KYC

Sickle cell disease (SCD) is characterized by impaired red blood cell (RBC) rheology, including increased hemoglobin S (HbS) polymerization, reduced sickle RBC deformability, and elevated blood viscosity, all features that promote lung vasocongestion and contribute to acute and chronic lung disease. Currently, there is an urgent need for new therapies to improve RBC rheology. Here, we investigate whether N-acetyl-lysyltyrosylcysteine amide (KYC), a redox-modulating end-capped tripeptide, improves RBC rheology by reducing oxidative stress. Steady-state and vaso-occlusive crisis (VOC) were modeled in SS mice using normoxic (NOX) and hypoxia/reoxygenation (H/R) protocols. KYC inhibition of HbS oxidation was assessed in vitro. The effects of KYC on plasma advanced oxidation protein products (AOPP), hematocrit (%Hct), blood viscosity, RBC sickling, lung vasocongestion, and RBC reactive oxygen species (ROS) in the mice were determined ex vivo. In vitro, KYC reduced H₂O₂-mediated HbS oxidation. KYC decreased plasma AOPP levels in NOX and H/R SS mice. Although KYC did not improve %Hct in NOX mice, it reduced blood viscosity and the percentage of sickled RBCs. After H/R injury, KYC partially restored %Hct, increased blood viscosity, reduced RBC sickling, ablated lung vasocongestion, and reduced RBC ROS production in H/R mice. These findings support the hypothesis that RBC-derived ROS causally impair rheology and promote lung vasocongestion in murine SCD. The H/R protocol models lung pathology associated with both VOC and acute chest syndrome (ACS) in SCD. Collectively, these data support a redox-mediated systems pathology model of SCD, where RBC oxidative stress is a critical driver of disease severity.