Eicosapentaenoic acid and protein modulation to induce anabolism in COPD

描述(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，涉及几个肺外组织的病理。COPD的全身特征包括慢性低度全身炎症和蛋白质代谢调节的改变，最初只导致肌肉萎缩，但在恶病质的后期。尽管用适当的营养治疗COPD患者恶病质的重要性是公认的，但目前的营养方法只取得了部分成功。我们最近观察到，为了增强蛋白质合成代谢，在正常体重的COPD患者中，需要控制营养中蛋白质和氨基酸的组成。恶病质COPD患者的特点是肌肉蛋白质合成减少和肌原纤维蛋白分解增加。这些以全身炎症反应增强为特征的相当数量的患者对营养治疗没有反应，营养治疗具有临床意义，因为营养治疗的体重增加是COPD死亡率的一个重要的独立预测因素。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。补充EPA DHA已被证明能有效地抑制体重下降，然而，体重和肌肉质量的增加并不能在癌症和COPD中实现。EPA-DHA日剂量低、EPA摄入后血浆EPA峰值延迟、缺乏蛋白质等合成代谢物质和特定氨基酸(即亮氨酸)等因素可能是EPA-DHA治疗失败的原因。我们的假设是，存在一种独特的EPA DHA、蛋白质和亮氨酸的组合，最大限度地刺激恶病质COPD患者膳食诱导的肌肉蛋白质净合成。在第一个实验中，我们将检验在刺激恶病质COPD患者全身净蛋白质合成方面，酪蛋白蛋白是否优于乳清蛋白，以及添加亮氨酸是否会有额外的好处。在第二个实验中，将测试恶病质COPD患者在4周内每天摄入4000毫克EPA DHA与2000 mg EPA DHA相比，是否会增加对目标1中确定的最佳营养混合物的肌肉净蛋白质合成的急性反应。在第三个实验中，将检验恶病质COPD患者在8周期间每天摄取这种最佳营养混合物和目标1和2中确定的EPA DHA的组合是否会改善营养、功能和整体临床结果，与等卡路里控制餐相比。结合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的评估，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.