title: Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration.
abstract: Haptoglobin (Hp) is an approved treatment in Japan for trauma, burns, and massive transfusion-related hemolysis. Additional case reports suggest uses in other acute hemolytic events that lead to acute kidney injury. However, Hp's protective effects on the pulmonary vasculature have not been evaluated within the context of mitigating the consequences of chronic hemoglobin (Hb) exposure in the progression of pulmonary hypertension (PH) secondary to hemolytic diseases. This study was performed to assess the utility of chronic Hp therapy in a preclinical model of Hb and hypoxia-mediated PH. Rats were simultaneously exposed to chronic Hb infusion (35 mg per day) and hypobaric hypoxia for 5 weeks in the presence or absence of Hp treatment (90 mg/kg twice a week). Hp inhibited the Hb plus hypoxia-mediated nonheme iron accumulation in lung and heart tissue, pulmonary vascular inflammation and resistance, and right-ventricular hypertrophy, which suggests a positive impact on impeding the progression of PH. In addition, Hp therapy was associated with a reduction in critical mediators of PH, including lung adventitial macrophage population and endothelial ICAM-1 expression. By preventing Hb-mediated pathology, Hp infusions: (1) demonstrate a critical role for Hb in vascular remodeling associated with hypoxia and (2) suggest a novel therapy for chronic hemolysis-associated PH.
authors: Cardiovascular Pulmonary Research Group, Division of Cardiology, School of Medicine, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: David C
authors: DC
authors: Irwin
authors: Laboratory of Biochemistry and Vascular Biology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland.
authors: Jin Hyen
authors: JH
authors: Baek
authors: Colorado Sickle Cell Treatment and Research Center, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: Kathryn
authors: K
authors: Hassell
authors: Colorado Sickle Cell Treatment and Research Center, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: Rachelle
authors: R
authors: Nuss
authors: Cardiovascular Pulmonary Research Group, Division of Cardiology, School of Medicine, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: Paul
authors: P
authors: Eigenberger
authors: Cardiovascular Pulmonary Research Group, Division of Cardiology, School of Medicine, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: Christina
authors: C
authors: Lisk
authors: Colorado Sickle Cell Treatment and Research Center, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: Zoe
authors: Z
authors: Loomis
authors: Cardiovascular Pulmonary Research Group, Division of Cardiology, School of Medicine, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: Joanne
authors: J
authors: Maltzahn
authors: Cardiovascular Pulmonary Research Group, Pediatrics, School of Medicine, University of Colorado Denver | Anschutz Medical Campus, Aurora Colorado.
authors: Kurt R
authors: KR
authors: Stenmark
authors: Cardiovascular Pulmonary Research Group, Pediatrics, School of Medicine, University of Colorado Denver | Anschutz Medical Campus, Aurora Colorado.
authors: Eva
authors: E
authors: Nozik-Grayck
authors: Laboratory of Biochemistry and Vascular Biology, Office of Blood Research and Review, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, Maryland.|Cardiovascular Pulmonary Research Group, Division of Cardiology, School of Medicine, University of Colorado Denver | Anschutz Medical Campus, Aurora, Colorado.
authors: Paul W
authors: PW
authors: Buehler
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D006242:Haptoglobins / Q000494:pharmacology*; D006454:Hemoglobins / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000473:pathology; D000860:Hypoxia; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007501:Iron / Q000378:metabolism; D008168:Lung / Q000098:blood supply*; D008171:Lung Diseases / Q000473:pathology; D016676:Macrophages, Alveolar / Q000473:pathology; D008297:Male; D010084:Oxidation-Reduction; D011014:Pneumonia / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014652:Vascular Diseases / Q000473:pathology; D066253:Vascular Remodeling / Q000187:drug effects; D014655:Vascular Resistance / Q000502:physiology
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D018799:Intercellular Adhesion Molecule-1; D007501:Iron
keywords: Free radicals; Heme; Hemoglobin; Hemolysis; Iron; Lipid peroxidation; Sickle cell disease; Thalassemia
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