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）被认为是一种涉及多个肺外组织病理的全身性疾病。慢性阻塞性肺病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的改变，最初仅导致肌肉萎缩，但在后期出现恶病质。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得到了广泛的认识，但目前的营养方法仅部分成功。我们最近观察到，为了增强蛋白质的合成代谢，在正常体重的COPD中需要对营养中蛋白质和氨基酸的组成进行操纵。病毒性慢阻肺患者的特征是肌肉蛋白合成减少和肌纤维蛋白分解升高。这些患者中有相当数量的患者，其特点是全身性炎症反应增强，对营养治疗没有反应，这与临床相关，因为营养治疗导致体重增加是COPD死亡率的一个重要的独立预测因素。二十碳五烯酸（EPA）和二十二碳己酸（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地抑制体重减轻，然而，在癌症和COPD中，体重和肌肉质量的增加并没有实现。EPA+DHA的日剂量较低，摄入后血浆EPA峰值延迟，以及蛋白质和特定氨基酸（如亮氨酸）等合成代谢剂的缺乏可能是EPA+DHA治疗不成功的原因。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患者膳食诱导的净肌蛋白合成。在第一个实验中，我们将研究在刺激病毒性慢阻肺患者全身净蛋白合成方面，小剂量喂养酪蛋白是否优于乳清蛋白，以及添加亮氨酸是否会有额外的益处。在第二个实验中，我们将检验在4周内，与2000 mg EPA+DHA相比，恶化性COPD患者每日摄入4000 mg EPA+DHA是否会增加肌网蛋白合成对Aim 1中确定的最佳营养混合物的急性反应。在第三个实验中，研究人员将检验在目标1和目标2中确定的病毒性慢性阻塞性肺病患者的8周内，每日摄入这种最佳营养混合物和EPA+DHA的组合是否会改善营养、功能和总体临床结果，与等热量控制餐相比。血浆和肌肉组织取样、稳定同位素方法以及身体成分、功能状态和生活质量评估相结合，将实现所有终点的量化。本研究结果将为新的营养配方提供基础，以支持慢性阻塞性肺疾病病毒质患者的蛋白质合成代谢和改善总体预后。公共卫生相关性：本研究的结果应该为一种新的营养配方提供基础，以支持慢性阻塞性肺疾病恶病质患者的蛋白质合成代谢和改善总体预后。

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.