Laboratory studies have demonstrated that short-term single exposure of adult humans to ambient levels of O3 leads to inflammation of the airway. Lung inflammation is observable 3-18 hr after exposure, and is not correlated to the functional changes that arise during exposures or slowly dissipate during recovery, 1-2 hr post-exposure. The inflammation is characterized by an influx of polymorphonuclear leukocytes and increases in total protein, albumin, pro-inflammatory cytokines, and granulocyte-macrophage colony-stimulating factor in bronchoalveolar lavage fluid. Significant inter-individual variation in the inflammatory response is found among otherwise homogeneous subjects suggesting that intrinsic host factors contribute to the magnitude of beta3-induced lung injury. Further, although ambient exposure to beta3 is frequently intermittent, whether the severity of inflammation increases upon re-exposure remains controversial. Thus, basic questions remain: 1) is the inter-individual nature of the inflammatory response to O3 explained by host factors, i.e., genetic background, and 2) do inflammatory airway responses in sensitive subjects adapt upon re-exposure to O3? Understanding the mechanisms intrinsic to O3-induced airway inflammation is essential for predicting host susceptibility and risk of lung and epithelial injury from exposure to O3. Our HYPOTHESIS is that specific gene polymorphisms/mutations contribute to differential susceptibility to O3-induced lung injury in healthy subjects and are host factors that regulate risk of exposure to O3. We will use a multi-disciplinary approach that applies physiologic and genetic techniques to a controlled human exposure system.
Specific aims will determine: 1) the range in susceptibility of humans to develop airway inflammation and hyperpermeability after a single exposure to O3, and 2) if subjects differentially susceptible to ozone maintain their sensitivity during intermittent exposure to O3, and 3) the association of selected genetic markers with O3-induced lung injury and airway inflammatory responses. These investigations will help to establish genetic background as a host factor in the susceptibility of humans to O3 exposure and utility of genetic factors as biomarkers of lung injury induced by inhalable oxidants and environmental pollutants.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062641-05
Application #
6638540
Study Section
Special Emphasis Panel (ZRG1-ALTX-1 (01))
Program Officer
Harabin, Andrea L
Project Start
2000-04-01
Project End
2007-03-31
Budget Start
2003-04-01
Budget End
2007-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$383,823
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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