Mechanisms of hepcidin effects in the anemia of chronic disease

铁调素在慢性病贫血中的作用机制

• 批准号: 8586860
• 负责人: ROBERT T MEANS
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8586860
• 关键词: Acute-Phase Proteins; Address; Anemia; Anemia due to Chronic Disorder; Anti-Bacterial Agents; Antigen-Presenting Cells; Apoptosis; Blood; Bone Marrow; CFU-E; Cell Survival; Characteristics; Chronically Ill; Clinical; Data; Diagnostic; Disease; Down-Regulation; Erythrocytes; Erythroid; Erythroid Cells; Erythropoiesis; Etiology; Gene Expression; Genetic Transcription; Hepatic; In Vitro; Inflammation Mediators; Inflammatory; Interleukin-1; Interleukin-6; Investigation; Iron; Kidney; Lead; Link; Liver; Marrow; Medicine; Mission; Modeling; Morbidity - disease rate; Pathogenesis; Pathologic Processes; Patients; Population; Process; Production; Protein Export Pathway; Proteins; Research Personnel; Reticuloendothelial System; Role; Serum; Syndrome; Time; Transgenic Animals; Tumor Necrosis Factor-alpha; Urine; Variant; cytokine; effective therapy; hepcidin; iron metabolism; macrophage; metal transporting protein 1; mortality; protein expression; public health relevance

DESCRIPTION (provided by applicant): The anemia of chronic disease (ACD) is one of the most common clinical syndromes encountered in the practice of medicine. This disorder typically manifests itself as a hypoproliferative anemia accompanied by a low serum iron concentration despite adequate reticuloendothelial iron stores. ACD has generally been considered to result from a combination of pathologic processes which can be linked to the cytokine mediators of inflammation. However, the diagnostic importance of altered iron metabolism in ACD has led many investigators to consider that this feature denotes the dominant pathophysiologic mechanism of this syndrome. Hepcidin is an antibacterial protein which is produced in the liver, circulates in the blood, and is excreted in the urine. It is a type II acute phase protein, the expression of which is induced by interleukin (IL)-6, and down-regulated by tumor necrosis factor (TNF). The specific iron regulatory functions of hepcidin, as well as the anemia syndromes observed in patients and transgenic animals with abnormalities of hepcidin gene expression (discussed below), have led many to consider that it is the key to unlocking "the mysteries of ACD ". Three major processes are involved in the pathogenesis of ACD. A slight shortening of red cell survival creates a demand for a small increase in red cell production by the bone marrow. The marrow cannot respond adequately to this demand due to impaired erythropoiesis and impaired mobilization of reticuloendothelial system iron stores. A potential role for hepcidin in the iron anomalies of ACD is strongly supported by available data. However, iron changes are not the sole abnormality characteristic of ACD. If hepcidin is the major factor responsible for ACD, then it should also contribute to the impaired erythropoiesis observed in this syndrome. The hypothesis that hepcidin contributes to impaired erythropoiesis in ACD will be addressed through the following specific aims: 1. Determination of hepcidin effects on erythroid colony formation, and investigation of the mechanisms involved. This will include A., whether the effects of hepcidin on erythropoiesis are direct-acting, or require an accessory cell; B., the role of Epo concentration in hepcidin effects on erythropoiesis; C., the role of apoptosis/anti-proliferation in inhibitory effects of hepcidin on erythropoiesis; D., the effects of cytokines on the hepcidin/erythropoiesis relationship; E., the contributions of iron to hepcidin effects on CFU-E colony formation; F., the role of ferroportin (FPN) and variant FPN in hepcidin effects on CFU-E; and G., effects of Epo and inflammatory cytokines on FPN variant expression in erythroid cells. 2. Determination of the interactions of hepcidin and cytokines in bone marrow macrophage iron transport. Hepcidin inhibits egress of iron from bone marrow macrophages by downregulation of the iron export protein FPN. The ability of inflammatory cytokines to enhance or diminish this effect will be determined, as well as any effects on the expression of variant FPN.3. Determination of hepcidin effects on induced Epo production in vitro, and delineation of involved mechanisms. This will include A., determination and quantification of the effects of hepcidin on the induction of Epo protein in hepatic and renal models, and of the time-course of these effects; and B., determination of the roles of inflammatory cytokines in modulating these effects; C., the role of iron availability in these effects; and D., determination of the effects of hepcidin on Epo transcription, and the mechanism involved in these effects. 4. Effects of rhEpo on hepcidin production in vitro. In this Aim, we will determine A., the effects of Epo on hepcidin production by HepG2, as well as B., the extent to which these effects are modulated by TNF, IL-1, and IL-6. Relevance to VA mission: The proposed studies can potentially lead to an enhanced understanding of the mechanisms of ACD, and lead to more effective therapy. PUBLIC HEALTH RELEVANCE: Anemia is a major contributor to morbidity and mortality in chronically ill patients, and the anemia of chronic disease (ACD) is the major etiology of this anemia. This disorder typically manifests itself as a hypoproliferative anemia accompanied by a low serum iron concentration despite adequate reticuloendothelial iron stores. ACD is highly prevalent in the VA population. In ACD, a slight shortening of red cell survival creates a demand for a small increase in red cell production by the bone marrow. The marrow cannot respond adequately to this demand due to impaired erythropoiesis and impaired mobilization of reticuloendothelial system iron stores. A potential role for hepcidin in the iron anomalies of ACD is strongly supported by available data. If hepcidin is the major factor responsible for ACD, then it should also contribute to the impaired erythropoiesis observed in this syndrome. The proposed studies can potentially lead to an enhanced understanding of the mechanisms of ACD, and therefore to more effective therapy.

描述（由申请人提供）： 慢性病贫血（ACD）是医学实践中遇到的最常见的临床综合症之一。这种疾病通常表现为一种低增生性贫血，尽管有足够的网状内皮铁储存，但伴随着低血清铁的浓度。通常认为ACD是由于病理过程的结合而导致的，这些过程可以与炎症的细胞因子介质有关。但是，ACD中铁代谢改变的诊断重要性使许多研究者认为此特征表示该综合征的主要病理生理机制。肝素是一种在肝脏中产生的抗菌蛋白，在血液中循环，并在尿液中排出。它是II型急性期蛋白，其表达是由白介素（IL）-6诱导的，并由肿瘤坏死因子（TNF）下调。肝素的特异性铁调节功能以及在患者和具有肝素基因表达异常的患者和转基因动物中观察到的贫血综合征（如下所述），许多人认为这是解锁“ ACD的奥秘”的关键。 ACD的发病机理涉及三个主要过程。红细胞存活的略有缩短会导致对骨髓产生红细胞产生的需求。由于红细胞生成受损和动员网状内皮系统铁储存，骨髓无法对这一需求做出充分的反应。可用数据强烈支持肝素在ACD的铁异常中的潜在作用。但是，铁的变化不是ACD的唯一异常特征。如果肝素是负责ACD的主要因素，那么它也应有助于该综合征中观察到的促红细胞生成。 肝素在ACD中有助于甲型激素促进性促红细胞生成的假设将通过以下具体目的解决：1。确定肝素对红细胞生成对红细胞菌落形成的影响，并研究所涉及的机制。这将包括A。 B.，EPO浓度在肝素对促红细胞生成的作用中的作用； C.，凋亡/抗增殖在肝素对促红细胞生成的抑制作用中的作用； D.，细胞因子对肝素/红细胞生成关系的影响； E.，铁对肝素对CFU-E菌落形成的作用的贡献； F.，铁蛋白（FPN）和变体FPN在肝素对CFU-E的作用中的作用；和G.，EPO和炎性细胞因子对红细胞细胞FPN变异表达的影响。 2。测定骨髓巨噬细胞铁中肝素和细胞因子的相互作用。肝素通过下调铁出口蛋白FPN来抑制铁从骨髓巨噬细胞中流出。将确定炎症细胞因子增强或减少这种作用的能力，以及对变体FPN.3的表达的任何影响。测定肝素对体外诱导的EPO产生的作用以及涉及机制的描述。这将包括A.，确定和定量肝素对肝和肾模型中EPO蛋白诱导的作用以及这些作用的时间顺序。和B.，确定炎性细胞因子在调节这些作用中的作用； C.，铁的作用在这些作用中；和D.，确定肝素对EPO转录的作用以及这些作用所涉及的机制。 4。Rhepo在体外对肝素产生的影响。在此目标中，我们将确定A。，EPO对HEPG2以及B的影响。与VA任务的相关性：拟议的研究可能会导致对ACD机制的理解增强，并导致更有效的治疗。 公共卫生相关性： 贫血是慢性病患者发病率和死亡率的主要因素，慢性疾病（ACD）的贫血是这种贫血的主要病因。这种疾病通常表现为一种低增生性贫血，尽管有足够的网状内皮铁储存，但伴随着低血清铁的浓度。 ACD在VA人群中非常普遍。在ACD中，红细胞存活的略有缩短会导致骨髓对红细胞产生的略有增加的需求。由于红细胞生成受损和动员网状内皮系统铁储存，骨髓无法对这一需求做出充分的反应。可用数据强烈支持肝素在ACD的铁异常中的潜在作用。如果肝素是负责ACD的主要因素，那么它也应有助于该综合征中观察到的促红细胞生成。拟议的研究可能会导致对ACD机制的理解增强，从而获得更有效的治疗。