Ozone is a ubiquitous air pollutant and the main component of photochemical smog. It remains a federally regulated air pollutant of ongoing public health concern. Inhaled ozone has been shown to irritate and damage the lung in both healthy and susceptible individuals, including children and the elderly. Ozone causes inflammation and constriction of the airways, reducing pulmonary function. Ozone also exacerbates asthma and suppresses nonspecific immunity, increasing susceptibility to respiratory infections. Thus, elucidating the specific inflammatory mechanisms contributing to toxicity is highly relevant in terms of identifying new strategies to reduce lung injury from ozone and potentially other air pollutants. Our laboratories have discovered that macrophages play a dual role in ozone toxicity, contributing to both lung injury and repair and that this activity is mediated by distinct macrophage subpopulations. We hypothesize that ozone toxicity is the result of cytotoxic proinflammatory macrophages overwhelming the activity of anti-inflammatory reparative macrophages. To test this hypothesis, the phenotype of macrophages responding to ozone-induced injury will be assessed in human subjects and in rodents using techniques in flow cytometry/cell sorting and confocal microscopy. Lineage tracking strategies and chimeric mice will be used to analyze the origin of macrophage subpopulations and mechanisms mediating their accumulation in the lung. Genetically altered mice with conditional defects in proinflammatory macrophages or monocytes precursors will be used to assess their contribution to toxicity. These studies are important as our preliminary data suggest that monocyte precursors originate not only from the bone marrow, but also the spleen. We will also analyze mechanisms mediating macrophage accumulation in the lung using mutant mice with defects in specific chemokines receptors. Successful completion of these studies will result in a more precise mechanistic understanding of the specific roles of different types of macrophages in ozone toxicity, their origin, and mechanisms mediating their accumulation in the lung. This will have significant translational implications for the development of new strategies for preventing and treating the toxicity of ozone, and possibly other agents that induce inflammatory lung injury.

Public Health Relevance

Ozone is a ubiquitous urban air pollutant that causes significant adverse health effects in healthy and susceptible individuals, including children and the elderly. Our studies are focused on elucidating inflammatory mechanisms contributing to ozone toxicity in humans and experimental animals. This is key to development of new strategies to reduce lung injury and disease arising from exposure to ozone, as well as other agents that cause inflammatory lung damage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES004738-22
Application #
9034574
Study Section
Special Emphasis Panel (ZRG1-DKUS-C (90))
Program Officer
Nadadur, Srikanth
Project Start
1989-06-01
Project End
2019-12-31
Budget Start
2016-01-01
Budget End
2016-12-31
Support Year
22
Fiscal Year
2016
Total Cost
$523,031
Indirect Cost
$181,891
Name
Rutgers University
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
001912864
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
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