The fundamental role of innate and adaptive host response is to recognize and defend against air toxics, invading antigens, pathogens or altered self components with the purpose of restoring tissue integrity and homeostasis. While resolution occurs during normal host response, an exogenous insult cannot be contained if basic defense factor(s) become dysregulated, and/or environmental-induced injury leads to tissue remodelling and chronic respiratory disease. The program will investigate a protein, surfactant protein A (SP-A) that is essential to host defense. The focus on SP-A narrows in on structural and metabolic changes regulated by host factors and/or oxidative changes in asthma that may reduce the ability of the protein to defend the host from environmental challenges such as bacterial infection and exposure to the prototypal air pollutant, ozone. Exposures to these agents exacerbate asthma phenotypes: airflow obstruction, airway hyperpermability, and mucus hypersecretion. Case control studies associate ambient ozone levels with reduced lung growth in children, and retrospective review of hospital records suggest increased ER visits by subjects with asthma, both young and elderly, due to exacerbation of their airway disease, concurrent with ozone exposure.
Research Aims will test the hypothesis that the most common polymorphism of SP-A (rs1965708) dysregulates the protein's ability to protect the respiratory epthelial surfaces of humans from ozone-induced oxidative injury. The proposed research is human based and applied.
Aim 1 will determine if asthmatics are differentially responsive to ozone, and is senstivity to ozone dependent or modulated by the SP-A 223 polymorphism.
Aim 2 will determine if structural and biochemical changes in the SP-A protein associate with the SP-A 223 polymorphism, and do these changes alter the biologic function of the protein.
Aim 3 will investigate in mouse models of epithelial injury, and depletion of SP-A if anti-oxidant intervention, or repletion with SP-A, respectively can attentuate the oxidative effects of ozone, and protect SP-A. The research plan is at the interface of clinical asthma and environmental toxicology and will identify genetic factors that are intrinsic to oxidant induced lung injury, and has the potential to establish the functional status of the SP-A 223 polymorphism. Our extensive data base of healthy subjects supports the plan to study the most common polymorphism of the SP- A2 gene, and investigate its association in asthmatic subjects who sustain airway injury and increases in epithelial permeability during exposure to ozone.

Public Health Relevance

Diverse cellular defenses are available for protecting the lung from the harmful effects and penetration of airborne vectors that deposit onto epithelial surfaces. The three research Projects of the Program are complimentary, and will enhance understanding of genetic, immunologic, and physiologic factors that regulate host defense by SP-A and protect the lung from injury in the presence of chronic disease of asthma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
4P01AI081672-03
Application #
8325218
Study Section
Special Emphasis Panel (ZAI1-QV-I (J1))
Project Start
2009-09-12
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$355,454
Indirect Cost
Name
Duke University
Department
Type
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Mitsuhashi, Atsushi; Goto, Hisatsugu; Kuramoto, Takuya et al. (2013) Surfactant protein A suppresses lung cancer progression by regulating the polarization of tumor-associated macrophages. Am J Pathol 182:1843-53
Kaushik, S Sivaram; Freeman, Matthew S; Cleveland, Zackary I et al. (2013) Probing the regional distribution of pulmonary gas exchange through single-breath gas- and dissolved-phase 129Xe MR imaging. J Appl Physiol (1985) 115:850-60
Horr, Samuel; Roberson, Russell; Hollingsworth, John W (2013) Pseudohypoxemia in a patient with chronic lymphocytic leukemia. Respir Care 58:e31-3
Murphy, Susan K; Hollingsworth, John W (2013) Stress: a possible link between genetics, epigenetics, and childhood asthma. Am J Respir Crit Care Med 187:563-4
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

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