The paradoxical response to iron in pulmonary hypertension of sickle cell disease

镰状细胞病肺动脉高压对铁的矛盾反应

• 批准号: 10553099
• 负责人: Paul Werner Buehler
• 金额: $ 67.41万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553099
• 关键词: Acceleration; Adult; Affect; Animal Model; Applications Grants; Attenuated; Biology; Blood; Blood Vessels; Blood capillaries; Cardiopulmonary; Cell Communication; Cells; Childhood; Chlorides; Circulation; Coculture Techniques; Data; Development; Diagnosis; Endothelial Cells; Erythrocytes; Erythrophagocytosis; Excision; Exercise Tolerance; Extravasation; Ferritin; Fibroblasts; Fibrosis; Functional disorder; Gadolinium; Goals; Hematological Disease; Hemoglobin; Hemolysis; Homeostasis; Hospitalization; Human; Hypoxia; Immune response; Impairment; In Vitro; Inflammatory; Interleukin-2; Intervention; Investigation; Iron; Iron Chelation; Iron Overload; Knock-out; Lesion; Lipids; Liver; Lung; Macrophage; Macrophage Activation; Mediating; Mediator; Metabolic; Methodology; Modeling; Mus; Pathologic; Patients; Pericytes; Peripheral; Persons; Phagocytosis; Phenotype; Plasma; Population; Process; Proteome; Proteomics; Pulmonary Hypertension; Pulmonary arterial remodeling; Pulmonary artery structure; Pulmonary vessels; Rationalization; Rattus; Right Ventricular Dysfunction; Risk; Rodent Model; Role; Severities; Sickle Cell; Sickle Cell Anemia; Sorting; Spleen; Syndrome; Testing; Therapeutic Intervention; Tissues; Transferrin; Tunica Adventitia; United States; Vascular Proliferation; Vascular remodeling; Vasoconstrictor Agents; arteriole; cytokine; effectiveness testing; enhancing factor; exercise intolerance; heme oxygenase-1; hemodynamics; improved; in vivo; inhibitor; insight; lung hypoxia; metabolomics; metal transporting protein 1; monocyte; multiple omics; new therapeutic target; novel; oxidation; peripheral blood; pharmacologic; primary pulmonary hypertension; pulmonary vascular disorder; pulmonary vascular remodeling; recruit; response; right ventricular failure; sickling; small molecule; success; therapy development

PROJECT SUMMARY/ ABSTRACT Hemolytic syndromes including sickle cell disease (SCD) are devastating illnesses that affect over 100,000 people in the United States. Each of these patients suffers a broad spectrum of cardiopulmonary complications and exercise intolerance caused by red blood cell hemolysis, high plasma levels of cell free hemoglobin (Hb), endothelial cell dysfunction, and tissue hypoxia. Pulmonary vascular disease in the form of pulmonary hypertension, is significantly increased in this population, without any adequate treatment options. This grant application and projects herein focus on elucidating the mechanistic un- derpinnings of macrophage activation and their contribution to the progression of SCD PH. Our data shows a unique macrophage (Mϕ) phenotype occurs in both deceased adult SCD patients di- agnosed with PH as well rodent models of SCD PH. This phenotype is described by intracellular accu- mulation of Hb, expression of HO-1, and mitogenic, inflammatory and vasoconstrictor mediators that are also associated with hypoxia (HX) induced PH. Furthermore, like hypoxia driven PH, SCD patient lung macrophages accumulate in the pulmonary adventitial regions surrounding remodeled pre-capillary pulmonary arterioles that show plexiform lesions and re-canalization of small pulmonary arterioles. The phenotypic similarities between rodent models and human SCD with PH indicate a novel maladaptive immune response to concomitant bouts of Hb and HX exposure. Moreover, by knocking out circulating mϕs in a rat model of group 5 PH, the response to combined Hb and hypobaric HX was significantly at- tenuated in rats, suggesting a critical role for mϕs in the exacerbation of SCD PH. We hypotheses that persistent bouts of hypoxia-induced erythrocyte sickling are a critical process that drives Mϕ removal of damaged RBCs causing accumulation of Mϕ iron, loss of Mϕ iron homeostasis and progressive SCD-PH. We further hypothesize that impaired iron homeostasis facilitates in- tracellular oxidation and exposes the local pulmonary vascular micro-environments to labile iron mediated oxidation and accelerated lung peripheral vascular remodeling. To test this hypoth- esis we propose the following specific aims. Aim 1 will determine how circulating monocytes with a high iron content are metabolically reprogramed in patients with differing severity of SCD. Aim 2 in vivo and in vitro will determine the contribution and mechanism by which iron loaded Mϕ contribute to SCD; and Aim 3 will test the effectiveness of trans- ferrin, ferroportin inhibitor, and iron chelators alone or in combination as a therapeutic intervention to halt Mϕ contributions to SCD PH. An in-depth understanding of these relationships will allow us to identify new therapeutic targets to pulmonary hypertension concomitant with SCD.

项目摘要/摘要 包括镰状细胞病（SCD）在内的溶血综合症是影响灾难 美国有100,000人。这些患者中的每一个都患有广泛的心肺 由红细胞溶血引起的并发症和运动摄入率，细胞的高血浆水平 游离血红蛋白（HB），内皮细胞功能障碍和组织缺氧。肺血管疾病 该人群中肺动脉高压的形式显着增加，没有任何适当的 治疗选择。此赠款应用程序和此处的项目着重于阐明机械性的 巨噬细胞激活的derpinning及其对SCD pH进展的贡献。 我们的数据显示，在两名已故的成年SCD患者中都发生了独特的巨噬细胞（Mϕ）表型。 与pH和SCD pH的啮齿动物模型相关。这种表型由细胞内概念描述 Hb的序列，HO-1的表达以及有丝分裂，炎症和血管收缩介质的序列 还与缺氧（HX）诱导的pH相关。此外，像缺氧驱动的PH一样，SCD患者 肺巨噬细胞积聚在重塑前毛细管周围的肺冒险区域 肺部的肺动脉菌显示出丛状病变并重新分配小肺动脉菌。这 啮齿动物模型与人类SCD之间的表型相似性，pH表示新型不良适应性 对HB和HX暴露的伴随反应的免疫反应。而且，通过淘汰流通 在5组pH的大鼠模型中，对HB组合和低母级HX的响应显着 在大鼠中占据，这表明M ϕ在SCD pH的加剧中起关键作用。我们假设 缺氧引起的红细胞疾病的持续爆发是一个关键过程，可以驱动 M ϕ去除受损的RBC，导致Mϕ铁的加速，Mϕ铁稳态的丧失 和渐进式SCD-PH。我们进一步假设铁稳态设施受损 细胞氧化并将局部肺血管微环境暴露至不稳定 铁介导的氧化和加速的肺周围血管重塑。测试这个假设 ESIS我们提出以下特定目标。 AIM 1将确定如何对具有高铁含量的循环单核细胞代谢重新编程 SCD严重程度分化的患者。 AIM 2体内和体外将确定贡献和 铁负载的Mϕ有助于SCD的机制； AIM 3将测试转移的有效性 铁蛋白，铁托蛋白抑制剂和铁螯合剂单独或合并为治疗干预措施 对SCD pH的贡献。 对这些关系的深入了解将使我们能够确定新的治疗靶标 SCD伴有肺动脉高压。