Ozone enhancement of lower airway allergic inflammation is prevented by γ-tocopherol

Abstract

Ozone is a commonly encountered environmental oxidant which has been linked to asthma exacerbation in epidemiological studies. Ozone induces airway inflammation and enhances response to inhaled allergen. It has been suggested that antioxidant therapy may minimize the adverse effects of ozone in asthma. We have previously shown that the antioxidant gammatocopherol (γT), an isoform of vitamin E, also has anti-inflammatory effects. We employed a Brown Norway rat model of ozone-enhanced allergic responses to test the therapeutic effects of γT on O 3 -induced airway inflammation. Ovalbumin (OVA) -sensitized rats were intranasally challenged with 0 or 0.5% OVA on Days 1 and 2, and exposed to 0 or 1 ppm ozone (8h/day) on Days 4 and 5. Rats were also given 0 or 100 mg/kg γT on Days 2 through 5. Pulmonary tissue and bronchoalveolar lavage fluid (BALF) were collected on Day 6. OVA challenge caused increased total cells (267% increase) and eosinophils (4000%) in BALF that was unaffected by ozone exposure. Morphometric evaluation of lung tissue revealed increases in intraepithelial mucosubstances (IM) (300%) and subepithelial eosinophils (400%) in main axial airways. Ozone exposure of allergic rats enhanced IM increases in proximal axial airways (200%), induced cysleukotrienes, MCP-1 and IL-6 production in BALF, and upregulated expression of IL-5 and IL-13 mRNA. γT treatment had no effect on IM increases by allergen, but blocked enhancement by ozone. γT attenuated both OVA-or ozone -stimulated eosinophilic infiltration, and increases of BALF cys-leukotrienes, MCP-1 and IL-6, as well as IL-5 and IL-13 mRNA. These data Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript demonstrate broad anti-inflammatory effects of a γT and suggest it may be an effective therapy of allergic airway inflammation.

Severe Vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model

“…In clinical studies, α-T appeared to both decrease IgE levels and clinical manifestations of atopy in patients with allergic dermatitis [56] and appeared to have had a small clinical benefit in allergic rhinitis [57]. Of some relevance to the current study is a recent report of dramatic inhibition of murine allergic sensitization responses by the administration of pharmacological doses of γ-T [58,59].…”

“…Finally, it is likely that the administration schedules of α-T, like another pleuropotential biological metabolic modular, nitric oxide [53,61], effect overall allergic reactions differently at various stages of the sensitization-rechallenge cycle. The finding that γ-T administration appear to dramatically ameliorate allergic inflammation when given after antigen stimulation is relevant in this regard [58,59], possibly via mechanisms interacting with prostaglandin metabolic pathways [62][63][64]. Although it has been shown that vitamin E administration can modulate biomarkers of oxidative stress in this model [24], it is possible that non-antioxidant vitamin E functions [65] contribute to the vitamins' modulation of allergic responses.…”

Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases

“…However, compared with ␥-T, carboxychromanols generated from ␣-T are likely to be quantitatively much less important because ␣-T is protected by ␣-tocopherol transfer protein (12,16) and is degraded by tocopherol--hydroxylase to a much less extent (29). To this end, we and others have shown that ␥-T inhibits proinflammatory eicosanoids at the inflammatory site and attenuates inflammation-caused damage in various animal models (14,(30)(31)(32)(33). Himmelfarb et al (34) reported that ␥-T-enriched, but not ␣-T-enriched, mixed tocopherols inhibit proinflammatory C-reactive protein and IL-6 in kidney dialysis patients.…”

Effects of ozone on wild type and transgenic tobacco

“…Although the role of tocopherol in protecting against ozone toxicity is well known in animals (Wagner et al 2007), there are no previous reports, to our knowledge, of how plants with modified levels of tocopherol respond to ozone. Metabolic engineering and nutritional genomics can be used in manipulating the metabolic flux and micronutrients in plants (Chen et al 2006, Della Penna andLast 2006).…”