel Hill
Department
Pediatrics
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Miller, Rachel L; Peden, David B (2014) Environmental effects on immune responses in patients with atopy and asthma. J Allergy Clin Immunol 134:1001-8
Mills, K; Lay, J; Wu, W et al. (2014) Vitamin E, ?-tocopherol, diminishes ex vivo basophil response to dust mite allergen. Allergy 69:541-4