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Nitrogen Dioxide Promotes Allergic Sensitization to Inhaled Antigen¹

Mieke Bevelander^*, Jana Mayette^*, Laurie A. Whittaker^*, Sara A. Paveglio^*, Christine C. Jones^*, Justin Robbins, David Hemenway, Shizuo Akira, Satoshi Uematsu and Matthew E. Poynter^2,*

^* Vermont Lung Center and Department of Medicine and School of Engineering, University of Vermont, Burlington, VT 05405; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Allergen sensitization and allergic airway disease are likely to come about through the inhalation of Ag with immunostimulatory molecules. However, environmental pollutants, including nitrogen dioxide (NO₂), may promote adaptive immune responses to innocuous Ags that are not by themselves immunostimulatory. We tested in C57BL/6 mice whether exposure to NO₂, followed by inhalation of the innocuous protein Ag, OVA, would result in allergen sensitization and the subsequent development of allergic airway disease. Following challenge with aerosolized OVA alone, mice previously exposed via inhalation to NO₂ and OVA developed eosinophilic inflammation and mucus cell metaplasia in the lungs, as well as OVA-specific IgE and IgG1, and Th2-type cytokine responses. One hour of exposure to 10 parts per million NO₂ increased bronchoalveolar lavage fluid levels of total protein, lactate dehydrogenase activity, and heat shock protein 70; promoted the activation of NF-B by airway epithelial cells; and stimulated the subsequent allergic response to Ag challenge. Furthermore, features of allergic airway disease were not induced in allergen-challenged TLR2^–/– and MyD88^–/– mice exposed to NO₂ and aerosolized OVA during sensitization. These findings offer a mechanism whereby allergen sensitization and asthma may result under conditions of high ambient or endogenous NO₂ levels.

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 National Institutes of Health, National Center for Research Resources Centers of Biomedical Research Excellence, Grant RR15557 (to M.E.P. and L.A.W.) and by the National Institutes of Health/National Institute on Environmental Health Sciences Transition to Independent Positions Grant K22 ES011652 (to M.E.P.).

² Address correspondence and reprint requests to Dr. Matthew E. Poynter, University of Vermont, Department of Medicine, Division of Pulmonary Disease and Critical Care Medicine, 149 Beaumont Avenue, HSRF 220, Burlington, VT 05405. E-mail address: matthew.poynter{at}uvm.edu

³ Abbreviations used in this paper: NO₂, nitrogen dioxide; Alum, aluminum hydroxide; BAL, bronchoalveolar lavage; BALF, BAL fluid; C_T, threshold cycle; DC, dendritic cell; HEPA, high-efficiency particle air; HSP, heat shock protein; LDH, lactate dehydrogenase; PAS, periodic acid-Schiff; ppm, parts per million; RT, room temperature.

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