Targeting lung heme iron by aerosol hemopexin adminstration in sickle cell disease pulmonary hypertension
Lung tissue from human patients and murine models of sickle cell disease pulmonary hypertension (SCD-PH) show perivascular regions with excessive iron accumulation. The iron accumulation arises from chronic hemolysis and extravasation of hemoglobin (Hb) into the lung adventitial spaces, where it is linked to nitric oxide depletion, oxidative stress, inflammation, and tissue hypoxia, which collectively drive SCD-PH. Here, we tested the hypothesis that intrapulmonary delivery of hemopexin (Hpx) to the deep lung is effective at scavenging heme-iron and attenuating the progression of SCD-PH. Herein, we evaluated in a murine model of hemolysis driven SCD-PH, if intrapulmonary Hpx administration bi-weekly for 10 weeks improves lung iron deposition, exercise tolerance, cardiovascular function, and multi-omic indices associated with SCD-PH. Data shows Hpx delivered with a micro-sprayer deposits Hpx in the alveolar regions. Hpx extravasates into the perivascular compartments but does not diffuse into the circulation. Histological examination shows Hpx therapy decreased lung iron deposition, 4-HNE, and HO-1 expression. This was associated with improved exercise tolerance, cardiopulmonary function, and multi-omic profile of whole lung and RV tissue. Our data provides proof of concept that treating lung heme-iron by direct administration of Hpx to the lung attenuates the progression of PH associated with SCD.
Authors
- Kathryn L. Hassell (ORCID: https://orcid.org/0000-0001-6077-775X)
- Nathan Brinkman (ORCID: https://orcid.org/0000-0003-0815-4592)
- Christina Lisk (ORCID: https://orcid.org/0000-0001-6217-4063)
- Kiruphagaran Thangaraju (ORCID: https://orcid.org/0000-0002-3414-3638)
- Pavel Davizon‐Castillo (ORCID: https://orcid.org/0000-0002-3677-4476)
- Francesca Cendali (ORCID: https://orcid.org/0000-0002-8874-2150)
- Saini Setua (ORCID: https://orcid.org/0000-0002-9874-6948)
- Gemlyn George (ORCID: https://orcid.org/0000-0002-4518-0629)
- Melissa Lucero (ORCID: https://orcid.org/0000-0002-1619-6322)
- David Irwin (ORCID: https://orcid.org/0000-0002-1743-8266)
- Nishant Kumar Rana
- Angelo D’Alessandro (ORCID: https://orcid.org/0000-0002-2258-6490)
- Thomas Gentinetta (ORCID: https://orcid.org/0009-0004-9470-9877)
- Quintin O’Boyle (ORCID: https://orcid.org/0000-0003-1499-9620)
- Andre Francis Palmer (ORCID: https://orcid.org/0000-0002-3378-3772)
- Rachelle Nuss (ORCID: https://orcid.org/0000-0001-8756-1967)
- David I. Pak (ORCID: https://orcid.org/0009-0004-9779-8000)
- Shuwei Lu (ORCID: https://orcid.org/0000-0003-2454-7820)
- Delaney Swindle
- Paul W. Buehler (ORCID: https://orcid.org/0000-0003-0687-3008)
- Seth Zaeske
- Robert Tolson (ORCID: https://orcid.org/0009-0007-1382-1835)
- Saqib Khan
- Natalie Westover
Institutions
- University of Maryland, Baltimore (US)
- Bloodworks Northwest (US)
- University of Colorado Anschutz Medical Campus (US)
- The Ohio State University (US)
- CSL (Switzerland) (CH)
- University of Colorado Denver (US)
Publication Details
- Journal
- Free Radical Biology and Medicine
- Published
- 2025-01-23
- DOI
- https://doi.org/10.1016/j.freeradbiomed.2025.01.045
- Citations
- 2
- Primary Topic
- Hemoglobinopathies and Related Disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.25
Funders
- American Heart Association
- National Heart, Lung, and Blood Institute