Gamma tocopherol chemoprevention of wood smoke PM2.5-induced airway inflammation

 描述（由申请人提供）：来自荒地和其他火灾的木材烟雾颗粒（WSP）产生了相当大一部分的环境空气颗粒物。与WSP相关的健康影响包括健康人和哮喘患者的急性支气管炎、哮喘恶化、肺炎、咳嗽和全身炎症。据报告，接触WSP也会对心血管产生影响。野火产生的WSP会导致环境空气中PM 2.5水平的突然增加，避免快速增加的PM空气污染是不可行的，因为许多居民无法离开燃烧区域，而荒地消防员通常会连续几天进入荒地火灾现场。由于在这些环境中避免PM是不可行的，因此显然需要采取干预措施，以减少急性WSP暴露造成的不良健康影响。我们的团队已经开发出伽马生育酚（gT），一种具有强大抗炎作用的维生素E亚型，作为环境污染物引起的炎症的化学预防干预。我们的动物研究表明，gT抑制过敏原，臭氧和内毒素诱导的气道炎症。我们的人体I期研究表明，gT降低循环单核细胞的炎症反应，降低亚硝化应激，并抑制中性粒细胞（PMN）内流到气道内毒素攻击后体内。因此，gT补充是减少吸入WSP的不良健康影响的有吸引力的营养/保健方法。我们还开发了一种500µg/m3 WSP暴露方案，可诱导人类志愿者气道和全身PMN增加。使用该激发方案，我们将进行随机、安慰剂对照研究，以确定在健康和哮喘志愿者中补充1200 mg的WSP诱导的气道和全身PMN是否增加。探索性终点将包括非特异性支气管反应性（NSBR）和报告受PM暴露影响的心血管反应。这些研究还将使我们能够比较过敏性哮喘（AA）和健康志愿者（HV）的反应，以确定是否过敏性或哮喘的其他方面改变对WSP的炎症反应的风险。这项研究将是第一个测试一种特定的营养补充剂作为WSP诱导的炎症的化学预防干预的AAs或NV，并专门比较这些群体对WSP诱导的炎症的反应。

 DESCRIPTION (provided by applicant): Wood smoke particles (WSP) derived from wildland and other fires produce a significant fraction of ambient air particulate matter. Health effects associated with WSP include acute bronchitis, asthma exacerbation, pneumonia, cough and systemic inflammation in in healthy persons and those with asthma. Cardiovascular effects have also been reported with WSP exposure. WSP from wildland fires can cause abrupt increases in ambient air PM 2.5 levels, and avoidance of rapidly increasing PM air pollution is not feasible as many residents cannot leave the burn region, and wildland firefighters move into wildland fire sites, often for several consecutive days. As avoidance of PM is not feasible in these settings, there is a clear unmet need for interventions to reduce adverse health effects caused by acute WSP exposure. Our team has developed gamma tocopherol (gT), an isoform of vitamin E with robust anti-inflammatory actions, as a chemopreventive intervention for inflammation caused by environmental contaminants. Our animal studies show that gT inhibits allergen, ozone and endotoxin-induced airway inflammation. Our human phase I studies show that gT decreases inflammatory response of circulating monocytes, decreases nitrosative stress, and inhibits neutrophil (PMN) influx to the airway in vivo after endotoxin challenge. Thus, gT supplementation is an attractive nutritional/nutraceutical approach to decreasing the adverse health effects of inhaled WSP. We have also developed a 500µg/m3 WSP exposure protocol which induces both airway and systemic increases in PMNs in human volunteers. Using this challenge protocol, we will undertake a randomized, placebo-controlled study to determine if of supplementation with 1200 mg of on WSP-induced airway and systemic PMN increases in healthy and asthmatic volunteers. Exploratory endpoints will include non-specific bronchial reactivity (NSBR), and cardiovascular responses reported to be impacted by PM exposure. These studies will also allow us to compare responses of allergic asthmatic (AA) and healthy volunteers (HV) to determine if atopy or other facets of asthma modify risk for inflammatory response to WSP. This study will be the first to test a specific nutritional supplement as a chemopreventive intervention for WSP-induced inflammation in either AAs or NVs, and to specifically compare the response of these groups to WSP-induced inflammation.