Gene Expression Effect of Antioxidant Supplementation on Epithelium of Lung:ExSEL

描述（由申请人提供）： 本研究的目的是探讨肺组织中的基因表达是否受抗氧化状态的调节。慢性阻塞性肺疾病（COPD）的特征在于不可逆气流限制的发展，并且是美国第四大死亡原因。目前对COPD发病机制的理解暗示了疾病易感性中的氧化剂/抗氧化剂失衡。尽管80-90%的COPD患者是当前或以前的吸烟者，但只有15%的肺功能变化是由吸烟参数解释的，因此很明显，疾病病因涉及其他未发现的因素。观察性流行病学研究支持这一假设，即增强的抗氧化防御减少肺组织中的氧化剂负荷，从而减轻导致COPD发作和进展的组织损伤。对暴露的适应性反应反映在基因表达模式中，正常基因表达的改变在无症状吸烟者和COPD患者中是明显的。改变的基因表达模式预期先于疾病发展和进展途径的生物化学和组织变化，因此对基因表达的修饰剂如抗氧化状态的研究提供了转录水平干预以中断疾病发病机制的靶点。我们提出了一个两部分的研究，以调查是否由氧化应激引起的损害是由更高的抗氧化状态衰减。首先，抗氧化剂补充剂的双盲、安慰剂对照干预研究将调查补充剂是否调节无症状吸烟者肺上皮细胞中氧化剂相关基因的基因表达。如果补充抗氧化剂可以改变基因表达，从而减轻吸烟造成的损害，那么这将提供一种简单，廉价的方法来降低对COPD的易感性。其次，使用肺组织研究联盟（LTRC）的样本，研究COPD患者氧化相关基因表达对全身和组织特异性抗氧化状态、氧化应激负荷和GOLD分期的依赖性。如果较低的抗氧化剂状态与COPD患者基因表达的较大改变有关，这可能为进一步研究抗氧化剂减缓COPD进展的潜力提供目标。了解抗氧化状态和补充剂如何调节肺中的基因表达将增强我们对香烟烟雾暴露和疾病状态反应变化的理解。由此产生的知识可能会导致更好地了解疾病的易感性和进展，并确定一级和二级预防的机会。公共卫生相关性：“抗氧化剂补充对肺上皮细胞的基因表达影响：ExSEL”将提高对营养与疾病发展中基因组之间相互作用的理解。这项拟议的研究将调查抗氧化剂补充剂作为新型，廉价的COPD发作预防剂的潜力。这项拟议中的研究还试图了解一个人体内的抗氧化剂水平（可以通过膳食补充剂改变）是否与慢性阻塞性肺疾病（COPD）患者的疾病严重程度有关。因此，该项目的研究结果可能最终有助于通过确定预防COPD发作和/或减缓COPD进展的新疗法来减轻疾病负担。(End摘要）

DESCRIPTION (provided by applicant): The goal of this research is to explore whether gene expression in lung tissue is modulated by antioxidant status. Chronic Obstructive Pulmonary Disease (COPD) is characterized by the development of irreversible airflow limitation and is the fourth leading cause of mortality in the United States. The current understanding of COPD pathogenesis implicates an oxidant/antioxidant imbalance in disease susceptibility. Although 80-90% of COPD patients are current or former smokers, only 15% of the variation in lung function is explained by smoking parameters, thus it is clear that disease etiology involves other, undiscovered factors. Observational epidemiologic studies support the hypothesis that enhanced antioxidant defenses diminish oxidant burden in lung tissue thus mitigating tissue damage contributing to COPD onset and progression. Adaptive response to an exposure is reflected in gene expression patterns, and alterations in normal gene expression are evident in asymptomatic smokers and COPD patients. Altered gene expression patterns are expected to precede biochemical and tissue changes on disease development and progression pathways, thus investigations of modifiers of gene expression such as antioxidant status provide targets for transcription-level intervention to interrupt disease pathogenesis. We propose a two part study to investigate whether damage caused by oxidative stress is attenuated by higher antioxidant status. First, a double-blinded, placebo-controlled intervention study of antioxidant supplements will investigate whether supplements modulate gene expression of oxidant-related genes in lung epithelial cells of asymptomatic smokers. If antioxidant supplementation alters gene expression and therefore mitigates damage caused by cigarette smoking, then this would offer a simple, inexpensive way to reduce susceptibility to COPD. Second, an investigation of the dependency of expression of oxidant-related genes in COPD patients on systemic and tissue-specific antioxidant status, oxidative stress burden, and GOLD stage is proposed using samples from the Lung Tissue Research Consortium (LTRC). If lower antioxidant status is related to greater alteration of gene expression in COPD patients this may provide a target for further investigation of antioxidants' potential to slow progression of COPD. Understanding how antioxidant status and supplementation modulate gene expression in the lung will enhance our understanding of variation in the response to cigarette smoke exposure and disease states. The resulting knowledge may lead to a better understanding of disease susceptibility and progression and identify primary and secondary prevention opportunities. PUBLIC HEALTH RELEVANCE: "Gene Expression Effect of Antioxidant Supplementation on Epithelium of Lung:ExSEL" will improve understanding of the interaction between nutrition and the genome in disease development. The proposed study will investigate the potential of antioxidant supplements to function as novel, inexpensive preventives of COPD onset. The proposed research also seeks to understand whether a person's body level of antioxidants, which can be modified by dietary supplements, is related to severity of disease in Chronic Obstructive Pulmonary Disease (COPD) patients. Thus, the findings from this project may ultimately help to reduce the burden of disease by identifying novel therapies to prevent the onset and/or slow the progression of COPD. (End of Abstract)