Cardiovascular Response to CAP Microbial Components in Controlled Human Exposures

描述（由申请人提供）：环境颗粒污染可引发心肌梗死，据估计是导致过早死亡的第13大主要原因，也是全球疾病负担的十大因素之一。尽管有证据表明环境颗粒携带不同数量的革兰氏阴性细菌内毒素，但微生物群落对污染颗粒的炎症和心血管影响的贡献尚不明确。研究表明，由于气候对空气中微生物模式的影响，北美的暖季正在延长。我们发表的初步数据表明，在我们完成的55名多伦多成年人的随机交叉对照人体暴露研究中，浓缩环境颗粒（CAPs）的内毒素成分与全身炎症、氧化应激和血压升高有关。高达百分之四十的白细胞计数增加归因于颗粒

DESCRIPTION (provided by applicant): Ambient particle pollution, which can be a trigger for myocardial infarction, has been estimated to be the 13th leading cause of premature death and one of the top ten contributors to the global burden of disease world- wide. Despite evidence that ambient particles carry variable amounts of the gram-negative bacterial component endotoxin, the contribution of microbial communities on pollution particles to their inflammatory and cardiovascular effects is poorly defined. Studies suggest that the warm season is lengthening in North America with climate influences on patterns of airborne microbes. We have published and preliminary data demonstrating associations of the endotoxin component of concentrated ambient particles (CAPs) with increased systemic inflammation, oxidative stress and blood pressure in our completed randomized cross-over controlled human exposure study of 55 Toronto adults. Up to forty-percent of the increase in leukocyte count attributed to particle mass could be attributed to its endotoxin content. Endotoxin may be a sentinel marker for a complex array of microbial exposures with other pathogen-associated-molecular patterns (PAMPs) that stimulate human innate immune inflammation potentially relevant to cardiovascular outcomes. Leveraging on our Toronto study, we will combine 16S,18S, ITS rRNA gene and selective whole genome shotgun sequencing with innovative bioinformatic methods to characterize the bacterial and fungal communities on coarse, fine and ultrafine CAP exposures, at the phylum and genus level (Aim 1). We will evaluate how the relative abundance of microbial taxa on CAPS is influenced by ambient temperature and humidity levels in the two weeks prior to testing (Aim 4). We will test the hypothesis that increased abundance of gram-negative phylum Proteobacteria on CAPs will be associated with increased blood pressure, brachial artery narrowing and, secondarily, with increases in intermediate biomarkers of vascular stimulation(vascular endothelial growth factor), systemic inflammation (e.g., white blood cell count), and oxidative stress (e.g., 8-hydroxy-deoxy-guanosine), and will assess the relative contribution of individual bacterial genera within Proteobacteria to these associations (Aim 2). We will evaluate whether the most abundant fungal taxa on CAPs are independently associated with our outcomes (Aim 3). Finally, we will apply bioinformatic methods to our metagenomic data to quantify the relative abundance of synthesis pathways for active components of PAMPS, and explore how pathway abundance influences blood pressure, inflammation and oxidative stress. Understanding the microbial contributions to particle toxicity will help define mechanisms whereby particle pollution increases cardiovascular risk, and will inform regulators estimating the benefits of controlling particle pollution to improve cardiovascular health.