Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled O3 Exposure
Condition: Allergic Asthma
Study type: Interventional
Phase: Phase 2

Summary: 
      To study the effects of 1200mg gamma tocopherol, a form of vitamin E, given daily on the
      response of the airway in mild asthmatics after exposure to ozone (O3)
    

Detailed description: 
      Allergic asthma (AA) is the most commonly encountered respiratory disease in children and
      adults in the United States and is a leading cause of morbidity worldwide. Among the most
      disruptive expressions of disease in AA is acute asthma exacerbation. The Center for Disease
      Control (CDC) lists ambient air pollutants and environmental tobacco smoke as among the most
      common triggers for acute asthma exacerbation. Ozone (O3) is the most commonly encountered
      ambient air pollutant in the US.

      Increased oxidative stress and decreased antioxidant capability have been observed in
      asthmatics. These pollutants are pro-inflammatory and are associated with increased oxidative
      stress, which would exacerbate reactive oxygen and reactive nitrogen species (ROS and
      RNS)-induced injury in asthmatics. O3 injures epithelial cells, releasing secondary mediators
      which activate inflammatory cells, in part by ligation of Toll-like receptor 4 (TLR4), the
      primary receptor for lipopolysaccharide (LPS). TLR4 activation of inflammatory cells
      activates (nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and induces
      oxidative stress. O3 and LPS has been associated with exacerbation of asthma, and the
      investigators have reported that O3 and LPS augments allergic airway inflammation in allergic
      asthmatics (AA). Development of interventions to mitigate these responses will greatly
      decrease disease morbidity. Given the role that oxidants play in the pathophysiology of
      asthma exacerbation, defects in antioxidant levels would increase risk for acute asthma
      exacerbation. Nutritional deficiencies in vitamin E, ascorbate and selenium have been linked
      to asthma severity, and asthmatics have decreased antioxidant levels in airway fluid. It has
      been shown that vitamins C and E are decreased in airway fluids of asthmatics. Additionally,
      genetic factors may increase risk for oxidant induced exacerbation of asthma. Many
      investigators have reported that persons who are homozygous for the null polymorphism of the
      Glutathione-S-Transferase Mu1 (GSTM1) gene and unable to produce GSTM1 protein (the GSTM1
      null genotype) have increased risk of acute pollutant-induced exacerbation of asthma. This
      lab has shown in healthy volunteers that the GSTM1 null genotype is associated with increased
      inflammatory response to O3, with no impact on the nociceptive response to this pollutant.

      Other researchers have shown that the GSTM1 null genotype is associated with increased
      response to secondhand tobacco smoke, diesel exhaust, and other particulate matter
      components. Romieu et al demonstrated that children with asthma in Mexico City had increased
      susceptibility to O3-induced exacerbations if they had the GSTM1 null genotype. This group
      also found that GSTM1 null AAs selectively benefited from antioxidant intervention. The GSTM1
      null genotype is found in 20-40% of the population, and may be overrepresented in allergic
      populations. Taken together, these observations show that the sizable GSTM1 null population
      is at risk for pollutant-induced airway disease, and that antioxidant intervention targeting
      the action of ROS and RNS will benefit asthmatics and especially GSTM1 null asthmatics.

      A non-exclusive list of proposed antioxidants includes radical scavengers such as ascorbate,
      a-tocopherol (aT), y-tocopherol (γT) or inducers of Nuclear factor erythroid-2-related factor
      2 (NRF2), which activate NRF2 with subsequent broad upregulation of acute phase II and
      antioxidant proteins. These agents are available in naturally occurring foods and as
      nutritional supplements. A number of animal, cell culture and epidemiological studies support
      the idea that antioxidant supplementation is useful in allergic airway disease. However,
      despite these studies and widespread public and scientific enthusiasm regarding use of such
      agents in asthmatics, there are scant human data to support or refute the use of such
      interventions for either acute or chronic allergic airways disease.

      Gamma tocopherol has both radical scavenging and anti-inflammatory actions which may play
      important roles in decreasing pollutant-induced and allergic injury to the airway. Like other
      isoforms of vitamin E, γT is a potent ROS scavenger and is also a powerful nucleophile that
      traps electrophiles such as peroxynitrite in lipophilic compartments. One mechanism by which
      γT is cytoprotective is scavenging of RNS at the un-substituted C-5 position on the
      hydroxy-chroman ring of γT to form 5-NO-γ-tocopherol (5-NO-γT). Overall, vitamin E provides
      general protection of DNA, lipids and proteins from radical stress. An example of such
      protection is shown in rodent studies of prostate cancer in which intake of γT is associated
      with decreased DNA methylation of CpG rich regions of the NRF2. NRF2 is a master regulator of
      numerous cytoprotective antioxidant enzymes.

      Supplementation with γT also prevents protein nitration and attenuates loss of plasma vitamin
      C in plasma in a rodent peritonitis model of inflammation. The investigators have also shown
      that γT inhibits Cyclooxygenase (COX)-2 and 5-Lipoxygenase (LO) in LPS-stimulated macrophages
      and interleukin (IL)-1b stimulated epithelial cells. These actions are mediated primarily by
      the γT metabolite 2, 7, 8-trimethyl-2S-(.-carboxyethyl)-6-hydroxychroman (γ-CEHC) which
      requires hydroxylation of the γ-methyl group of γT by cytochrome P450 (CYP450). In
      carrageenan- induced inflammation in male Wistar rats, γT decreases prostaglandin (PGE2) and
      leukotriene (LTB4) production, suggesting that LO-mediated production of leukotrienes may
      also be inhibited by γT. Tocopherols, including γT, also modulate gene expression of a number
      of inflammatory genes. Thus, γT and other tocopherols decrease production of a number of
      pro-inflammatory cytokines at the transcriptional level.

      In animals, it has also been shown that gamma tocopherol reduces baseline eosinophilia in the
      airway. In early phase I studies of gamma tocopherol-enriched mixed tocopherols (γT-mT) the
      investigators have shown that γT-mT inhibits monocyte induced cytokine production, decreases
      baseline nitrosative stress, and inhibits LPS eosinophil and neutrophil influx in healthy
      volunteers.

      SUMMARY:

      There is widespread opinion that antioxidant nutrients like gamma tocopherol ( γT, a form of
      Vitamin E) are an untapped and inexpensive intervention for environmentally triggered acute
      asthma. However, there is a crucial gap in evidence-based support of such interventions in
      asthma. A lack of coordinated research assessing specific antioxidant regimens from
      preclinical, phase I and phase II studies impedes development of phase III antioxidant trials
      in asthmatic populations. It is also unclear which physiological endpoints are most relevant
      in such studies.
    

Intervention name(s): gamma tocopherol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): The effect of supplemental with gamma tocopherol on O3 response will be assessed using the difference pre and after γT dosing.; The effect of supplemental with gamma tocopherol on O3 response will be assessed using the difference pre and after placebo dosing.
Other intervention name(s): Vitamin E; Safflower oil
Intervention MeSH terms: Vitamin E; Tocopherols; Tocotrienols; alpha-Tocopherol; gamma-Tocopherol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment