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:
    10340518
  • 负责人:
  • 金额:
    $ 71.11万
  • 依托单位:
  • 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

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.
项目摘要/摘要 包括镰状细胞病(SCD)在内的溶血综合征是一种毁灭性的疾病,影响着 美国有10万人。这些患者中的每一个都患有广泛的心肺疾病。 红细胞溶血、高血浆细胞水平引起的并发症和运动耐量 游离血红蛋白(Hb)、内皮细胞功能障碍和组织缺氧。中国的肺血管疾病 肺动脉高压的形式,在这一人群中显著增加,没有足够的 治疗方案。这项拨款申请和项目在此集中在阐明机制上的非。 巨噬细胞活化的松解及其在SCD PH进展中的作用 我们的数据显示,一种独特的巨噬细胞(Mϕ)表型出现在两名已故的成年SCD患者中。 不能识别PH以及SCD PH的啮齿动物模型。这种表型是由细胞内ACU-1来描述的。 模拟Hb,HO-1的表达,以及促有丝分裂、炎症和血管收缩介质 也与低氧(HX)诱导的PH有关。此外,与低氧驱动的PH、SCD患者一样 肺巨噬细胞聚集在重塑的前毛细血管周围的肺外膜区域 肺小动脉表现为丛状病变和小肺小动脉再通道化。这个 啮齿类动物模型与伴有PH的人类SCD的表型相似性表明一种新的适应不良 对伴随的HB和HX暴露的免疫反应。此外,通过剔除循环 MϕS在第5组PH大鼠模型中,联合应用Hb和低压HX的反应显著高于正常对照组。 提示m-ϕS在慢性阻塞性肺疾病的发病机制中起重要作用。我们假设 持续的低氧诱导的红细胞病变是一个关键的过程, M-ϕ清除受损红细胞导致M-ϕ铁积累,M-ϕ铁稳态丧失 进展性SCD-PH。我们进一步假设,铁稳态受损有助于- 微细胞氧化,使局部肺血管微环境处于不稳定状态 铁介导氧化,加速肺外周血管重塑。为了验证这一假设- 我们提出了以下具体目标。 目标1将确定高铁含量的循环单核细胞是如何代谢重新编程的 在不同严重程度的SCD患者中。AIM 2在体内和体外将确定其贡献和 载铁M-ϕ参与SCD的机制;Aim 3将测试反式- 铁蛋白、铁蛋白抑制剂和铁络合剂单独或联合作为治疗干预措施 停止Mϕ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点 慢性阻塞性肺疾病合并肺动脉高压。

项目成果

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Paul Werner Buehler其他文献

Paul Werner Buehler的其他文献

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{{ truncateString('Paul Werner Buehler', 18)}}的其他基金

Bioengineering a novel therapeutic protein complex to minimize the effects of medical device induced hemolysis
生物工程新型治疗性蛋白质复合物可最大程度地减少医疗设备引起的溶血的影响
  • 批准号:
    10542403
  • 财政年份:
    2022
  • 资助金额:
    $ 71.11万
  • 项目类别:
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
  • 财政年份:
    2022
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a novel therapeutic protein complex to minimize the effects of medical device induced hemolysis
生物工程新型治疗性蛋白质复合物可最大程度地减少医疗设备引起的溶血的影响
  • 批准号:
    10380296
  • 财政年份:
    2022
  • 资助金额:
    $ 71.11万
  • 项目类别:
Engineering a novel biomaterial for oxygen transport applications
设计用于氧传输应用的新型生物材料
  • 批准号:
    10545751
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a Dual Function Protein Construct to Detoxify Heme and Hemoglobin
生物工程双功能蛋白质结构以解毒血红素和血红蛋白
  • 批准号:
    10437908
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a Dual Function Protein Construct to Detoxify Heme and Hemoglobin
生物工程双功能蛋白质结构以解毒血红素和血红蛋白
  • 批准号:
    10308814
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Engineering a novel biomaterial for oxygen transport applications
设计用于氧传输应用的新型生物材料
  • 批准号:
    10322431
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a Dual Function Protein Construct to Detoxify Heme and Hemoglobin
生物工程双功能蛋白质结构以解毒血红素和血红蛋白
  • 批准号:
    10663258
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Aerosolized therapy for hemoglobin toxicity in the treatment of hemolytic diseases
溶血性疾病治疗中血红蛋白毒性的雾化治疗
  • 批准号:
    10374485
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Aerosolized therapy for hemoglobin toxicity in the treatment of hemolytic diseases
溶血性疾病治疗中血红蛋白毒性的雾化治疗
  • 批准号:
    10531919
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:

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