Eicosapentaenoic acid and protein modulation to induce anabolism in COPD

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，涉及几种额外肺组织的病理学。COPD的全身性特征包括慢性低度全身性炎症和蛋白质代谢调节改变，其最初仅导致肌肉萎缩，但在晚期阶段导致恶病质。尽管通过适当的营养治疗COPD恶病质的重要性已得到公认，但目前的营养方法仅部分成功。我们最近观察到，为了增强蛋白质的抗氧化性，在正常体重的COPD中需要操纵营养中的蛋白质和氨基酸的组成。恶病质COPD患者的特征在于肌肉蛋白质合成减少和肌原纤维蛋白质分解升高。这些患者中有相当数量的患者，其特征是全身炎症反应增强，对营养治疗无反应，这具有临床意义，因为营养治疗后体重增加是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1 -3脂肪酸，已知其通过抑制细胞因子产生而发挥抗炎作用。EPA+DHA补充剂已被证明可有效抑制体重减轻，但在癌症和COPD中均未实现体重和肌肉质量增加。EPA+DHA的每日剂量低，摄入后延迟的血浆EPA峰值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限度地刺激恶病质COPD患者的膳食诱导的净肌肉蛋白质合成。在第一个实验中，我们将检查在恶病质COPD患者中，在刺激全身净蛋白质合成方面，酪蛋白的啜喂是否优于乳清蛋白，以及添加亮氨酸是否会有额外的益处。在第二个实验中，将检查恶病质COPD患者在4周期间每天摄入4000 mg EPA + DHA与2000 mg EPA+DHA相比是否会增加肌肉网蛋白质合成对目标1中确定的最佳营养混合物的急性反应。在第三个实验中，将检查与等热量对照餐相比，恶病质COPD患者在8周期间每日摄入如目标1和2中确定的最佳营养混合物和EPA+DHA的这种组合是否会改善营养、功能和总体临床结果。血浆和肌肉组织采样、稳定同位素方法学以及身体成分、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一种新的营养配方提供基础，以支持蛋白质的摄入，并改善慢性阻塞性肺疾病恶病质患者的总体预后。公共卫生相关性：这项研究的结果应该为一种新的营养配方提供基础，以支持蛋白质的摄入，并改善慢性阻塞性肺疾病恶病质患者的总体预后。

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.