ABSTRACT

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV₁) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV₁ declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV₁ increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression.

摘要

空气污染与肺功能的早期下降和哮喘相关的半胱氨酰白三烯 (CysLT) 水平升高有关，但与这种快速反应相关的生物学途径尚未确定。在这项针对 16 名成人哮喘患者的随机对照柴油机尾气 (DE) 挑战研究中，可归因于暴露的尿白三烯 E4（uLTE4，一种半胱氨酰白三烯产生的生物标志物）增加与 1 秒内用力呼气量的下降相关（p = 0.04） (FEV ₁) 暴露后 6 小时内。暴露归因的 uLTE4 增加与外周血单核细胞中 CysLT 受体 1 (CysLTR1) 甲基化增加相关 (p = 0.02)，而后者又与 CysLTR1 表达减少相关 (p = 0.06)。反过来，降低的 CysLTR1 表达与 FEV ₁下降相关（p = 0.0007）。在同一时期，在 DE 暴露后观察到 GPR17（CysLTR1 的负调节因子）甲基化增加（p = 0.02）；这种甲基化增加与 CysLTR1 甲基化减少相关（p = 0.001），而 CysLTR1 甲基化减少又与 CysLTR1 表达增加相关（p = 0.06）；CysLTR1 表达增加与 FEV _{1相关（p = 0.0007）}增加。总的来说，这些数据描绘了一个潜在的机制途径，通过 CysLTR1 相关甲基化和基因表达的变化将增加的 DE 暴露归因于 CysLT 水平与肺功能下降联系起来。