Serum Inflammatory Biomarkers as Predictors of COPD Morbidity and Morality

描述（由申请人提供）：COPD是美国的第四大死因，其对全球公共卫生的影响注定会在全球范围内进一步增加。COPD的特征在于对源自气道的有害试剂（如吸烟）的炎症反应，但从长期来看，可能延伸到肺以外，并导致与该疾病相关的发病率和死亡率负担。迄今为止，全身性炎症蛋白表达与COPD发病之间的时间关系尚未得到解决，全身性炎症是否与COPD发展有因果关系，或者它仅仅是疾病的结果，仍有待确定。在这项提议中，我们的目的是确定血清中炎性细胞因子（IL-6，IL-8，TNF-α）和急性期反应物（CRP，sCD 14和LBP）的水平是否可预测吸烟者COPD的发展，以及一旦疾病发生，其临床进展和死亡风险（具体目标1）。由于内毒素暴露可能导致吸烟者肺部和全身炎症的发生和持续，我们还将确定LPS受体复合物中的功能性单核苷酸多态性是否与炎症标志物的血清水平相关（特异性目的2）。最后，将使用蛋白质组学分析探索COPD发展的总体蛋白质表达谱的预测价值（具体目标3）。为了实现这些特定目标，我们将使用TESAOD研究的大型纵向人群队列，该研究于1972年启动，在33年的随访期内，提供了大量的表型信息和广泛的前瞻性血清样本。与COPD发展及其临床进展相关的全身性生物标志物的鉴定可能对疾病的预防和治疗具有重要意义。这项研究将导致亚利桑那呼吸中心的分子和遗传流行病学核心与亚利桑那大学蛋白质组学分析实验室之间建立一个合作项目，反过来，它可能会促进长期研究项目的发展，以扩大我们对COPD分子组成的理解，并探索降低这种疾病发病率和死亡率的创新策略。

DESCRIPTION (provided by applicant): COPD is the fourth leading cause of death in US and its global public health impact is destined to further increase worldwide. COPD is characterized by an inflammatory response to noxious agents (such as smoking) that originates in the airways but, in the long-term, may extend beyond the lung and contribute to the morbidity and mortality burden associated with this disease. To date, the temporal relationship between systemic inflammatory protein expression and COPD inception has not been resolved and whether systemic inflammation is causally linked to COPD development or it is simply a consequence of the disease remains to be determined. In this proposal, we aim at determining whether serum levels of inflammatory cytokines (IL-6, IL-8, TNF-alpha) and acute phase reactants (CRP, sCD14, and LBP) predict development of COPD among smokers and, once the disease has occurred, its clinical progression and mortality risk (Specific Aim 1). Because endotoxin exposure may contribute to initiate and sustain pulmonary and systemic inflammation in smokers, we will also determine whether functional single nucleotide polymorphisms in the LPS Receptor Complex are associated with serum levels of inflammatory markers (Specific Aim 2). Finally, the predicitve value of global protein expression profiles for COPD development will be explored using proteomic analyses (Specific Aim 3). To address these specific aims, we will use the large longitudinal population-based cohort of the TESAOD study, which was intitiated in 1972 and - over the 33-year follow-up period - has provided an enormous amount of phenotypic information and an extensive collection of prospective serum samples. The identification of systemic biomarkers linked to COPD development and its clinical progression may have important implications for the prevention and treatment of the disease. This study will lead to the establishment of a collaborative project between the molecular and genetic epidemiology core of the Arizona Respiratory Center and the Proteomics Analysis Laboratory at the University of Arizona and, in turn, it may foster the growth of a long-term research project to expand our understanding of the molecular components of COPD and to explore innovative strategies to reduce the morbidity and mortality of this disease.