Effect of Gamma Tocopherol Enriched Supplementation on Response to Inhaled LPS
Condition: Mild, Allergic Asthma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      To test the hypothesis that gamma tocopherol (vitamin E) supplement inhibits endotoxin
      induced airways inflammation in allergic asthmatics
    

Detailed description: 
      BACKGROUND:

      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 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. Endotoxin (or lipopolysaccharide or LPS) is a component of
      bioaerosols found in both the indoor and outdoor environment, is a component of tobacco
      smoke, and is increased in indoor settings where smokers live. LPS is also a component of
      coarse and fine mode particle matter air pollution.

      OXIDATIVE STRESS AND ASTHMA:

      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 LPS. TLR4 activation of inflammatory cells activates Nuclear Factor-kB
      (NF-kB) and induces oxidative stress. O3 and LPS has been associated with exacerbation of
      asthma, and we 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. We and others have 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. We have
      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. We
      have also shown that GSTM1 null volunteers have enhanced airway and systemic inflammation
      following LPS challenge.

      Others 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 were had increases 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.

      ANTIOXIDANTS AND ASTHMA:

      A non-exclusive list of proposed antioxidants includes radical scavengers such as ascorbate,
      a-tocopherol (aT), y-tocopherol (yT) or inducers of the antioxidant gene response element
      transcription factor 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. It is crucial that
      adequate, well-designed human studies assess the role of antioxidants for allergic asthma to
      either confirm their efficacy, or refute claims that these are effective, safe and low cost
      interventions for allergic disease.

      GAMMA TOCOPHEROL AND ASTHMA:

      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, yT is a potent ROS scavenger and is also a powerful
      nucleophile that traps electrophiles such as peroxynitrite in lipophilic compartments. One
      mechanism by which y-T is cytoprotective is scavenging of RNS at the un-substituted C-5
      position on the hydroxy-chroman ring of y-T to form 5-NO-y-tocopherol (5-NO-yT). 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
      yT 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 yT also prevents protein nitration and attenuates loss of plasma vitamin
      C in plasma in a rodent peritonitis model of inflammation. Our group has also shown that yT
      inhibits cyclo-oxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) in LPS-stimulated macrophages
      and interleukin (IL)-1b stimulated epithelial cells. These actions are mediated primarily by
      the yT metabolite 2, 7, 8-trimethyl-2S-(.-carboxyethyl)-6-hydroxychroman (y-CEHC) which
      requires hydroxylation of the y-methyl group of yT by cytochrome P450 (CYP450). In
      carrageenan- induced inflammation in male Wistar rats, yT decreases prostaglandin (PGE2) and
      leukotriene (LTB4) production, suggesting that 5-LO-mediated production of leukotrienes may
      also be inhibited by yT. Tocopherols, including yT, also modulate gene expression of a number
      of inflammatory genes. Thus, yT and other tocopherols decrease production of a number of
      pro-inflammatory cytokines at the transcriptional level.

      In animals, we have also shown that gamma tocopherol reduces baseline eosinophilia in the
      airway. In our early phase I studies of gamma tocopherol-enriched mixed tocopherols (gT-mT)
      we have shown that gT-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 ( yT, 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. This project focuses on phase II studies of yT in AA based on our
      preclinical and phase I studies. For this protocol we will be testing the hypothesis that a
      gamma tocopherol supplement will baseline eosinophil numbers in airway sputa of asthmatics
      (specific aims 1) and (specific aim 2) inhibit LPS induced airway inflammation in mild
      allergic asthmatics.

      The investigators will also do an exploratory assessment of the specific impact of the GSTM1
      null genotype on response to LPS and effect of gamma tocopherol enriched supplementation on
      this response.

      If gamma tocopherol decreases LPS-induced response in asthmatics, this would provide proof of
      concept that this agent would be a useful intervention for asthma, confirming teh need for a
      phase III study of gamma tocopherol enriched supplements as a treatment for asthma.
    

Intervention name(s): Gamma Tocopherol 700 mg capsules,; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 2 capsules daily; Safflower oil capsules
Intervention MeSH terms: Tocopherols; Vitamin E; Tocotrienols; alpha-Tocopherol; gamma-Tocopherol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment