Serum Inflammatory Biomarkers as Predictors of COPD Morbidity and Morality

描述（由申请人提供）：COPD是美国第四大死亡原因，其全球公共卫生影响注定会在全球范围内进一步增加。慢性阻塞性肺病的特点是对源自气道的有害物质（如吸烟）产生炎症反应，但从长期来看，可能会扩展到肺部以外，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的发展有因果关系，还是仅仅是疾病的一个后果仍有待确定。在本提案中，我们旨在确定血清炎症细胞因子（IL-6、IL-8、tnf - α）和急性期反应物（CRP、sCD14和LBP）水平是否能预测吸烟者COPD的发展，以及一旦疾病发生，其临床进展和死亡风险（Specific aim 1）。由于内毒素暴露可能有助于吸烟者引发和维持肺部和全身炎症，我们还将确定LPS受体复合物的功能性单核苷酸多态性是否与血清炎症标志物水平相关（特异性目标2）。最后，将使用蛋白质组学分析来探索全球蛋白质表达谱对COPD发展的预测价值（Specific Aim 3）。为了实现这些具体目标，我们将使用大规模纵向人群队列的TESAOD研究，该研究始于1972年，在33年的随访期间，提供了大量的表型信息和广泛收集的前瞻性血清样本。识别与慢性阻塞性肺病发展及其临床进展相关的系统性生物标志物可能对该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的合作项目的建立，反过来，它可能会促进长期研究项目的发展，以扩大我们对慢性阻塞性肺病分子成分的理解，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.