Melissa J. Lucero, Eva Nozik, Kathryn Hassell, David C. Irwin, Paul W. Buehler, Scott K. Ferguson
University of Colorado Anschutz Medical Campus. University of Maryland. Embry-Riddle Aeronautical University.
United States
International Journal of Molecular Science
Int J Mol Sci 2026; 27:
DOI: 10.3390/ijms27188170
Abstract
Pulmonary hypertension (PH) is a well-recognized complication of chronic hemolytic anemias such as sickle cell disease and thalassemia, yet the relative contributions of hypoxia and cell-free hemoglobin (Hb) to disease progression remain incompletely understood. Patients with hemolytic anemia experience a lifelong cycle of chronic and inter bitten hypoxia that compounds vascular injury driven by extracellular Hb and its degradation products, heme and iron. While the effects of hypoxia and Hb exposure have historically been studied in isolation, the combined impact of sustained, low-level plasma Hb together with chronic hypoxia-more representative of steady-state hemolysis-has been largely overlooked. A rat model incorporating chronic hypoxia with continuous low-dose Hb infusion via an implanted pump demonstrates that even modest plasma Hb concentrations (10-20 µM heme) exert an additive effect on hypoxia-induced PH. This effect is associated with increased adventitial macrophage accumulation, oxidative stress, and inflammation, driving more severe pulmonary vascular remodeling. Building on this model, therapeutic strategies targeting Hb-mediated vascular injury are evaluated, with particular focus on repeated-dose haptoglobin (Hp) therapy, given that Hp is often severely depleted in sickle cell disease. Restoring circulating Hp sequesters plasma Hb into a non-reactive, compartmentalized Hb-Hp complex, limiting NO scavenging and oxidative damage. These mechanistic findings are further linked to functional outcomes through studies of skeletal muscle microvascular oxygen tension and exercise capacity in Berkeley sickle cell disease mice. This review synthesizes findings across these studies to clarify the interplay between hypoxia, macrophage biology, and extracellular Hb in driving pulmonary vascular remodeling and to highlight emerging Hb-targeted therapeutic strategies for hemolysis-associated PH.
Category
Class V. Pulmonary Hypertension Associated with Hematological, Systemic, Metabolic, Nutritional and Other Disorders
Class III. Pulmonary Hypertension Associated with Alveolar Hypoxia
Review Articles Concerning Pulmonary Vascular Disease
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