{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T05:03:23Z","timestamp":1789535003637,"version":"build-2803163510"},"reference-count":64,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH","award":["PO1HL152161"],"award-info":[{"award-number":["PO1HL152161"]}]},{"name":"NIH","award":["R01 HL159862"],"award-info":[{"award-number":["R01 HL159862"]}]},{"name":"NIH","award":["R01HL158076"],"award-info":[{"award-number":["R01HL158076"]}]},{"name":"NIH","award":["R01 HL162120-01"],"award-info":[{"award-number":["R01 HL162120-01"]}]},{"name":"NIH","award":["R01 HL161004"],"award-info":[{"award-number":["R01 HL161004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>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\u2014more representative of steady-state hemolysis\u2014has 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\u201320 \u00b5M 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\u2013Hp 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.<\/jats:p>","DOI":"10.3390\/ijms27188170","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:09:51Z","timestamp":1789387791000},"page":"8170","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Extracellular Hemoglobin, Hypoxia, and Macrophage-Mediated Pulmonary Vascular Remodeling in Hemolytic Disease"],"prefix":"10.3390","volume":"27","author":[{"given":"Melissa J.","family":"Lucero","sequence":"first","affiliation":[{"name":"Translational Research Laboratory of Red Blood Cell Diseases and Hypoxia Related Illnesses, Division of Cardiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Cardiovascular Pulmonary Research Group, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7229-5528","authenticated-orcid":false,"given":"Eva","family":"Nozik","sequence":"additional","affiliation":[{"name":"Cardiovascular Pulmonary Research Group, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Pediatric Critical Care Medicine, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1779-6386","authenticated-orcid":false,"given":"Kathryn","family":"Hassell","sequence":"additional","affiliation":[{"name":"Division of Hematology Colorado Sickle Cell Treatment and Research Center, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1743-8266","authenticated-orcid":false,"given":"David C.","family":"Irwin","sequence":"additional","affiliation":[{"name":"Translational Research Laboratory of Red Blood Cell Diseases and Hypoxia Related Illnesses, Division of Cardiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"},{"name":"Cardiovascular Pulmonary Research Group, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0687-3008","authenticated-orcid":false,"given":"Paul W.","family":"Buehler","sequence":"additional","affiliation":[{"name":"Center for Blood Oxygen Transport and Hemostasis, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4446-6131","authenticated-orcid":false,"given":"Scott K.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Integrative Aerospace and Exercise Physiology Laboratory, Embry-Riddle Aeronautical University, Daytona Beach, FL 32114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1172\/JCI89741","article-title":"Intravascular hemolysis and the pathophysiology of sickle cell disease","volume":"127","author":"Kato","year":"2017","journal-title":"J. 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