Imatinib Protects Against Hypoxia/Reoxygenation Induced Lung and Kidney Injury in a Humanized Mouse Model for SCD

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder characterized by chronic hemolytic anemia in association with acute and chronic life-threatening complications mainly related to acute vaso-occlusive events (VOCs) due to amplified inflammatory response and defective pro-resolving events.Imatinib is an oral Tyrosine (Tyr)-kinase inhibitor, developed for the treatment of chronic myeloid leukemia (CML). Few case reports on SCD patients with CML undergoing imatinib treatment highlight the beneficial impact of imatinib on severity and recurrence of acute VOCs in SCD. In red blood cells (RBCs), Imatinib has been shown to interfere with Tyr-phosphorylation state of the integral membrane protein band 3, affecting RBC microparticle formation. Here, we study the actions of Imatinib on a model of acute VOCs using humanized SCD mice (Hbatm1(HBA)TowHbbtm2(HBG1,HBB*)Tow). We treated SCD and control healthy mice (AA, Hbatm1(HBA)Tow Hbbtm3(HBG1,HBB)Tow) (n=6-7 animals in each group) with Imatinib 50 mg/Kg/d for 2 weeks before hypoxia/Reoxygenation (H/R) stress used to mimic acute VOCs. Under normoxia, we found that in SCD mice Imatinib significantly reduced (i) Tyr-phosphorylation state of sickle red cell membrane proteins; (ii) the amount of phosphatidyl-serine (PS)+ sickle RBCs; and (iii) the release of erythroid microparticles, which was associated with accumulation of hemichromes and a more efficient erythrophagocytosis compared to vehicle treated animals....
Source: Blood - Category: Hematology Authors: Tags: 113. Hemoglobinopathies, Excluding Thalassemia-Basic and Translational Science: Sickle Cell Disease-Genomic, Gene Regulation, and Pain Mechanisms Source Type: research