# Diverse effects of hemin on the endothelium contribute to pulmonary complications of sickle cell disease

> **NIH NIH R56** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $607,535

## Abstract

Hemolysis, with the release of extracellular free heme and hemin, is thought to play a major role in the deadly
pulmonary complications of sickle cell disease. Acute chest syndrome is the second most common cause of
hospitalization for sickle cell disease patients and the leading cause of death. Pulmonary hypertension
complicates sickle cell disease in up to 10% of patients and is associated with significant morbidity and
mortality. Current therapies, including hydroxyurea and blood transfusions, are mostly supportive and have
been used for decades, while specific therapeutics targeting the pulmonary circulation have been elusive. We
hypothesize that hemin, as a breakdown product of cell-free hemoglobin, has direct effects on the pulmonary
endothelium and that concentration specific effects contribute to both the acute and chronic complications of
sickle cell disease. In this proposal, we will evaluate the specific effects of chronic, low concentration hemin in
the development of pulmonary vascular remodeling and pulmonary hypertension. We propose direct effects on
pulmonary artery endothelial cells through Toll-like receptor 4 lead to endothelial-to-mesenchymal transition.
Endothelial cells undergoing trans-differentiation will have increased proliferative and migratory properties as
well as cytoskeletal rearrangement leading to an invasive, dysfunctional phenotype. In animal models of
chronic hemolysis, this will manifest as pulmonary vascular remodeling with the development and progression
of pulmonary hypertension. Similarly, high concentration hemin will have effects on the pulmonary endothelium
through Toll-like receptor 4, but overwhelming stimulation will lead to activation of necroptosis and
programmed necrosis. This necroptotic cell death will result in endothelial barrier dysfunction and acute lung
injury in cell and animal models as a mechanism for the development of non-cardiogenic pulmonary edema
and acute chest syndrome. The concentration dependent effects of hemin on pulmonary artery endothelial
cells and animal models of hemolysis in our work mimic the spectrum of pulmonary complications in sickle cell
disease patients. Therefore, this mechanistic work will complement a translational approach associating
circulating hemin abundance with pulmonary complications in sickle cell disease patients and utilizing RNA
sequencing technology to identify differentially expressed genes and genomic signatures associated with the
presence of pulmonary hypertension and acute chest syndrome. Our long-term goals are to utilize our
understanding of the mechanisms of endothelial dysfunction in both acute and chronic pulmonary
complications of sickle cell disease and other chronic hemolytic syndrome in order to identify novel molecular
targets, develop innovative therapies, impact health and survivorship of patients through our research and
clinical care.

## Key facts

- **NIH application ID:** 11175772
- **Project number:** 1R56HL167875-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Dustin Fraidenburg
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $607,535
- **Award type:** 1
- **Project period:** 2024-09-17 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11175772

## Citation

> US National Institutes of Health, RePORTER application 11175772, Diverse effects of hemin on the endothelium contribute to pulmonary complications of sickle cell disease (1R56HL167875-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11175772. Licensed CC0.

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