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）：慢性阻塞性肺疾病（COPD）被认为是一种全身性疾病，涉及多种肺部组织中的病理学。 COPD中的全身特征包括慢性低度系统性炎症和蛋白质代谢的调节改变，这最初仅导致肌肉萎缩，但在缓存的后期阶段。尽管以适当的营养治疗CACHEXIA具有广泛认可的重要性，但目前的营养方法仅在部分成功。我们最近观察到，为了增强蛋白质合物，在正常体重COPD中需要在营养中对蛋白质和氨基酸组成的操纵。缓存COPD患者的特征是肌肉蛋白合成降低和肌原纤维蛋白分解升高。这些患者中有大量以增强全身性炎症反应的特征，未能对营养疗法反应，这是临床相关性，因为体重增加与营养疗法是COPD死亡率的重要，独立的预测指标。 eicosapentaenoic酸（EPA）和二十二烷酰己酸（DHA）是I-3脂肪酸，已知通过抑制细胞因子产生而起着抗炎症作用。 EPA+DHA的补充已被证明可以有效抑制体重减轻，但是，在癌症和COPD中，体重和肌肉质量增加均未实现。诸如EPA+DHA的每日剂量低，摄入后的延迟血浆EPA峰以及不存在蛋白质和特定氨基酸（IE亮氨酸）等合成代谢剂的因素可能解释了EPA+DHA治疗是不成功的。我们的假设是，EPA+DHA，蛋白质和亮氨酸具有独特的组合，可最大程度地刺激饮食诱导的缓存COPD患者的净肌肉蛋白质合成。在第一个实验中，我们将检查酪蛋白蛋白在缓存COPD患者中刺激全身净蛋白质合成的酪蛋白蛋白的饮食是否在乳清蛋白上方是可取的，以及添加亮氨酸是否会带来更多好处。在第二个实验中，将检查是否每天摄入4000 mg EPA+DHA，与2000 mg EPA+DHA相比，在4周内，在缓存COCD患者中，是否会增加肌肉净蛋白合成中的急性反应到最佳营养混合物中的最佳营养混合物。在AIM 1和2中，与等量平衡的对照粉相比，在缓存的COPD患者中，在8周内将改善营养，功能和全球临床结果。血浆和肌肉组织采样，稳定的同位素方法论以及人体组成，功能状态和生活质量的评估的组合将有助于对所有终点进行定量。这项研究的结果应为一种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部疾病的缓存患者的总体预后。公共卫生相关性：这项研究的结果应为一种新的营养配方提供基础，以支持蛋白质合成蛋白代谢并改善慢性阻塞性肺部疾病的缓存患者的总体预后。