Experimental intravascular hemolysis induces hemodynamic andpathological pulmonary hypertension: association with accelerated purinemetabolism

摘要

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 angioproliferativePH. We also report the development of a rat model of HA-PH that closely mimicspulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggeststhat in hemolytic diseases released ADA and PNP may increase the risk of PH,likely by abolishing the vasoprotective effects of adenosine, inosine andguanosine. Further characterization of this new rat model of hemolysis-inducedangioproliferative PH and additional studies of the role of purines metabolismin HA-PH are warranted.