Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism

• Type of Material: Article
• Authors: Victor P. Bilan, University of Pittsburgh; Frank Schneider, Emory University; Enrico M. Novelli, University of Pittsburgh; Eric E. Kelley, West Virginia University; Sruti Shiva, University of Pittsburgh; Mark T. Gladwin, University of Pittsburgh; Edwin K. Jackson, University of Pittsburgh; Stevan P. Tofovic, University of Pittsburgh
• Language: English
• Date: 2018-08-06
• Publisher: University of Chicago Press: No Paid Open Access
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2018
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1177/2045894018791557
• Title of Journal or Parent Work: Pulmonary Circulation
• ISSN: 2045-8932
• Volume: 8
• Issue: 3
• Start Page: 2045894018791557
• End Page: 2045894018791557
• Grant/Funding Information: This work was supported in part by a P3HVBG grant from Vascular Medicine Institute, Hemophilia Center of Western Pennsylvania, and the Institute of Transfusion Medicine, Pittsburgh (SPT), and grants HL069846, HL109002, and DK079307 (EKJ).
• Keywords: ADENOSINE-DEAMINASE; Life Sciences & Biomedicine; PLATELET ACTIVATION; Cardiovascular System & Cardiology; REPERFUSION INJURY; hemolysis; PROTECTIVE MECHANISMS; Respiratory System; Cardiac & Cardiovascular Systems; purine nucleoside phosphorylase; Science & Technology; ENDOTHELIAL-CELL; sickle cell disease; RIGHT HEART CATHETERIZATION; ARTERIAL-HYPERTENSION; SICKLE-CELL-DISEASE; purines; adenosine deaminase; NUCLEOSIDE PHOSPHORYLASE; pulmonary hypertension; OXIDATIVE STRESS
• Research Categories: Health Sciences, Pathology; Health Sciences, Pharmacology

Abstract

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200 mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 ± 1.1, 41.5 ± 0.5 and 85.1 ± 5.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted.