The overall goal of this project is to understand how and why air pollufion alters lung host defense. The environmental, clinical, and biological significance of this project is supported by the following observations. First, air pollution accounts for substantial morbidity and mortality throughout the world, including lung infecfions and preventable deaths in children. Second, endotoxin is ubiquitous in the environment and is associated with the development and progression of asthma and other forms of ainvay disease. Third, the ability of the host to respond to lipopolysaccharide and other PAMPs (pathogen associated molecular patterns) is highly variable in mice and humans, yet polymorphic host defense genes only account for a portion of this variable response. Fourth, innate immunity provides a first line of host defense against microbial pathogens that is conserved over a wide variety of species from flies to mammals, and innate immune signaling mechanisms in mice are almost idenfical to those in humans. Finally, the innate immune system is dynamic biologically, and is responsive to both ozone and PAMPs. We have recently found that the expression of innate immune receptors on macrophages can be enhanced by ozone or PAMPs. Moreover, others have reported that innate immune cells avoid excessive PAMP induced inflammation by downregulafing proinflammatory genes while continuing to transcribe anfimicrobial genes. Thus, the overall hypothesis of this project is that the expression of toll-like receptors (TLRs) in the lung are influenced by environmental (ozone and/or PAMPs) and genefic factors, and the dynamic expression of TLRs has profound effects on lung host defense and consequently the development of lung infections and allergic airway disease. To test this hypothesis, we will pursue the following aims. 1.Determine the effect of in vitro exposures to ozone and/or PAMPs on the expression of TLRs in murine macrophages and dendritic cells. 2.Determine the effect of in vivo exposures to ozone and/or PAMPs on the expression of TLRs in mouse lungs. 3.Determine the effect of in vivo exposures to ozone and/or PAMPs on suscepfibility to lung pathogens. 4.Determine the effect of in vivo exposures to ozone and/or PAMPs on house dust mite (HDM) sensitization and the development of HDM induced allergic ainvay disease in mice.

Public Health Relevance

Respiratory conditions in children are a serious public health concern throughout the world. Asthma is the most common chronic childhood disease, affecting 9 million children in the U.S. This disease is increasing in prevalence, incidence, and severity, particularly in developed countries. Air pollution accounts for substantial morbidity and mortality in children. The overall goal of this project is to understand how and why air pollution alters lung host defense and places children at risk of developing lung infections and asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Program Projects (P01)
Project #
5P01ES018181-05
Application #
8529258
Study Section
Special Emphasis Panel (ZES1-LKB-G)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$355,512
Indirect Cost
$127,670
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
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Szefler, Stanley J (2012) Advances in pediatric asthma in 2011: moving forward. J Allergy Clin Immunol 129:60-8
Yang, Ivana V; Tomfohr, John; Singh, Jaspal et al. (2012) The clinical and environmental determinants of airway transcriptional profiles in allergic asthma. Am J Respir Crit Care Med 185:620-7

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