Ambient ozone is associated with increased respiratory illness, hospitalizations, and cardiovascular mortality. Because the lung is recurrently exposed to low level ozone, understanding how ozone modifies immune mechanisms is of considerable importance to human health. The investigators have recently demonstrated that ozone enhances both systemic and pulmonary innate immune response to lipopolysaccharide (LPS) including cytokine production, lung injury, and airway hyper-responsiveness. In addition, ozone exposure enhances subsequent LPS-induced inflammatory cell apoptosis, lowering the concentration of inflammatory cells in the alveoli. The investigators have discovered that the mechanism of ozone-priming of innate pulmonary immunity, in part, involves enhanced surface expression of toll-like receptor 4 (tlr4) on alveolar macrophages, which amplifies the biological response to inhaled LPS. The investigators now have evidence that ozone-induced release of short-fragment hyaluronan contributes to the innate immune response, and published work supports the role of NF-?B in both the response to ozone and trafficking of toll-like receptors. It is also clear that ozone inhalation is associated with the formation of reactive oxygen species (ROS), and the investigators observe that activation of NF-?B in the lung after ozone is facilitated by NADPH oxidase (NOX). However, it remains unknown whether either NOX or ROS regulate surface expression of toll-like receptor 4 and the role of surface recognition of hyaluronan in ozone priming innate immunity remain unexplored. Mechanistic understanding of the pathways that regulate trafficking of toll-like receptor 4 after exposure to this common air pollutant is of considerable interest in the pathogenesis of environmental airways disease. Thus, the overall hypothesis of this proposal is that ambient ozone modulates pulmonary innate immunity through enhanced trafficking of tlr4 to the surface of alveolar macrophages resulting in an enhanced functional response to lipopolysaccharide. Furthermore, ozone-induced trafficking of tlr4 is the result of proteolytic release of short-fragment hyaluronan, leading to NF-?B activation and amplification of the airway inflammatory response in a manner dependent on NOX2 and ROS-production. The investigators will address this hypothesis through the following Specific Aims.
Specific Aim 1 : Determine whether release of soluble hyaluronan contributes to ozone-dependent priming of LPS response in the lung and macrophages.
Specific Aim 2 : Determine the role of NF-?B activation in ozone priming of pulmonary innate immunity in lung macrophages.
Specific Aim 3 : Determine the role of NOX2 in regulating tlr4-dependent responses in macrophages after exposure to ozone.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES016126-05
Application #
8294728
Study Section
Special Emphasis Panel (ZES1-JAB-C (R2))
Program Officer
Nadadur, Srikanth
Project Start
2008-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$400,456
Indirect Cost
$140,358
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
Stober, Vandy P; Szczesniak, Christopher; Childress, Quiana et al. (2014) Bronchial epithelial injury in the context of alloimmunity promotes lymphocytic bronchiolitis through hyaluronan expression. Am J Physiol Lung Cell Mol Physiol 306:L1045-55
Li, Zhuowei; Tighe, Robert M; Feng, Feifei et al. (2013) Genes of innate immunity and the biological response to inhaled ozone. J Biochem Mol Toxicol 27:3-16
Horr, Samuel; Roberson, Russell; Hollingsworth, John W (2013) Pseudohypoxemia in a patient with chronic lymphocytic leukemia. Respir Care 58:e31-3
Potts-Kant, Erin N; Li, Zhuowei; Tighe, Robert M et al. (2012) NAD(P)H:quinone oxidoreductase 1 protects lungs from oxidant-induced emphysema in mice. Free Radic Biol Med 52:705-15
Ledford, Julie G; Mukherjee, Sambuddho; Kislan, Michele M et al. (2012) Surfactant protein-A suppresses eosinophil-mediated killing of Mycoplasma pneumoniae in allergic lungs. PLoS One 7:e32436
Tighe, Robert M; Li, Zhuowei; Potts, Erin N et al. (2011) Ozone inhalation promotes CX3CR1-dependent maturation of resident lung macrophages that limit oxidative stress and inflammation. J Immunol 187:4800-8
Heise, Rebecca L; Stober, Vandy; Cheluvaraju, Chaitra et al. (2011) Mechanical stretch induces epithelial-mesenchymal transition in alveolar epithelia via hyaluronan activation of innate immunity. J Biol Chem 286:17435-44
Lindsey, James Y; Ganguly, Koustav; Brass, David M et al. (2011) c-Kit is essential for alveolar maintenance and protection from emphysema-like disease in mice. Am J Respir Crit Care Med 183:1644-52
Al-Hegelan, Mashael; Tighe, Robert M; Castillo, Christian et al. (2011) Ambient ozone and pulmonary innate immunity. Immunol Res 49:173-91
Li, Zhuowei; Potts-Kant, Erin N; Garantziotis, Stavros et al. (2011) Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. PLoS One 6:e27137

Showing the most recent 10 out of 22 publications