Phase II studies of gamma tocopherol as an intervention for environmental asthma

描述（由申请人提供）：过敏性哮喘（AA）是美国最常见的呼吸系统疾病，也是世界范围内发病率的主要原因。本项目的目标是开展富含γ生育酚的混合生育酚(？T-mT制剂对慢性嗜酸性粒细胞炎症和过敏性哮喘（AAs）与LPS和O3攻击相关的急性嗜中性粒细胞炎症增加的影响。内毒素（脂多糖或LPS）是粗、细模式PM、生物气溶胶、烟草和生物质烟雾的组成部分。臭氧（O3）是美国最常见的环境空气污染物。流行病学研究表明，LPS和O3都是哮喘的重要诱因。在AAs的挑战研究中，我们已经表明，LPS和O3诱导中性粒细胞（pmn）和嗜酸性粒细胞流入AAs，并增强对吸入过敏原的反应。O3也是一种氧化剂，O3和LPS都会增加气道细胞的自由基产生，营养和基因上确定的抗氧化剂缺乏（如GSTM1基因型缺失）与污染物诱发哮喘恶化的风险增加有关。在挑战研究中，我们报道了GSTM1无效志愿者的LPS和O3 PMN反应增加。已知γ -生育酚具有抗氧化和抗炎作用。我们已经证明了？T可预防致敏原、O3和脂多糖引起的啮齿动物呼吸道炎症。我们的I期人体研究？T-mT确定的剂量维持？T及其抗炎代谢物，降低单核细胞对LPS的反应和ige介导的嗜碱性细胞对过敏原的反应。我们最初在健康志愿者中进行的双盲、安慰剂对照ii期研究的数据表明？T-mT抑制lps诱导的粒细胞内流。AAs的IIa期研究的成功完成将指导这种低成本营养干预预防污染物引起的哮喘恶化的III期疗效研究的发展。

DESCRIPTION (provided by applicant): Allergic asthma (AA) is the most commonly encountered respiratory disease in the United States and is a leading cause of morbidity worldwide The goals of this project are to undertake phase IIa studies of a gamma tocopherol enriched mixed tocopherol (?T-mT) preparation on chronic eosinophilic inflammation and acute increases in neutrophilic inflammation in allergic asthmatics (AAs) associated with LPS and O3 challenge. Endotoxin (lipopolysaccharide or LPS) is a component of coarse and fine mode PM, bioaerosols, tobacco and biomass smoke. Ozone (O3) is the most commonly encountered ambient air pollutant in the US. Epidemiological studies have shown that both LPS and O3 are important asthma triggers. In challenge studies of AAs, we have shown that LPS and O3 induces influx of neutrophils (PMNs) and eosinophils in AAs as well as augmenting response to inhaled allergens. O3 is also an oxidant, and both O3 and LPS increase radical production by airway cells, with both nutritional and genetically defined antioxidant deficiencies (such as the GSTM1 null genotype) being associated with increased risk for pollutant-induced asthma exacerbation. In challenge studies, we have reported that LPS and O3 PMN responses are increased in GSTM1 null volunteers. Gamma tocopherol has known antioxidant and anti-inflammatory actions. We have shown that ?T prevents allergen, O3 and LPS-induced respiratory tract inflammation in rodents. Our phase I human studies with ?T-mT established a dose which maintains ?T and its anti-inflammatory metabolites, decreases monocyte responses to LPS and IgE-mediated basophil response to allergen. Data from our initial double-blinded, placebo controlled phase IIa study in healthy volunteers demonstrates that ?T-mT inhibits LPS-induced granulocyte influx. Successful completion of this phase IIa study in AAs will guide development of a phase III efficacy study of this low cost nutriceutical intervention for preventio of pollutant-induced asthma exacerbations.