Inflammation, proteolysis and IL-1beta receptor inhibition in CHD patients

慢性血液透析（CHD）患者表现出与晚期尿毒症相关的多种代谢异常。尽管采取了强有力的措施来预防这些异常及其后果，但大多数冠心病患者都患有一种独特的营养紊乱，这种紊乱被称为“尿毒症耗损”。多项研究表明，尿毒症消耗的存在，特别是肌肉质量损失的程度，急剧增加了冠心病患者的死亡率和住院率。有几个因素被认为与尿毒症消耗有关，包括激素紊乱、厌食症、缺乏运动和并发疾病。慢性炎症在这些患者中也非常普遍，在动物模型和某些临床条件下引起肌肉分解代谢。流行病学研究表明慢性炎症与血液透析患者尿毒症消耗之间存在关联，表明可能存在因果关系。冠心病患者炎症状态激活的原因被认为是多因素的。然而，对于宿主来说，通过诱导更强的抗炎反应来限制其生物活性当然是很重要的，例如通过产生天然存在的受体拮抗剂。白细胞介素1 β是主要的促炎细胞因子之一，已被证明与几种慢性疾病（包括晚期尿毒症）的蛋白质分解代谢有关。白细胞介素1 β（激动剂）与其天然受体拮抗剂IL-1ra之间的平衡可能在控制该人群的炎症反应及其后果中发挥关键作用。这项特别拨款申请的总体目标是研究重组形式的IL-1ra对慢性炎症性冠心病患者1)蛋白质稳态和2)慢性炎症状态的短期影响。我们假设在慢性炎症性冠心病患者中，给予IL-1ra超过4周将减少其肌肉蛋白质分解，导致净蛋白质合成代谢状态，并改善其炎症状态。我们将通过一项为期4周的IL-1ra给药的前瞻性随机试验来检验这一假设，该试验旨在检验其对以下方面的影响：1)肌肉蛋白周转率（通过稳定同位素动力学研究评估），以及2)慢性炎症状态（通过血清CRP浓度测量）。如果成功，拟议的研究将为更详细和可能更长期的研究提供强有力的依据，以评估对更容易获得的营养参数以及发病率和死亡率的影响。最终，抗炎药物的使用可能是治疗冠心病患者尿毒症浪费的一种新的有效途径。造成这种情况的最重要因素之一是一种被称为“尿毒症消瘦”的营养不良形式。尿毒症消瘦的一个表现是肌肉量的逐渐减少。慢性炎症常见于透析患者，并与尿毒症消耗有关。我们想测试用消炎治疗减少炎症是否会减少透析患者的肌肉损失。

DESCRIPTION (provided by applicant): / Abstract Chronic hemodialysis (CHD) patients display multiple metabolic abnormalities related to advanced uremia. Despite vigorous attempts to prevent these abnormalities and their consequences, most CHD patients suffer from a unique form of nutritional derangement, which can be termed as "uremic wasting". Several studies have demonstrated that the presence of uremic wasting, especially the degree of loss of muscle mass, sharply increases mortality and hospitalization rate in CHD patients. Several factors have been thought to be associated with uremic wasting, including hormonal derangement, anorexia, physical inactivity, and concurrent illnesses. Chronic inflammation, also highly prevalent in these patients, causes muscle catabolism in animal models and certain clinical conditions. Epidemiological studies show an association between chronic inflammation and uremic wasting in hemodialysis patients indicating a possible causal relationship. The cause for the activated inflammatory state in CHD patients is believed to be multi-factorial. Nevertheless, it is certainly important for the host to limit its biological activity by eliciting a stronger anti-inflammatory response, for example through the production of naturally occurring receptor antagonist. Interleukin 1 beta, one of the major pro-inflammatory cytokines has been shown to be associated with protein catabolism in several chronic disease states, including advanced uremia. A balance between interleukin 1 beta (agonist) and its naturally occurring receptor antagonist IL-1ra may play a pivotal role in controlling the inflammatory response and its consequences in this population. The overall goal of this particular grant application is to examine the short-term effects of the administration of the recombinant form of IL-1ra on 1) protein homeostasis in chronically inflamed CHD patients and in2) the chronic inflammatory state . We hypothesize that in chronically inflamed CHD patients, the administration of IL-1ra over 4 weeks will decrease their muscle protein breakdown leading to a net protein anabolic state and improve their inflammatory state. We will test this hypothesis through a prospective, randomized trial of IL-1ra administration over 4weeks designed to examine its effects on: 1) Muscle protein turnover rate (as assesed by stable isotope kinetic studies), and 2) Chronic inflammatory state (as measured by serum CRP concentration). If successful, the proposed studies will provide strong rationale for more detailed and potentially longer-term studies assessing the effects on more readily available nutritional parameters as well as morbidity and mortality. Ultimately, the administration of an anti-inflammatory agent may represent a new effective pathway for the treatment of uremic wasting in CHD patients Patients on dialysis suffer a high death rate. One of the most important factors responsible for this is a form of malnutrition termed as "uremic wasting". A manifestation of uremic wasting is progressive loss of muscle mass. Chronic inflammation is commonly seen in dialysis patients and has been linked to uremic wasting. We want to test if reducing inflammation with an anti-inflammatory treatment will reduce muscle loss in dialysis patients.