COPD Metabolome, Smoking Oxidants and Aberrant Ciliated Cell Function

描述(由申请人提供)：在美国，吸烟是慢性阻塞性肺疾病(COPD)的主要原因，是导致死亡的第四大原因。COPD发病机制的核心是“纤毛病变”，这是一种呼吸道纤毛细胞功能障碍，负责调节黏液的运输，以清除吸入的病原体。慢性阻塞性肺疾病的睫毛病变导致粘液堆积、宿主防御功能受损和反复感染。初步的代谢数据为我们带来了第一条线索--COPD吸烟者血清瓜氨酸水平降低，这与肺一氧化氮合酶(NOS)活性缺乏一致，从而导致肺一氧化氮(NO)缺乏。目的2.结合人和小鼠呼吸道上皮的代谢谱和体外研究，评估COPD代谢组(侧重于推测的NO缺乏)与COPD纤毛病变潜在机制之间存在联系的假说。目的3.对香烟烟雾引起的肺和血清中氧化还原体进行表征和定量，并评价其在纤毛细胞功能障碍中的作用。研究试图确定吸烟、氧化剂对肺上皮细胞的负担与慢性阻塞性肺疾病发病机制之间的联系-可能提供预测哪些吸烟者将患上慢性阻塞性肺疾病的生物标志物(S)，并为慢性阻塞性肺疾病的治疗寻找新的靶点。

DESCRIPTION (provided by applicant): With >1014 oxidants/puff, cigarette smoking is the major cause of chronic obstructive pulmonary disease (COPD), the 4th cause of mortality in the US. Central to COPD pathogenesis is "ciliopathy", dysfunction of the airway ciliated cells that mediate transport of mucus to remove inhaled pathogens. The COPD ciliopathy leads to mucus accumulation, impaired host defense and recurrent infections. Using a state-of-the-art platform for global metabolite profiling and unique cohorts with serum and lung biologic samples, our deliverables are to identify a metabolome focused on biomarkers related to airway ciliopathy in COPD, and use the observed metabolic changes to: (1) direct mechanistic studies to define ciliopathy at a molecular level; (2) identify novel targets for therapeutic intervention in COPD; and (3) identify smokers at high risk for COPD. Preliminary metabolic data led to our first clues - COPD smokers have decreased serum citrulline levels, consistent with a deficiency in lung nitric oxide synthase (NOS) activity, and thus lung nitric oxide (NO) deficiency. This, together with supporting data of a smoking-induced NOS/NO-related ciliopathy, and knowledge that smokers have significant oxidant-related changes in the airway epithelial transcriptome, led to our aims, combining metabolomics of defined cohorts, murine and human mechanistic studies and computational / statistical integration. Aim 1. To carry out metabolic profiling of banked biologic samples from our characterized cohorts to assess the hypothesis that smoking-induced COPD is associated with a unique metabolome in serum and lung ELF, and that subsets of the COPD metabolome are linked to the ciliopathy of COPD. Aim 2. To combine metabolic profiling and in vitro studies of human and murine airway epithelium to evaluate the hypothesis that there is a link between the COPD metabolome (focusing on the inferred NO deficiency) and mechanisms underlying the ciliopathy of COPD. Aim 3. Characterize and quantify the cigarette smoke induced "redoxome" in lung and serum and assess its role in ciliated cell dysfunction. Studies seek to identify a link between smoking, burden of oxidants to the lung epithelium and the pathogenesis of COPD - potentially providing biomarker(s) that predict which smokers will develop COPD and identifying new targets for therapy of COPD.