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).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL089177-03S1
Application #
7839235
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
2009-07-01
Project End
2012-04-30
Budget Start
2009-07-01
Budget End
2012-04-30
Support Year
3
Fiscal Year
2009
Total Cost
$270,817
Indirect Cost
Name
University of Vermont & St Agric College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Ather, Jennifer L; Burgess, Edward J; Hoyt, Laura R et al. (2016) Uricase Inhibits Nitrogen Dioxide-Promoted Allergic Sensitization to Inhaled Ovalbumin Independent of Uric Acid Catabolism. J Immunol 197:1720-32
Ather, J L; Foley, K L; Suratt, B T et al. (2015) Airway epithelial NF-?B activation promotes the ability to overcome inhalational antigen tolerance. Clin Exp Allergy 45:1245-58
Ather, Jennifer L; Martin, Rebecca A; Ckless, Karina et al. (2014) Inflammasome Activity in Non-Microbial Lung Inflammation. J Environ Immunol Toxicol 1:108-117
Ubags, Niki D; Vernooy, Juanita H; Burg, Elianne et al. (2014) The role of leptin in the development of pulmonary neutrophilia in infection and acute lung injury. Crit Care Med 42:e143-51
Li, Shannon; Aliyeva, Minara; Daphtary, Nirav et al. (2014) Antigen-induced mast cell expansion and bronchoconstriction in a mouse model of asthma. Am J Physiol Lung Cell Mol Physiol 306:L196-206
Martin, Rebecca A; Ather, Jennifer L; Lundblad, Lennart K A et al. (2013) Interleukin-1 receptor and caspase-1 are required for the Th17 response in nitrogen dioxide-promoted allergic airway disease. Am J Respir Cell Mol Biol 48:655-64
Palvinskaya, Tatsiana; Antkowiak, Maryellen; Burg, Elianne et al. (2013) Effects of acute and chronic low density lipoprotein exposure on neutrophil function. Pulm Pharmacol Ther 26:405-11
Martin, Rebecca A; Ather, Jennifer L; Daggett, Rebecca et al. (2013) The endogenous Th17 response in NO2-promoted allergic airway disease is dispensable for airway hyperresponsiveness and distinct from Th17 adoptive transfer. PLoS One 8:e74730
Cipolla, Marilyn J; Pusic, Aya D; Grinberg, Yelena Y et al. (2012) Pregnant serum induces neuroinflammation and seizure activity via TNFýý. Exp Neurol 234:398-404
Riesenfeld, Erik; Allen, Gilman B; Bates, Jason Ht et al. (2012) The Temporal Evolution of Airways Hyperresponsiveness and Inflammation. J Allergy Ther 1:1-7

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