Nitrogen Dioxide in the Sensitization to Allergic Airway Disease

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DESCRIPTION (provided by applicant): The incidence of allergic asthma has risen steadily over the last 20 years and now represents an enormous health and financial burden. Reasons for this rise remain unclear, but increases in ambient pollutant levels, including the toxic free radical gas, nitrogen dioxide (NO2), correlate with the incidence of allergy and asthma. Additionally, children with severe respiratory viral infections, in which NO2 is generated endogenously, are at an elevated risk of developing asthma later in life. However, the molecular mechanisms by which NO2 exposure may facilitate allergic sensitization, leading to the development of allergic airway disease remains unknown. Elucidating these mechanisms is the subject of this proposal. Certain endogenous molecules, including components of the debris released from necrotic cells, may be immunostimulatory by signaling through Toll-Like Receptor (TLR)2 or TLR4, leading to intracellular signaling involving the adaptor protein, MyD88, and activation of the transcription factor, NF-kappaB. In pulmonary epithelial cells, NF-kappaB modulates expression of CCL20, which promotes the recruitment of dendritic cells (DCs) to the lungs. DCs induce adaptive immune responses by stimulating T helper cells in an antigen- specific manner and may polarize them towards Th2, steps necessary to confer sensitization to allergic airway disease. The central hypothesis of this proposal is that NO2 exposure facilitates the sensitization to inhaled antigen through the stimulation of pulmonary epithelial TLR2 orTLR4, MyD88, and NF-kappaB, promoting dendritic cell recruitment and maturation. This hypothesis will be tested in three specific aims in which allergic sensitization and the generation of cardinal features of allergic airway disease will be measured in mice deficient (TLR2, TLR4 or MyD88) or inhibited (airway and/or alveolar type 2 epithelial NF-kappaB) in members of these signaling pathways, as well as in bone marrow chimeric mice, in order to distinguish the importance of these molecules in cells of hematopoietic origin (DCs) versus structural lung cells (epithelium).