THE ROLE OF INFLAMMATION IN ANEMIA OF THE ELDERLY

描述（由申请人提供）：老年人贫血是一个重要的临床问题，影响着美国约300万患者。其中约25%有炎症性贫血的生化标志物：血清铁降低与铁蛋白正常或升高的结合。在许多老年人中，贫血似乎是由年龄相关的炎症增加引起的，与临床明显的炎性疾病无关，但其特征在于IL-6浓度增加。我们将这种疾病命名为不明原因炎症性贫血（ADI），以将其与铁参数正常且无炎症证据的不明原因贫血（UA）区分开来。我们认为ADI是一种对促红细胞生成素（EPO）相对抵抗的状态，这是由于炎症诱导的骨髓铁供应受限所致。抑制EPO的产生可能会进一步加剧AUI。临床经验表明，中度炎症中的铁阻滞可以通过药理学剂量的EPO克服，但尚不清楚EPO通过何种机制抵消IL- 6/铁调素轴以释放铁用于红细胞生成。本研究的目的是阐明AUI的发病机制及其对EPO的应答机制，并确定EPO与IL-6/ hepcidin轴之间的交叉调节机制。我们提出了一系列在人类受试者和动物模型中的实验：具体目标1：分析炎症和EPO在老年人贫血的发病机制和治疗中的相互作用具体目标2：在患有炎症性贫血的小鼠中，分析铁调素和EPO的相互作用具体目标3：在患有炎症性贫血的小鼠中，分析IL-6和EPO的相互作用具体目标4：在转基因小鼠中，表征可诱导的慢性IL-6过量对铁代谢和EPO抗性的影响老年人贫血是一种常见的疾病，损害他们的健康，独立性和生活质量。这项研究旨在发现炎症是如何导致老年人贫血的，以及可用的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.