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Ambient Ozone Primes Pulmonary Innate Immunity in Mice¹

John W. Hollingsworth^2,*, Shuichiro Maruoka, Zhuowei Li^*, Erin N. Potts^*, David M. Brass, Stavros Garantziotis^*,, Alan Fong, W. Michael Foster^* and David A. Schwartz

^* Duke University Medical Center, Durham, NC 27710; National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; and University of North Carolina, Chapel Hill, NC 27599

Exposure to ozone in air pollution in urban environments is associated with increases in pulmonary-related hospitalizations and mortality. Because ozone also alters clearance of pulmonary bacterial pathogens, we hypothesized that inhalation of ozone modifies innate immunity in the lung. To address our hypothesis, we exposed C57BL/6J mice to either free air or ozone, and then subsequently challenged with an aerosol of Escherichia coli LPS. Pre-exposure to ozone resulted in enhanced airway hyperreactivity, higher concentrations of both total protein and proinflammatory cytokines in lung lavage fluid, enhanced LPS-mediated signaling in lung tissue, and higher concentrations of serum IL-6 following inhalation of LPS. However, pre-exposure to ozone dramatically reduced inflammatory cell accumulation to the lower airways in response to inhaled LPS. The reduced concentration of cells in the lower airways was associated with enhanced apoptosis of both lung macrophages and systemic circulating monocytes. Moreover, both flow cytometry and confocal microscopy indicate that inhaled ozone causes altered distribution of TLR4 on alveolar macrophages and enhanced functional response to endotoxin by macrophages. These observations indicate that ozone exposure increases both the pulmonary and the systemic biologic response to inhaled LPS by priming the innate immune system.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institute on Environmental Health Services (ES12717, ES11961), the National Institute of Allergy and Infectious Diseases (AI58161), and the National Heart, Lung, and Blood Institute (HL91335). This work was also supported, in part, by the Intramural Research Program of the National Institutes of Health, the National Institute on Environmental Health Sciences, and the National Heart, Lung, and Blood Institute.

² Address correspondence and reprint requests to Dr. John W. Hollingsworth, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Box 3136, Durham, NC 27710. E-mail address: holli017{at}mc.duke.edu

³ Abbreviations used in this paper: COPD, chronic obstructive pulmonary disease; AHR, airway hyperresponsiveness; FA, filtered air; LTB₄, leukotriene B₄; PMN, polymorphonuclear cell; ppm, parts per million.