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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：
Paul Werner Buehler
金额：
$ 71.11万
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/10340518
关键词：
Adult Affect Animal Model Applications Grants Attenuated Biology Blood Blood Circulation Blood Vessels Blood capillaries Cardiopulmonary Cells Childhood Coculture Techniques Data Development Endothelial Cells Environment Erythrocytes Erythrophagocytosis Excision Exercise Tolerance Ferritin Fibroblasts Fibrosis Functional disorder Gadolinium Goals Hematological Disease Hemoglobin Hemolysis Homeostasis Human Hypoxia Immune response Impairment In Vitro Inflammatory Interleukin-2 Intervention Investigation Iron Iron Chelating Agents Iron Overload Knock-out Lesion Lipids Liver Lung Macrophage Activation Mediating Mediator of activation protein Metabolic Methodology Modeling Mus Pathologic Patients Pericytes Peripheral Persons Phagocytosis Pharmacology Phenotype Plasma Population Process Proteome Proteomics Pulmonary Hypertension Pulmonary arterial remodeling Pulmonary artery structure Pulmonary vessels Rattus Right Ventricular Dysfunction Risk Rodent Model Role Severities Sickle Cell Sickle Cell Anemia Sorting - Cell Movement Spleen Syndrome Tenuate Testing Therapeutic Intervention Tissues Transferrin Tunica Adventitia United States Vascular Proliferation Vascular remodeling Vasoconstrictor Agents arteriole base cytokine effectiveness testing enhancing factor exercise intolerance heme oxygenase-1 hemodynamics improved in vivo inhibitor insight lung hypoxia macrophage metabolomics metal transporting protein 1 monocyte multiple omics new therapeutic target novel oxidation peripheral blood 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.

项目摘要/摘要