Iron-mediated vascular disease in sickle cell disease.

描述(由申请人提供)：本提案涉及广泛的挑战领域(15)翻译和具体的挑战主题，15-DK-106：翻译血液学基本概念。长期暴露于心脏、肝脏、内分泌腺和其他组织的铁会导致严重的氧化剂损伤、器官衰竭、恶性转化和死亡，如果不认识和不治疗的话。镰状细胞病(SCD)是一种遗传性疾病，会导致严重的终生疼痛、衰弱的器官毒性和过早死亡。许多并发症可以通过输血来改善，而输血又会导致严重的铁负荷。由于人类没有有效的方法来清除多余的铁，除非进行螯合治疗，否则铁在一生中都会保留。正在接受长期输血计划并出现铁超载的患者会在专门的中心接受常规监测，并接受铁离子螯合治疗。相比之下，大量患者只在不同的医院接受零星输血，以治疗急性事件，由不熟悉SCD和铁超载的提供者提供。尽管零星输血的数量可能很高，但这些患者的铁状况在很大程度上是未知的。此外，年轻时长期输血的患者，往往在成年后停止输血，并且没有因铁负荷过高而接受治疗。因此，相当数量的SCD患者可能有未被认识到的铁超载，并且可能没有意识到相关的风险。很少有研究检查SCD的铁负荷，大多数研究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成人铁超载的患病率。我们将使用我们开发和验证的MRI方法来确定SCD患者铁超载的患病率。这些技术可以方便、准确和非侵入性地测量多个器官的铁超载。在SCD患者中，铁负荷与器官损害和不良预后相关；然而，铁负荷发挥其毒性的机制尚未被研究，铁负荷损害的影响还没有与血管闭塞本身造成的器官损害分开。SCD患者患有慢性进行性血管病变，导致肺动脉高压、肾功能衰竭和中风。慢性血管内溶血，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而起作用。铁介导的氧化应激和不稳定的血浆铁(LPI)水平升高，可能会恶化血管内溶血和损害内皮功能，这在地中海贫血综合征中明显可见。确定非侵入性、标准化的血管内皮功能指标、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理解镰状血管病至关重要，必须在设计治疗镰状血管病的介入性研究之前完成。假设：我们怀疑临床上显著的铁超载在SCD受试者中很常见，并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预测内皮功能障碍、颈动脉内膜中层增厚和肺动脉高压，与溶血、炎症和夜间低氧无关。具体目标：1)我们将确定SCD患者肝脏、胰腺和活化铁升高的发生率和幅度。通过MRI测量的肝脏铁浓度(LIC)和含量将作为全身铁的替代物。胰腺R2*将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)将被测量为铁状态的急性标记物。2)我们将确定铁超载是否会加剧镰状血管病变。我们将通过测量血流介导的肱动脉扩张、颈动脉内膜中层增厚和肺动脉高压来量化镰刀状血管病变。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C反应蛋白)、一氧化氮代谢障碍(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)和夜间低氧(夜间脉搏血氧仪)预测血管病变。我们期望在此授权期内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。这项建议是设计后续临床试验以改善血管功能的重要第一步。 公共卫生相关性：我们假设临床上显著的铁超载在镰状细胞病(SCD)受试者中很常见，并加剧镰状血管病变。我们将测量肝脏， 对150名SCD患者进行胰腺和肾脏铁负荷的MRI检查，以确定铁负荷是否独立于溶血、炎症和夜间低氧预测内皮功能障碍、颈动脉内膜中层增厚和肺动脉高压。这项建议是设计后续临床试验以改善SCD患者血管功能的重要第一步。

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.