METABOLIC ALTERATIONS IN CACHECTIC PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY D

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 慢性阻塞性肺疾病（COPD）是一种由暴露于香烟烟雾引起的疾病，其特征在于由气道阻塞和炎症引起的气流限制。 虽然COPD主要影响肺部，但它对全身有显著影响，包括体重减轻和外周肌肉功能障碍。 由于肌肉质量优先于脂肪损失，COPD中的体重减轻可以被表征为恶病质，并且与生活质量差、运动耐量受损和死亡率增加相关。 与其他疾病（如癌症和获得性免疫缺陷综合征（AIDS））中的恶病质相关的多种因素也可能在COPD中发挥作用。 这些包括促炎细胞因子水平升高、低氧血症、酸中毒和不活动。 虽然COPD恶病质的确切机制尚不清楚，但大多数研究将其归因于这种疾病中发生的炎症。 这种炎症可能导致蛋白质和葡萄糖代谢的变化。 本研究的目的是使用稳定同位素和生物化学方法来确定体重减轻的COPD患者与体重未减轻的COPD患者在1）蛋白质合成和分解，2）葡萄糖产生和清除，以及3）葡萄糖转化为丙酮酸和乳酸的差异。 这项研究的结果将增加我们对COPD患者恶病质机制的理解，并可能为未来的治疗确定潜在的靶点。 与无恶病质的COPD患者相比，COPD伴恶病质患者将： 假设#1：蛋白质净损失增加继发于蛋白质催化剂增加和蛋白质合成减少。 假设2：继发于胰岛素生成增加和葡萄糖清除率降低的高胰岛素血症和高血糖症。 假设#3：由于丙酮酸可用性增加，继发于丙酮酸氧化减少和转化为丙氨酸减少，乳酸产量增加。 假设4：炎症标志物水平升高，疾病严重程度增加。 将使用稳定同位素示踪剂和生化方法研究和比较两组受试者：无恶病质的COPD患者和COPD伴恶病质的患者。 将在吸收后状态下进行以下测量： 具体目标#1：支链氨基酸的全身蛋白质分解、合成、代谢和血浆浓度 具体目标#2：内源性葡萄糖流量、总葡萄糖生成、葡萄糖清除率和血浆胰岛素水平 具体目标#3：丙酮酸通量、丙酮酸氧化、丙酮酸转化为丙氨酸的速率、乳酸通量以及血浆谷氨酸和丙氨酸浓度 具体目标#4：TNF-α、IL-6、C-反应蛋白和谷胱甘肽的血浆浓度;以及FEV 1、BODE评分、6分钟步行距离和使用测力计的肌肉力量

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chronic obstructive pulmonary disease (COPD) is a disease caused by exposure to cigarette smoke and is characterized by airflow limitation resulting from airway obstruction and inflammation. Although COPD primarily affects the lung, it has significant consequences in the whole body, including weight loss and peripheral muscle dysfunction. Because of a preferential loss of muscle mass over fat, weight loss in COPD can be characterized as cachexia and is associated with poor quality of life, impaired exercise tolerance, and increased mortality. Multiple factors associated with cachexia in other diseases such as cancer and acquired immunodeficiency syndrome (AIDS) may also play a role in COPD. These include increased levels of proinflammatory cytokines, hypoxemia, acidosis, and inactivity. While the exact mechanisms underlying cachexia in COPD remain unclear, most studies attribute it to the inflammation that occurs in this disease. This inflammation may lead to changes in both protein and glucose metabolism. The purpose of this study is to use stable isotope and biochemical methods to determine differences in 1) protein synthesis and breakdown, 2) glucose production and clearance, and 3) conversion of glucose to produce pyruvate and lactate in patients with COPD with weight loss compared with patients with COPD without weight loss. Results from this study will increase our understanding of the mechanisms of cachexia in patients with COPD and may identify potential targets for future therapy. As compared with patients with COPD without cachexia, patients with COPD and cachexia will have: Hypothesis #1: Increased net protein loss secondary to increased protein catabolism and decreased protein synthesis. Hypothesis #2: Hyperinsulinemia and hyperglycemia secondary to increased gluconeogenesis and decreased glucose clearance. Hypothesis #3: Increased lactate production because of increased pyruvate availability secondary to decreased pyruvate oxidation and decreased conversion to alanine. Hypothesis #4: Increased levels of inflammatory markers and increased severity of illness. Stable isotope tracer and biochemical methods will be used to study and compare two groups of subjects: patients with COPD without cachexia and patients with COPD and cachexia. The following measurements will be made in the postabsorptive state: Specific Aim #1: Whole body protein breakdown, synthesis, and catabolism and plasma concentrations of the branched chain amino acids Specific Aim #2: Endogenous glucose flux, total glucose production, glucose clearance, and plasma insulin levels Specific Aim #3: Pyruvate flux, pyruvate oxidation, the rate of conversion of pyruvate to alanine, lactate flux, and plasma glutamate and alanine concentrations Specific Aim #4: Plasma concentrations of TNF-a, IL-6, C-reactive protein, and glutathione; and FEV1, BODE score, 6 minute walk distance, and muscle strength using dynamometry