Melissa Lucero, Christina Lisk, Francesca Cendali, Delaney Swindle, Saini Setua, Kiruphagaran Thangaraju, David I. Pak, Quinton O’Boyle, Shuwei Lu, Robert Tolson, Seth Zaeske, Nishant Rana, Saqib Khan, Natalie Westover, Pavel Davizon Castillo, Gemlyn George, Kathryn Hassel, Rachelle Nuss, Nathan Brinkman, Thomas Gentinetta, Andre F. Palmer, Angelo D’Alessandro, Paul W. Buelher, David C. Irwin
University of Colorado, Anschutz Medical Campus School of Medicine. University of Maryland School of Medicine. Ohio State University. University of Washington and Seattle Children’s Hospital. CSL Behring LLC.
United States and Switzerland
Free Radical Biology and Medicine
Free Rad Biol Med 2025;
DOI: 10.1016/j.freeradbiomed.2025.01.045
Abstract
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.
Category
Class V. Pulmonary Hypertension Associated with Hematological, Systemic, Metabolic and Other Disorders
Medical Therapy. Efficacy or Lack of Efficacy
Medical Therapy. Adverse Effects or Lack of Adverse Effects
Medical Therapy. Pharmacokinetics and Pharmacology
Age Focus: Pediatric Pulmonary Vascular Disease or Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes