Serum Inflammatory Biomarkers as Predictors of COPD Morbidity and Morality

描述(申请人提供)：慢性阻塞性肺病是美国第四大死因，其对全球公共健康的影响注定会在全球范围内进一步增加。慢性阻塞性肺疾病的特点是对有害物质(如吸烟)产生炎症反应，这种反应起源于呼吸道，但从长远来看，可能会延伸到肺以外，导致与这种疾病相关的发病率和死亡负担。到目前为止，全身炎症蛋白表达和COPD发病之间的时间关系尚未得到解决，全身炎症是与COPD的发展存在因果关系，还是仅仅是疾病的结果，仍有待确定。在这项建议中，我们旨在确定血清炎症细胞因子(IL-6、IL-8、TNF-α)和急性时相反应物(CRP、sCD14和LBP)水平是否预测吸烟者中COPD的发展，以及一旦疾病发生，其临床进展和死亡风险(特定目标1)。由于内毒素暴露可能有助于引发和维持吸烟者的肺部和全身炎症，我们还将确定脂多糖受体复合体中功能性单核苷酸多态性是否与血清炎症标志物水平相关(特定目标2)。最后，将使用蛋白质组学分析(特定目标3)来探索全球蛋白质表达谱对COPD发展的预测价值。为了解决这些具体目标，我们将使用TESAOD研究的大型纵向人群队列，该研究始于1972年，在33年的随访期内提供了大量的表型信息和广泛的预期血清样本收集。识别与COPD发生和临床进展相关的系统生物标志物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州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，进而可能促进一个长期研究项目的发展，以扩大我们对COPD分子组成的了解，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.