title: Inhalation exposure to ethylene induces eosinophilic rhinitis and nasal epithelial remodeling in Fischer 344 rats.
abstract: This study investigated the time- and concentration-dependent effects of inhaled ethylene on eosinophilic rhinitis and nasal epithelial remodeling in Fisher 344 rats exposed to 0, 10, 50, 300, or 10,000 ppm ethylene, 6 h/day, 5 days/week for up to 4 weeks. Morphometric quantitation of eosinophilic inflammation and mucous cell metaplasia/hyperplasia (MCM) and nasal mucosal gene expression were evaluated at anatomic sites previously shown to undergo ethylene-induced epithelial remodeling. Serum levels of total IgE, IgG1 and IgG2a were measured to determine if ethylene exposure increased the expression of Th2-associated (IgE and IgG1) relative to Th1-associated (IgG2a) antibody isotypes. Rats exposed to 0 or 10,000 ppm for 1, 3, 5, 10, or 20 days were analyzed to assess the temporal pattern of ethylene-induced alterations in nasal epithelial cell proliferation, morphology and gene expression. Rats exposed to 0, 10, 50, 300, and 10,000 ppm ethylene for 20 days were analyzed to assess concentration-dependent effects on lesion development. Additional rats exposed 4 weeks to 0, 300, or 10,000 ppm ethylene were held for 13 weeks post-exposure to examine the persistence of ethylene-induced mucosal alterations. The data indicate that cell death and reparative cell proliferation were not a part of the pathogenesis of ethylene-induced nasal lesions. Enhanced gene expression of Th2 cytokines (e.g., IL-5, IL-13) and chitinase (YM1/2) in the nasal mucosa was much greater than that of Th1 cytokines (e.g., IFNγ) after ethylene exposure. A significant increase in MCM was measured after 5 days of exposure to 10,000 ppm ethylene and after 20 days of exposure 10 ppm ethylene. Ethylene-induced MCM was reversible after cessation of exposure. No increase in total serum IgE, IgG1 or IgG2a was measured in any ethylene-exposed group. These data do not support involvement of an immune-mediated allergic mechanism in the pathogenesis of ethylene-induced nasal lesions in rats. Repeated inhalation of ethylene can induce a local Th2-mediated response in the nasal mucosa of rats, however the mechanisms which induce nasal inflammatory and epithelial responses are yet to be determined.
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Brandenberger
authors.affiliation: Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, 48674, MI, USA. Electronic address: jahotchkiss@dow.com.
authors.forename: Jon A
authors.initials: JA
authors.lastname: Hotchkiss
authors.affiliation: Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, 48674, MI, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Krieger
authors.affiliation: Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, 48674, MI, USA.
authors.forename: Lynn H
authors.initials: LH
authors.lastname: Pottenger
authors.affiliation: Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, 48823, MI, USA.
authors.forename: Jack R
authors.initials: JR
authors.lastname: Harkema
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D005030:Ethylenes / Q000009:adverse effects*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006965:Hyperplasia / Q000139:chemically induced / Q000378:metabolism; D007136:Immunoglobulins / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D019570:Inhalation Exposure / Q000009:adverse effects*; D008679:Metaplasia / Q000139:chemically induced / Q000378:metabolism; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D012220:Rhinitis / Q000139:chemically induced* / Q000378:metabolism
chemical_list: D005030:Ethylenes; D007136:Immunoglobulins; C036216:ethylene
keywords: Eosinophilic rhinitis; Ethylene; Mucoushyperplasia/metaplasia; Nasal epithelial remodeling; Rat