Ozone toxicity: targeting the resolution of inflammation

Rutgers, The State Univ Of N.J., New Brunswick NJ

Investigators

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Abstract

Project Summary Abstract Ozone is a ubiquitous urban air pollutant generated from the reaction of automobile emissions and sunlight. Inhaled ozone is highly reactive and causes airway inflammation and hyperresponsiveness in both healthy and susceptible populations including children, the elderly, and individuals with chronic lung disease. Extensive evidence from our research team indicates that macrophages play a critical role in ozone-induced lung injury. Inhalation of ozone results in an accumulation of macrophages in the lung where the tissue microenvironment sequentially polarizes them into distinct subpopulations that release pro- or anti- inflammatory mediators to coordinate the acute inflammatory and later resolution phases of tissue injury and repair. Recent data from our group indicate that impaired accumulation of anti-inflammatory macrophages, in the absence of pro-inflammatory macrophages, is sufficient to promote toxicity after ozone exposure in mice; this suggests that ozone-induced lung injury results from aberrant resolution of inflammation and wound repair. The goal of the proposed studies is to elucidate anti-inflammatory signaling mechanisms in macrophages that regulate the resolution of inflammation that may be targeted therapeutically to reduce ozone-induced lung injury. Preliminary data indicate that ozone causes reduced mRNA expression of peroxisome proliferator activated receptor ? (PPAR?) and downstream signaling targets of PPAR?, which play key roles in limiting inflammation and promoting tissue repair. Our central hypothesis is that ozone causes dysregulation of PPAR? signaling in macrophages resulting in defective development of an anti-inflammatory/pro- resolution phenotype; this leads to prolonged injury, oxidative stress, and inflammation. To test this hypothesis, we will characterize PPAR? signaling in lung macrophages from mice and humans exposed to ozone. Then, we will analyze effects of modulating PPAR? on macrophage phenotype and ozone toxicity. This will be accomplished using myeloid-specific PPAR? coactivator 1 beta (PGC1b) knockout mice, which exhibit impaired PPAR? signaling, and by administering nitrated oleic acid (OaNO2), an endogenous PPAR? ligand to wild type mice. Our expectation is that mice lacking PGC1b will be hypersensitive to ozone, while enhancing PPAR? signaling with OaNO2 will result in reduced ozone-induced oxidative stress, tissue injury, and altered pulmonary function. This will be associated with decreases and increases in anti-inflammatory/wound repair macrophages in the transgenic mice and mice supplemented with OaNO2, respectively. Results of these studies will have significant translational implications for the development of new strategies for preventing and treating ozone toxicity, and possibly other agents that induce lung inflammation. The described coursework, training, and research activities will facilitate the PI?s development into an independent scientist in academic toxicology.