THE ROLE OF INFLAMMATION IN ANEMIA OF THE ELDERLY

描述（由申请人提供）：老年人贫血是影响美国约300万患者的重要临床问题。其中约25%的人有炎症性贫血的生化标志物：血清铁含量降低，铁蛋白正常或升高。在许多老年人中，贫血似乎是由与年龄相关的炎症增加引起的，与临床明显的炎症性疾病无关，但以IL-6浓度升高为特征。我们将这种疾病称为不明原因炎症性贫血（ADI），以区别于铁参数正常且无炎症证据的不明原因贫血（UA）。我们认为，ADI是一种对促红细胞生成素（EPO）的相对抵抗状态，这是由于炎症诱导的骨髓铁供应限制所致。抑制EPO的产生可能进一步加剧AUI。临床经验提示，中等炎症的铁阻滞可通过EPO药理学剂量克服，但EPO通过何种机制抵消IL- 6/hepcidin轴释放铁用于红细胞生成尚不清楚。本研究旨在阐明AUI的发病机制及其对EPO的应答机制，并确定EPO与IL-6/ hepcidin轴交叉调控的机制。我们提出了一系列的人体实验和动物模型：特异性Aim 1：分析炎症与EPO在老年贫血发病和治疗中的相互作用特异性Aim 2：在炎症性贫血小鼠中，分析hepcidin与EPO的相互作用3：在炎症性贫血小鼠中，分析IL-6与EPO的相互作用4；在转基因小鼠中，表征诱导性慢性IL-6过量对铁代谢和EPO抵抗的影响。老年人贫血是损害其健康、独立性和生活质量的常见疾病。这项研究旨在发现炎症如何导致老年人贫血，以及现有治疗方法如何改变疾病过程。

DESCRIPTION (provided by applicant): Anemias in the elderly are an important clinical problem affecting around 3 million patients in the US. About 25% of these have biochemical markers of anemia of inflammation: the combination of decreased serum iron with normal or elevated ferritin. In many elderly the anemia appears to be caused by an age-related increase in inflammation not related to clinically-evident inflammatory diseases but characterized by increased concentrations of IL-6. We designate this disorder as anemia of unexplained inflammation (ADI) to differentiate it from unexplained anemia (UA) in which iron parameters are normal and there is no evidence of inflammation. We propose that ADI is a state of relative resistance to erythropoietin (EPO) due to inflammation-induced restriction of iron supply to the bone marrow. Suppression of EPO production may further exacerbate AUI. Clinical experience suggests that the iron block in moderate inflammation can be overcome by pharmacologic doses of EPO but it is not known by what mechanism EPO counteracts the IL- 6/hepcidin axis to release iron for erythropoiesis. The goal of this proposal is to elucidate the pathogenesis of AUI and the mechanisms of its response to EPO, and to identify the mechanisms of crossregulation between EPO and the IL-6/ hepcidin axis. We propose a series of experiments in human subjects and animal models: Specific Aim 1: Analyze the interaction of inflammation and EPO in the pathogenesis and treatment of anemia in the elderly Specific Aim 2: In mice with anemia of inflammation, analyze the interactions of hepcidin and EPO Specific Aim 3: In mice with anemia of inflammation, analyze the interactions of IL-6 and EPO Specific Aim 4: In transgenic mice, characterize the effect of inducible chronic IL-6 excess on iron metabolism and resistance to EPO Anemia in the elderly is a common condition that impairs their health, independence and quality of life. This study is designed to find how inflammation causes anemia in the elderly and how the disease processes are changed by available treatments.