Iron-mediated vascular disease in sickle cell disease.

镰状细胞病中铁介导的血管疾病。

• 批准号: 7933804
• 负责人: JOHN C WOOD
• 金额: $ 49.52万
• 依托单位: CHILDREN'S HOSPITAL OF LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933804
• 关键词: 7,8-dihydrobiopterin; Acute; Address; Adult; Affect; African American; Age; Area; Arginine; Ascorbic Acid; Biological Availability; Biological Markers; Blood Circulation; Blood Transfusion; Blood Vessels; Blood Viscosity; Blood flow; Cells; Cellular Structures; Cessation of life; Chelation Therapy; Child; Chronic; Citrulline; Clinical Trials; Collection; Communities; Cooley' s anemia; Data; Development; Disease Management; Endocrine Glands; Erythrocytes; Event; Exposure to; Ferritin; Frequencies; Functional disorder; Genetic; Grant; Health Services Accessibility; Heart; Hematological Disease; Hematology; Hemoglobin; Hemolysis; Hepatic; Hereditary Disease; Hispanics; Hospitalization; Hospitals; Human; Hypoxia; Inflammation; Institutes; Iron; Iron Chelation; Iron Overload; Kidney; Kidney Failure; Lactate Dehydrogenase; Life; Liver; Los Angeles; Magnetic Resonance Imaging; Malignant - descriptor; Measurement; Measures; Mediating; Metabolism; Methodology; Monitor; Morbidity - disease rate; National Heart, Lung, and Blood Institute; Nitric Oxide; Organ; Organ failure; Ornithine; Outcome; Oxidants; Oxidative Stress; Pain; Pancreas; Patients; Pharmaceutical Preparations; Physiology; Plasma; Population; Population Study; Positioning Attribute; Prevalence; Prevalence Study; Provider; Pulmonary Hypertension; Pulse Oximetry; Reporting; Risk; Sample Size; Serum; Sickle Cell; Sickle Cell Anemia; Specialized Center; Stroke; Syndrome; Techniques; Technology; Thalassemia; Time; Tissues; Toxic effect; Transferrin; Transfusion; Translating; Translational Research; United States; Vascular Diseases; Work; brachial artery; clinically relevant; clinically significant; design; experience; improved; intimal medial thickening; iron metabolism; metropolitan; mortality; oxidant stress; programs; public health relevance; sickling; standardize measure; tetrahydrobiopterin

DESCRIPTION (provided by applicant): This proposal addresses broad Challenge Area (15) Translational and specific Challenge Topic, 15- DK-106: Translating Basic Hematology Concepts. Prolonged exposure to iron of the heart, liver, endocrine glands and other tissues results in severe oxidant damage, organ failure, malignant transformation and death, if unrecognized and untreated. Sickle cell disease (SCD) is a genetic disease that causes severe, lifelong pain, debilitating organ toxicity and early death. Many of the complications can be ameliorated by blood transfusions, which in turn cause significant iron overload. As humans have no effective way to remove excess iron, the iron remains throughout life unless chelation therapy is instituted. Patients who are on chronic transfusion programs and develop iron overload are routinely monitored at specialized centers and receive iron chelation. In contrast, a large number of patients only receive sporadic transfusions for treatment of acute events at different hospitals by providers unfamiliar with SCD and iron overload. Even though the number of sporadic transfusions may be high, these patients' iron status is largely unknown. In addition, patients who were chronically transfused when young, often stop transfusions in adulthood and are not treated for their iron overload. Thus, a significant number of SCD patients may have unrecognized iron overload and may not be aware of the associated risks. Very few studies have examined iron overload in SCD and most have used ferritin, clearly recognized as an inadequate measure of total body iron, for the assessment of iron burden. In fact, no study has examined the prevalence of iron overload in SCD adults by direct measurement of total body or tissue iron. We will determine the prevalence of iron overload in SCD patients using MRI methodologies that we developed and validated. These techniques permit easy, accurate, and non-invasive measurement of iron overload in multiple organs. Iron overload is associated with organ damage and poor outcomes in SCD patients; however, the mechanisms by which iron overload exert its toxicity have not been studied and the effects of damage from iron overload have not been separated from organ damage due to vaso-occlusion itself. SCD patients suffer from chronic, progressive vasculopathy leading to pulmonary hypertension, renal failure and stroke. Chronic intravascular hemolysis, which releases red cell components in the circulation, is a leading cause of vasculopathy and acts by impairing nitric oxide bioavailability. Iron-mediated oxidative stress and increased levels of labile plasma iron (LPI), may worsen intravascular hemolysis and impair endothelial function, as clearly seen in the thalassemia syndromes. Determination of the relation between non-invasive, standardized measures of vascular endothelial function, biomarkers of oxidant stress, modulators of nitric oxide metabolism and iron loading is critical for the understanding of sickle vasculopathy and must be accomplished before an interventional study to treat sickle vasculopathy can be designed. Hypothesis: We suspect that clinically significant iron overload is common in subjects with SCD and worsens with age. Furthermore, we anticipate that tissue localized and free plasma iron levels predict endothelial dysfunction, carotid intimal-medial thickening, and pulmonary hypertension, independently of hemolysis, inflammation, and night-time hypoxia. Specific Aims: 1) We will determine the prevalence, and magnitude of hepatic, pancreatic and labile iron elevation in patients with SCD. Liver iron concentration (LIC) and content measured by MRI will be used as a surrogate for total body iron. Pancreatic R2* will be measured as a surrogate for chronic labile iron exposure. Serum ferritin, transferrin saturation, and labile plasma iron (LPI) will be measured as acute markers of iron status. 2) We will determine whether iron overload exacerbates sickle vasculopathy. We will quantify sickle vasculopathy by measuring flow-mediated dilation of the brachial artery, carotid intimal-medial thickening, and pulmonary hypertension. We will determine if iron loading predicts vasculopathy independently of hemolysis (cell-free hemoglobin, lactate dehydrogenase), inflammation (high-sensitivity CRP), dysfunction of NO metabolism (arginine, ornithine & citrulline, vitamin C, tetrahydrobiopterin, dihydrobiopterin,) and night time hypoxia (overnight pulse oximetry). We anticipate that the results obtained during this granting period will solidly establish the prevalence of iron overload and its relation to biomarkers and endothelial function in SCD patients. This proposal represents an essential first step in the design of a subsequent clinical trial to improve vascular function. PUBLIC HEALTH RELEVANCE: We hypothesize that clinically significant iron overload is common in subjects with sickle cell disease (SCD) and exacerbates sickle vasculopathy. We will measure hepatic, pancreatic and renal iron overload by MRI in 150 SCD patients to determine whether iron overload predicts endothelial dysfunction, carotid intimal-medial thickening, and pulmonary hypertension, independently of hemolysis, inflammation, and night-time hypoxia. This proposal represents an essential first step in the design of a subsequent clinical trial to improve vascular function in SCD patients.

描述（由申请人提供）：该提案解决了广泛的挑战领域（15）翻译和特定挑战主题，15-dk-106：翻译基本血液学概念。长期暴露于心脏铁，肝脏，内分泌腺体和其他组织会导致严重的氧化剂损伤，器官衰竭，恶性转化和死亡，如果未被识别和未经治疗。镰状细胞疾病（SCD）是一种遗传疾病，会导致严重，终生疼痛，可使器官毒性和早期死亡。输血可以改善许多并发症，进而导致大量铁超负荷。由于人类没有有效的方法去除多余的铁，除非提出螯合疗法，否则将一生中的铁残留。正在接受慢性输血计划和发展铁超负荷的患者通常在专业中心监测并接受铁螯合。相比之下，大量患者仅接受零星的输血，以治疗不同医院的急性事件，而不熟悉SCD和铁超负荷的提供者。即使零星输血的数量可能很高，这些患者的铁状态在很大程度上尚不清楚。此外，年轻时长期输血的患者通常会在成年后停止输血，并且不接受铁超负荷治疗。因此，大量的SCD患者可能无法识别铁超负荷，并且可能不知道相关的风险。很少有研究检查了SCD中的铁超负荷，大多数人使用铁蛋白，清楚地被认为是对全身铁的量度不足，以评估铁负担。实际上，尚无研究通过直接测量全身或组织铁的直接测量来检查SCD成年人铁超载的流行。我们将使用我们开发和验证的MRI方法来确定SCD患者铁超负荷的患病率。这些技术允许在多个器官中轻松，准确且非侵入性测量铁超载。铁超负荷与SCD患者的器官损伤和不良结局有关。但是，铁超负荷施加其毒性的机制尚未被研究，由于血管肠结咬本身，铁超负荷造成的损害尚未与器官损伤分开。 SCD患者患有慢性，进行性血管病，导致肺动脉高压，肾衰竭和中风。慢性血管内溶血在循环中释放了红细胞成分，是血管病的主要原因，并通过损害一氧化氮生物利用度来起作用。如在Thalassya综合征中明显看到的那样，铁介导的氧化应激和不稳定血浆铁（LPI）的水平增加可能会恶化血管内溶血和损害内皮功能。确定血管内皮功能的非侵入性，标准化度量，氧化剂应激的生物标志物，一氧化氮代谢的调节剂和铁负荷的调节剂对了解镰状血管病至关重要，并且必须在设计介绍研究之前就可以设计出对镰状血管病的理解。假设：我们怀疑临床意义的铁超载在患有SCD的受试者中很常见，并且随着年龄的增长而恶化。此外，我们预计组织局部和游离血浆铁水平可以预测内皮功能障碍，颈动脉内膜中内增厚和肺动脉高压，独立于溶血，炎症和夜间缺氧。具体目的：1）我们将确定SCD患者的肝，胰腺和不稳定铁升高的患病率和幅度。 MRI测量的肝铁浓度（LIC）和含量将用作全身铁的替代物。胰腺R2*将作为慢性不稳铁暴露的替代物测量。血清铁蛋白，转铁蛋白饱和度和不稳定血浆铁（LPI）将被测量为铁状态的急性标记。 2）我们将确定铁超负荷是否加剧了镰状血管病。我们将通过测量流动介导的臂动脉扩张，颈动脉内膜增厚和肺动脉高压来量化镰状血管病。我们将确定铁负荷是否可以独立于溶血（无细胞血红蛋白，乳酸脱氢酶），炎症（高敏感性CRP），无代谢功能障碍（精氨酸，鸟嘌呤，鸟氨酸和瓜氨酸，维生素c，tetrahydrobiobibi andihydihydrobi（dihydihyydrobi）（dibybiia）（dihydihyydrobi（dibiiia）），炎症（高敏感性CRP）是否可以预测血管病变。血氧仪）。我们预计，在此授予期间获得的结果将牢固地确定铁超载的流行及其与SCD患者中生物标志物和内皮功能的关系。该提案代表了随后的临床试验设计以改善血管功能的重要第一步。 公共卫生相关性：我们假设在患有镰状细胞病（SCD）和加剧镰状血管病的受试者中，临床上具有重要的铁超负荷是常见的。我们将衡量肝脏， MRI在150名SCD患者中的胰腺和肾铁超负荷确定铁超负荷是否预测内皮功能障碍，颈动脉内膜中性增厚和肺动脉高压，独立于溶血，炎症和夜间缺氧。该提案代表了随后的临床试验设计以改善SCD患者血管功能的重要第一步。