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）：该提案涉及广泛的挑战领域 (15) 翻译和具体挑战主题，15-DK-106：翻译基本血液学概念。如果不加以识别和治疗，心脏、肝脏、内分泌腺和其他组织长期接触铁会导致严重的氧化损伤、器官衰竭、恶变和死亡。镰状细胞病 (SCD) 是一种遗传性疾病，会导致严重的终生疼痛、器官毒性衰弱和过早死亡。许多并发症可以通过输血来改善，输血反过来会导致严重的铁超负荷。由于人类没有有效的方法去除多余的铁，除非采用螯合疗法，否则铁会终生保留。接受长期输血计划并出现铁超负荷的患者会在专门中心进行常规监测并接受铁螯合治疗。相比之下，大量患者仅在不同医院接受不熟悉 SCD 和铁过载的提供者的零星输血治疗急性事件。尽管零星输血的次数可能很高，但这些患者的铁状况很大程度上未知。此外，年轻时长期接受输血的患者通常会在成年后停止输血，并且不会因铁超负荷而接受治疗。因此，大量 SCD 患者可能患有未被识别的铁超负荷，并且可能不知道相关风险。很少有研究检查 SCD 中的铁超负荷，大多数研究都使用铁蛋白来评估铁负荷，铁蛋白显然被认为不足以衡量全身铁的含量。事实上，还没有研究通过直接测量全身或组织铁来检查 SCD 成人铁超负荷的患病率。我们将使用我们开发和验证的 MRI 方法来确定 SCD 患者铁过载的患病率。这些技术可以轻松、准确、无创地测量多个器官中的铁过载。铁超负荷与 SCD 患者的器官损伤和不良预后相关；然而，尚未研究铁超负荷发挥其毒性的机制，并且铁超负荷造成的损伤的影响尚未与血管闭塞本身引起的器官损伤分开。 SCD 患者患有慢性进行性血管病变，导致肺动脉高压、肾衰竭和中风。慢性血管内溶血会在循环中释放红细胞成分，是血管病变的主要原因，并通过损害一氧化氮的生物利用度发挥作用。铁介导的氧化应激和不稳定血浆铁 (LPI) 水平的升高可能会加重血管内溶血并损害内皮功能，这一点在地中海贫血综合征中可以清楚地看到。确定血管内皮功能的非侵入性标准化测量、氧化应激生物标志物、一氧化氮代谢调节剂和铁负荷之间的关系对于了解镰状血管病至关重要，并且必须在治疗镰状血管病的介入研究之前完成。被设计。假设：我们怀疑临床上显着的铁超负荷在 SCD 患者中很常见，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预测内皮功能障碍、颈动脉内膜中层增厚和肺动脉高压，而与溶血、炎症和夜间缺氧无关。具体目标： 1) 我们将确定 SCD 患者肝脏、胰腺和不稳定铁升高的患病率和程度。肝脏铁浓度 (LIC) 和 MRI 测量的含量将用作全身铁的替代值。将测量胰腺 R2* 作为慢性不稳定铁暴露的替代指标。血清铁蛋白、转铁蛋白饱和度和不稳定血浆铁 (LPI) 将作为铁状态的急性标志物进行测量。 2）我们将确定铁超载是否会加剧镰状血管病。我们将通过测量血流介导的肱动脉扩张、颈动脉内膜内侧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独立于溶血（无细胞血红蛋白、乳酸脱氢酶）、炎症（高敏 CRP）、NO 代谢功能障碍（精氨酸、鸟氨酸和瓜氨酸、维生素 C、四氢生物蝶呤、二氢生物蝶呤）和夜间来预测血管病变。时间缺氧（夜间脉搏血氧饱和度）。我们预计，在此授权期间获得的结果将可靠地确定 SCD 患者铁超载的患病率及其与生物标志物和内皮功能的关系。该提案代表了设计后续改善血管功能的临床试验的重要第一步。 公共健康相关性：我们假设临床上显着的铁超负荷在镰状细胞病 (SCD) 患者中很常见，并会加剧镰状血管病。我们将测量肝脏， 通过 MRI 对 150 名 SCD 患者进行胰腺和肾铁超载，以确定铁超载是否预测内皮功能障碍、颈动脉内膜中层增厚和肺动脉高压，而与溶血、炎症和夜间缺氧无关。该提案代表了设计后续临床试验以改善 SCD 患者血管功能的重要第一步。