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，长期暴露于颗粒物（PM）会对儿童肺功能的发育产生负面影响，并可能导致成人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，我们解决了婴儿期暴露于生物质烟雾PM对儿童期呼吸系统健康的影响。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诱导氧化应激，上调炎症细胞因子的产生，以及随后的气道炎症。关键抗氧化酶基因型的变化（例如，GSTM 1和GSTP 1）可能有助于确定哪些儿童更容易受到吸入PM对呼吸系统健康的影响。我们建议对目前参加NIH资助的随机炉灶干预试验的婴儿出生队列进行纵向随访研究，以减少危地马拉农村的急性下呼吸道疾病（ALRI）。改进的炉灶显著减少了生物质烟雾暴露。在参与的儿童年满18个月后，所有家庭都得到了改进的炉子。我们提出的纵向随访研究旨在a）确定在生命的前18个月期间暴露于较高水平的PM是否与呼吸道症状增加、支气管扩张剂反应性、对空气过敏原的致敏性以及肺功能和躯体生长的生长速率降低相关;和B）确定GSTM 1缺失基因型是否使儿童对PM诱导的氧化应激和慢性呼吸作用的发展更敏感，而GSTP 1val 105变体是否使儿童对PM诱导的氧化应激和慢性呼吸作用的发展更不敏感。生物质烟雾暴露的影响从来没有研究过纵向设计与定量暴露评估。目前的随机干预试验提供了一个独特的机会，研究长期暴露于生物质烟雾/PM在肺发育的关键时间窗口，如果后续延长到儿童后期的长期影响。

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.