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Your Environment. Your Health.

ACTIVATED MACROPHAGES AND OZONE TOXICITY

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/R01ES004738/format/word)
Principal Investigator: Laskin, Debra L
Institute Receiving Award Rutgers, The State Univ Of N.J.
Location Piscataway, NJ
Grant Number R01ES004738
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jun 1989 to 31 Dec 2021
DESCRIPTION (provided by applicant): : 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.
Science Code(s)/Area of Science(s) Primary: 69 - Respiratory
Publications See publications associated with this Grant.
Program Officer Srikanth Nadadur
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