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
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