title: Ozone-Induced Type 2 Immunity in Nasal Airways. Development and Lymphoid Cell Dependence in Mice.
abstract: Inhalation exposures to ozone commonly encountered in photochemical smog cause airway injury and inflammation. Elevated ambient ozone concentrations have been epidemiologically associated with nasal airway activation of neutrophils and eosinophils. In the present study, we elucidated the temporal onset and lymphoid cell dependency of eosinophilic rhinitis and associated epithelial changes in mice repeatedly exposed to ozone. Lymphoid cell-sufficient C57BL/6 mice were exposed to 0 or 0.5 parts per million (ppm) ozone for 1, 2, 4, or 9 consecutive weekdays (4 h/d). Lymphoid cell-deficient, Rag2(-/-)Il2rg(-/-) mice were similarly exposed for 9 weekdays. Nasal tissues were taken at 2 or 24 hours after exposure for morphometric and gene expression analyses. C57BL/6 mice exposed to ozone for 1 day had acute neutrophilic rhinitis, with airway epithelial necrosis and overexpression of mucosal Ccl2 (MCP-1), Ccl11 (eotaxin), Cxcl1 (KC), Cxcl2 (MIP-2), Hmox1, Il1b, Il5, Il6, Il13, and Tnf mRNA. In contrast, 9-day ozone exposure elicited type 2 immune responses in C57BL/6 mice, with mucosal mRNA overexpression of Arg1, Ccl8 (MCP-2), Ccl11, Chil4 (Ym2), Clca1 (Gob5), Il5, Il10, and Il13; increased density of mucosal eosinophils; and nasal epithelial remodeling (e.g., hyperplasia/hypertrophy, mucous cell metaplasia, hyalinosis, and increased YM1/YM2 proteins). Rag2(-/-)Il2rg(-/-) mice exposed to ozone for 9 days, however, had no nasal pathology or overexpression of transcripts related to type 2 immunity. These results provide a plausible paradigm for the activation of eosinophilic inflammation and type 2 immunity found in the nasal airways of nonatopic individuals subjected to episodic exposures to high ambient ozone.
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation.
authors.forename: Chee Bing
authors.initials: CB
authors.lastname: Ong
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: 2 Comparative Medicine and Integrative Biology Program; and.
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Brooks
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation.
authors.forename: Christina
authors.initials: C
authors.lastname: Brandenberger
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Lewandowski
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation.
authors.forename: Daven N
authors.initials: DN
authors.lastname: Jackson-Humbles
authors.affiliation: 3 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
authors.forename: Rance
authors.initials: R
authors.lastname: Nault
authors.affiliation: 3 Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Zacharewski
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation.
authors.forename: James G
authors.initials: JG
authors.lastname: Wagner
authors.affiliation: 1 Department of Pathobiology and Diagnostic Investigation.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D018928:Immunity, Mucosal; D018836:Inflammation Mediators / Q000378:metabolism; D019570:Inhalation Exposure; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000276:immunology* / Q000378:metabolism; D010126:Ozone; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D012220:Rhinitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C507942:Il2rg protein, mouse; D018836:Inflammation Mediators; D053631:Interleukin Receptor Common gamma Subunit; D012333:RNA, Messenger; C499308:Rag2 protein, mouse; D010126:Ozone
keywords: mice; ozone; rhinitis; type 2 immunity