Eicosapentaenoic acid and protein modulation to induce anabolism in COPD

二十碳五烯酸和蛋白质调节诱导慢性阻塞性肺病的合成代谢

• 批准号: 7740483
• 负责人: Nicolaas E Deutz
• 金额: $ 36.25万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-06 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740483
• 关键词: Acids; Acute; Address; Amino Acids; Anabolic Agents; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Blood; Body Composition; Body Weight decreased; Cachexia; Caseins; Chronic; Chronic Obstructive Airway Disease; Clinical; Disease; Drug Formulations; Eicosapentaenoic Acid; Fatty Acids; Hour; Inflammation; Inflammatory Response; Ingestion; Intake; Leucine; Living Wills; Lung; Malignant Neoplasms; Methodology; Muscle; Muscle Proteins; Muscular Atrophy; Nutritional; Nutritional Support; Outcome; Pathology; Patients; Pattern; Peripheral; Plasma; Play; Production; Protein Biosynthesis; Proteins; Quality of life; Regulation; Role; Series; Staging; Supplementation; Systemic disease; Testing; Tissue Sample; Tissues; Weight; Weight Gain; Whey Protein; base; clinically relevant; cytokine; dosage; feeding; functional outcomes; functional status; improved; mortality; muscle form; muscle metabolism; nutrition; protein metabolism; public health relevance; research study; response; stable isotope

DESCRIPTION (provided by applicant): Chronic Obstructive Pulmonary Disease (COPD) is considered a systemic disease that involves pathology in several extra pulmonary tissues. Systemic features in COPD include chronic low-grade systemic inflammation and altered regulation of protein metabolism, which result initially in muscle atrophy only but in later stages in cachexia. Despite the well-recognized importance of treating cachexia in COPD with appropriate nutrition, current nutritional approaches are only partially successful. We recently observed that in order to enhance protein anabolism, manipulation of the composition of proteins and amino acids in nutrition is required in normal-weight COPD. Cachectic COPD patients are characterized by a decreased muscle protein synthesis and an elevated myofibrillar protein breakdown. A substantial number of these patients, characterized by an enhanced systemic inflammatory response, failed to respond to nutritional therapy, which is of clinical relevance as weight gain to nutritional therapy is a significant, independent predictor of mortality in COPD. Eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA) are I-3 fatty acids, known to play an anti- inflammatory role through inhibition of cytokine production. EPA+DHA supplementation has been shown to effectively inhibit weight loss, however, weight and muscle mass gain was not achieved both in cancer and COPD. Factors like the low daily dosage of EPA+DHA, the delayed plasma EPA peak after intake, as well as the absence of anabolic agents like proteins and specific amino acids (ie leucine) might explain that EPA+DHA treatment was unsuccessful. Our hypothesis is that there is a unique combination of EPA+DHA, protein and leucine that maximally will stimulate meal-induced net muscle protein synthesis in cachectic COPD patients. In the first experiment, we will examine whether sip feeding of casein protein is preferable above whey protein in the stimulation of whole body net protein synthesis in cachectic COPD patients and whether adding leucine will be of additional benefit. In the second experiment, it will be examined whether daily ingestion of 4000 mg EPA+DHA as compared to 2000 mg EPA+DHA during 4 weeks in cachectic COPD patients will increase the acute response in muscle net protein synthesis to the optimal nutritional mixture as determined in Aim 1. In the third experiment, it will be examined whether daily ingestion of this combination of optimal nutritional mixture and EPA+DHA, as determined in aim 1 and 2, during 8 weeks in cachectic COPD patients will improve nutritional, functional and global clinical outcome as compared to an isocaloric control meal. The combination of plasma and muscle tissue sampling, stable isotope methodology, and assessment of body composition, functional status and quality of life will enable quantification of all endpoints. The results of this study should provide the basis for a new nutritional formulation to support protein anabolism and improve overall outcome in cachectic patients with Chronic Obstructive Pulmonary Disease. PUBLIC HEALTH RELEVANCE: The results of this study should provide the basis for a new nutritional formulation to support protein anabolism and improve overall outcome in cachectic patients with Chronic Obstructive Pulmonary Disease.

描述（由申请人提供）：慢性阻塞性肺病（COPD）被认为是一种涉及多种肺外组织病理学的全身性疾病。慢性阻塞性肺病的全身特征包括慢性低度全身炎症和蛋白质代谢调节改变，这最初仅导致肌肉萎缩，但在后期会导致恶病质。尽管通过适当的营养治疗慢性阻塞性肺病恶病质的重要性已得到广泛认可，但目前的营养方法仅部分成功。我们最近观察到，为了增强蛋白质合成代谢，在正常体重的慢性阻塞性肺病中需要控制营养中蛋白质和氨基酸的组成。恶病质慢性阻塞性肺病患者的特征是肌肉蛋白质合成减少和肌原纤维蛋白质分解增加。这些以全身炎症反应增强为特征的患者中，有相当一部分对营养治疗没有反应，而营养治疗具有临床相关性，因为营养治疗引起的体重增加是 COPD 死亡率的重要、独立预测因素。二十碳五烯酸 (EPA) 和二十二碳六烯酸 (DHA) 是 I-3 脂肪酸，已知通过抑制细胞因子的产生发挥抗炎作用。 EPA+DHA 补充剂已被证明可以有效抑制体重减轻，但在癌症和慢性阻塞性肺病中并未实现体重和肌肉质量的增加。 EPA+DHA 每日剂量低、摄入后血浆 EPA 峰值延迟以及缺乏蛋白质和特定氨基酸（即亮氨酸）等合成代谢剂等因素可能解释 EPA+DHA 治疗不成功。我们的假设是，EPA+DHA、蛋白质和亮氨酸的独特组合将最大程度地刺激恶病质 COPD 患者中膳食诱导的净肌肉蛋白质合成。在第一个实验中，我们将研究在恶病质慢性阻塞性肺病患者中，在刺激全身净蛋白质合成方面，酪蛋白蛋白的饮饲是否优于乳清蛋白，以及添加亮氨酸是否会带来额外的益处。在第二个实验中，将检查恶病质 COPD 患者在 4 周内每天摄入 4000 mg EPA+DHA 与 2000 mg EPA+DHA 相比是否会增加肌肉网蛋白合成对最佳营养混合物的急性反应。在目标 1 中。在第三个实验中，将检查在 8 周内是否每天摄入最佳营养混合物和 EPA+DHA 的组合（如目标 1 和 2 中确定的那样）与等热量对照餐相比，恶病质慢性阻塞性肺病患者将改善营养、功能和整体临床结果。血浆和肌肉组织采样、稳定同位素方法以及身体成分、功能状态和生活质量评估的结合将能够量化所有终点。这项研究的结果应该为新的营养配方提供基础，以支持蛋白质合成代谢并改善慢性阻塞性肺病恶病质患者的总体结果。公共健康相关性：这项研究的结果应该为新的营养配方提供基础，以支持蛋白质合成代谢并改善慢性阻塞性肺病恶病质患者的总体结果。