title: Vitamin E Isoform γ-Tocotrienol Downregulates House Dust Mite-Induced Asthma.
abstract: Inflammation and oxidative damage contribute to the pathogenesis of asthma. Although corticosteroid is the first-line treatment for asthma, a subset of patients is steroid resistant, and chronic steroid use causes side effects. Because vitamin E isoform γ-tocotrienol possesses both antioxidative and anti-inflammatory properties, we sought to determine protective effects of γ-tocotrienol in a house dust mite (HDM) experimental asthma model. BALB/c mice were sensitized and challenged with HDM. Bronchoalveolar lavage (BAL) fluid was assessed for total and differential cell counts, oxidative damage biomarkers, and cytokine levels. Lungs were examined for cell infiltration and mucus hypersecretion, as well as the expression of antioxidants and proinflammatory biomarkers. Sera were assayed for IgE and γ-tocotrienol levels. Airway hyperresponsiveness in response to methacholine was measured. γ-Tocotrienol displayed better free radical-neutralizing activity in vitro and inhibition of BAL fluid total, eosinophil, and neutrophil counts in HDM mouse asthma in vivo, as compared with other vitamin E isoforms, including α-tocopherol. Besides, γ-tocotrienol abated HDM-induced elevation of BAL fluid cytokine and chemokine levels, total reactive oxygen species and oxidative damage biomarker levels, and of serum IgE levels, but it promoted lung-endogenous antioxidant activities. Mechanistically, γ-tocotrienol was found to block nuclear NF-κB level and enhance nuclear Nrf2 levels in lung lysates to greater extents than did α-tocopherol and prednisolone. More importantly, γ-tocotrienol markedly suppressed methacholine-induced airway hyperresponsiveness in experimental asthma. To our knowledge, we have shown for the first time the protective actions of vitamin E isoform γ-tocotrienol in allergic asthma.
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 119228; Immunology Program, Life Science Institute, National University of Singapore, Singapore 117456;
authors.forename: Hong Yong
authors.initials: HY
authors.lastname: Peh
authors.affiliation: Saw Swee Hock School of Public Health, National University Health System, Singapore 117597; Singapore-MIT Alliance for Research and Technology, National University of Singapore, Singapore 117543;
authors.forename: Wanxing Eugene
authors.initials: WE
authors.lastname: Ho
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 119228;
authors.forename: Chang
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 119228; Immunology Program, Life Science Institute, National University of Singapore, Singapore 117456; Singapore-MIT Alliance for Research and Technology, National University of Singapore, Singapore 117543;
authors.forename: Tze Khee
authors.initials: TK
authors.lastname: Chan
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 119228;
authors.forename: Ann Ching Genevieve
authors.initials: AC
authors.lastname: Seow
authors.affiliation: Department of Respiratory and Critical Care Medicine, Tan Tock Seng Hospital, Singapore 308433;
authors.forename: Albert Y H
authors.initials: AY
authors.lastname: Lim
authors.affiliation: Davos Life Science Private Limited, Singapore 637795; and.
authors.forename: Chee Wai
authors.initials: CW
authors.lastname: Fong
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 119228; Defence Medical and Environmental Research Institute, Defence Science Organisation National Laboratories, Singapore 117510.
authors.forename: Kok Yong
authors.initials: KY
authors.lastname: Seng
authors.affiliation: Saw Swee Hock School of Public Health, National University Health System, Singapore 117597;
authors.forename: Choon Nam
authors.initials: CN
authors.lastname: Ong
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore 119228; Immunology Program, Life Science Institute, National University of Singapore, Singapore 117456; phcwongf@nus.edu.sg.
authors.forename: W S Fred
authors.initials: WS
authors.lastname: Wong
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002839:Chromans / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000276:immunology; D040002:Dermatophagoides pteronyssinus / Q000276:immunology*; D004195:Disease Models, Animal; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011239:Prednisolone / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000276:immunology; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000485:Allergens; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D002839:Chromans; D016207:Cytokines; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D016210:Methacholine Chloride; D014810:Vitamin E; D007073:Immunoglobulin E; C013649:plastochromanol 8; D011239:Prednisolone; D024502:alpha-Tocopherol