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

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2022 · $711,122

## Abstract

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.

## Key facts

- **NIH application ID:** 10340518
- **Project number:** 1R01HL161004-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Paul Werner Buehler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $711,122
- **Award type:** 1
- **Project period:** 2022-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10340518

## Citation

> US National Institutes of Health, RePORTER application 10340518, The paradoxical response to iron in pulmonary hypertension of sickle cell disease (1R01HL161004-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10340518. Licensed CC0.

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