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.

TLR-7 agonist attenuates airway reactivity and inflammation through Nrf2-mediated antioxidant protection in a murine model of allergic asthma

“…Among these mediators, ROS generation is also thought to be responsible for various aspects of airway hyperresponsiveness and inflammation (Nadeem et al, 2014bRyu et al, 2013). This has been confirmed by ROS scavengers which attenuate allergen induced airway hyperresponsiveness and inflammation in various animal models of asthma (Nadeem et al, 2014b;Peh et al, 2015). Furthermore, different isoforms of NOX have been shown to regulate airway inflammation and hyperreactivity in both animal and human studies (Sutcliffe et al, 2012;Nadeem et al, 2014bNadeem et al, , 2015Voraphani et al, 2014).…”

Recent developments in the role of reactive oxygen species in allergic asthma

“…The role of LTC 4 in allergic asthma has been extensively evaluated (85). LTC 4 is produced in mast cells by assembly of a biosynthetic complex at the nuclear envelope, consisting of cytosolic phospholipase A2 (cPLA2), (64) Oxi-CaMKII inhibitor KN-93 KN-93 significantly decreased goblet cell hyperplasia, bronchial epithelial thickness, airway eosinophilia, the eosinophil chemoattractant molecule, Ccl-11, and NF-κB activity in allergic asthma (61) Leukotriene C4 (LTC 4 ) inhibitor A LTC 4 inhibitor reduced NOX4 levels and attenuated cell death (32) Galangin Galangin demonstrated decreased airway remodeling, angiogenic activity, and ASMC proliferation through the TGF-β1-ROS-MAPK pathway (65)(66)(67) Astragalin Astragalin suppressed LPS-induced ROS production and eotaxin-1 expression in epithelial cells through the TLR4-PKCγ1-PKCβ2-NADPH signaling pathway (68,69) Glutathione GSH balances Th1/Th2 responses, alters nitric oxide metabolism and inhibits ROS (55,59,70) SOD SODs protects against the harmful effects of ROS and airway inflammation (71)(72)(73) Glutathione peroxidases Glutathione peroxidases prevent airway inflammation and alveolar destruction (74)(75)(76) Vitamins C and E Vitamins C and E reduce AHR, inflammation, and oxidative stress (77)(78)(79) TLR7, toll-like receptor 7; Oxi-CaMKII, oxidative-CaMKII; SOD, superoxide dismutase; AHR, airway hyper-reactivity; Nrf2, nuclear factor E2-related factor 2; Cu/Zn SOD, copper/zinc superoxide dismutase; ROS, reactive oxygen species; NOX4, NADPH oxidase 4; LPS, lipopolysaccharide; Th2, type 2 helper T.…”

“…A study demonstrated that oral γ-tocotrienol markedly abated house dust mite (HDM)-induced increases in airway inflammatory, serum IgE levels, cytokine and chemokine levels, mucus production, and oxidative damage biomarkers. The protective mechanisms of γ-tocotrienol are likely mediated by blocking nuclear NF-κB translocation and augmenting Nrf2 nuclear levels, as shown in an allergic asthma model (78). Harada showed that γ-tocotrienol could contribute to the therapeutic airway remodeling benefits in asthma by inhibiting HASMC proliferation and migration (79).…”

Ribosomal protein S3 gene silencing protects against experimental allergic asthma

“…Ltd. (Singapore). Mice were anaesthetized with isoflurane (Halocarbon Products, River Edge, NJ, USA) and were given 40 μL of 100 μg HDM or saline (negative control) intratracheally on days 0, 7 and 14 to develop experimental asthma (Peh et al, 2015). RPS3 siRNA (1 and 5 nmol) or non-targeting control siRNA in 30 μL PBS was given once daily via the intratracheal route on days 11-13 (Goh et al, 2013).…”

“…Mice were anaesthetized, and tracheotomy and intubation were performed (Peh et al, 2015). The trachea was intubated with a cannula that was connected to the pneumotach, ventilator and nebulizer.…”