Chronic respiratory effects of early life PM exposure

描述（由申请人提供）：越来越多的证据表明，慢性暴露于颗粒物（PM）会对儿童肺功能的发育产生负面影响，并可导致成人COPD，但缺乏关于早期暴露于PM的长期影响的信息。在拟议的研究中，我们解决了婴儿时期暴露于生物质烟雾PM对儿童后期呼吸健康的影响。我们的机制假设是，燃烧产生的有机化合物存在于生物质烟雾中的细颗粒中，诱导氧化应激，炎症细胞因子产生的上调，以及随后的气道炎症。关键抗氧化酶（如GSTM1和GSTP1）基因型的变异可能有助于确定哪些儿童更容易受到吸入颗粒物对呼吸道健康的影响。我们建议对目前在危地马拉农村参加美国国立卫生研究院资助的一项减少急性下呼吸道疾病（ALRI）的随机炉灶干预试验的婴儿进行纵向随访研究。改进后的炉灶显著减少了生物质烟雾暴露。在参与的孩子年满18个月后，所有家庭都会得到改进的炉子。我们提出的纵向随访研究旨在a)确定在生命最初18个月暴露于较高水平的PM是否与呼吸系统症状、支气管扩张剂反应性、对空气过敏原的敏感性增加以及肺功能和躯体生长速度下降有关；b)确定GSTM1零基因型是否使儿童更容易发生pm诱导的氧化应激和慢性呼吸效应，而GSTP1val105变变体是否使儿童更不容易发生pm诱导的氧化应激和慢性呼吸效应。生物质烟雾暴露的影响从未在纵向设计和定量暴露评估中研究过。目前的随机干预试验提供了一个独特的机会来研究在肺部发育的关键时间窗期间高暴露于生物质烟雾/PM的长期影响，如果随访时间延长到儿童期后期。

DESCRIPTION (provided by applicant): Accumulating evidence suggests that chronic exposure to particulate matter (PM) negatively affects growth of lung function in children and can lead to COPD in adults, but there is a dearth of information on the long-term effects of early life exposure to PM. In the proposed research we address the effects of exposure during infancy to biomass smoke PM on respiratory health later in childhood. Our mechanistic hypothesis is that the combustion-generated organic compounds present on fine particles in biomass smoke induce oxidative stress, upregulation of inflammatory cytokine production, and subsequent airway inflammation. Variation in the genotypes of key antioxidant enzymes (e.g., GSTM1 and GSTP1) may help to identify which children are more susceptible to the effects of inhaled PM on respiratory health. We propose to conduct a longitudinal follow-up study of a birth cohort of infants currently enrolled in a NIH-funded, randomized stove intervention trial to reduce acute lower respiratory illness (ALRI) in rural Guatemala. The improved cookstove markedly reduces biomass smoke exposure. After the participating child is 18 months old all families are offered the improved stove. Our proposed longitudinal follow-up study is designed to a) determine whether exposure to higher levels of PM during the first 18 months of life is associated with increased respiratory symptoms, bronchodilator responsiveness, sensitization to aeroallergens, and decreased rate of growth of lung function and somatic growth; and b) determine whether the GSTM1 null genotype renders children more susceptible and the GSTP1val105 variant less susceptible to the development of PM-induced oxidative stress and chronic respiratory effects. The effects of biomass smoke exposure have never been studied in a longitudinal design with quantitative exposure assessment. The current randomized intervention trial provides a unique opportunity to study the long-term effects of high exposure to biomass smoke/PM during the critical time window of lung development if follow-up is extended until later in childhood.