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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要包括镰状细胞病 (SCD) 在内的溶血综合征是毁灭性的疾病，影响超过美国有 100,000 名患者患有广泛的心肺疾病。红细胞溶血、血浆细胞水平升高引起的并发症和运动不耐受游离血红蛋白 (Hb)、内皮细胞功能障碍和组织缺氧。肺动脉高压的形式在该人群中显着增加，但没有任何适当的措施本拨款申请和此处的项目重点是阐明机制。巨噬细胞激活的基础及其对 SCD PH 进展的贡献。我们的数据显示，在两名已故成年 SCD 患者中都出现了独特的巨噬细胞 (Mphi) 表型诊断 PH 以及 SCD PH 的啮齿动物模型该表型通过细胞内累积来描述。 Hb 的调节、HO-1 的表达以及促有丝分裂、炎症和血管收缩介质也与缺氧 (HX) 诱发的 PH 相关，此外，如缺氧驱动的 PH、SCD 患者。肺巨噬细胞聚集在重塑前毛细血管周围的肺外膜区域肺小动脉显示丛状病变和小肺小动脉的再通化。啮齿动物模型和人类 SCD 与 PH 之间的表型相似性表明一种新的适应不良此外，通过消除循环，对同时发生的 Hb 和 HX 暴露产生免疫反应。在第 5 组 PH 的大鼠模型中，对 Hb 和低压 HX 组合的反应显着处于 - 在大鼠中减弱，表明 mphis 在 SCD PH 的恶化中发挥着关键作用，我们假设。缺氧引起的红细胞镰状化的持续发作是驱动红细胞镰状化的关键过程 Mφ 去除受损红细胞，导致 Mφ 铁积累，Mφ 铁稳态丧失我们进一步发现铁稳态受损会促进- 微量氧化并使局部肺血管微环境暴露于不稳定的环境铁介导的氧化并加速肺周围血管重塑。 esis我们提出以下具体目标。目标 1 将确定高铁含量的循环单核细胞如何进行代谢重编程不同严重程度的 SCD 患者体内和体外的目标 2 将确定贡献和铁负载 Mψ 有助于 SCD 的机制；目标 3 将测试反式的有效性铁蛋白、铁转运蛋白抑制剂和铁螯合剂单独或组合作为治疗干预停止 Mφ 对 SCD PH 的贡献。深入了解这些关系将使我们能够确定新的治疗靶点肺动脉高压伴有 SCD。