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，在美国大约有300万患者受到影响。其中约25%的患者有炎症性贫血的生化标志：血清铁降低与铁蛋白正常或升高的组合。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，与临床上明显的炎症性疾病无关，但以IL-6浓度升高为特征。我们将这种疾病命名为不明原因炎症贫血(ADI)，以区别于不明原因贫血(UA)，在不明原因贫血中，铁参数正常，没有炎症的证据。我们认为ADI是一种对促红细胞生成素(EPO)相对抵抗的状态，这是由于炎症导致骨髓铁供应受限。抑制EPO的产生可能会进一步加重AUI。临床经验表明，中度炎症中的铁障碍可以通过药物剂量的EPO来克服，但目前尚不清楚EPO通过什么机制中和IL-6/海普西汀轴释放铁来促进红细胞生成。本研究的目的是阐明AUI的发病机制及其对EPO的反应机制，并确定EPO与IL-6/Hepsidin轴的交叉调节机制。我们提出了一系列在人体和动物模型中的实验：特定目的1：分析炎症和EPO在老年贫血发病和治疗中的相互作用特定目的2：在炎症性贫血小鼠中，分析海普西丁和EPO的相互作用3：在炎症性贫血小鼠中，分析IL-6和EPO的相互作用4：在转基因小鼠中，表征可诱导的慢性IL-6过量对铁代谢的影响以及对老年EPO贫血的抵抗是损害老年人健康、独立性和生活质量的常见疾病。这项研究旨在找出炎症是如何导致老年人贫血的，以及现有的治疗方法是如何改变疾病过程的。

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.