(21) Red Blood Cell Rheology and Lung Vasocongestion Sustain a Vicious Cycle in Sickle Cell Disease

Background: Sickle cell disease (SCD) is characterized by recurrent vaso-occlusion and organ damage driven by complex, interdependent pathophysiological mechanisms. A longstanding model proposes a self-amplifying vicious cycle in which sickled red blood cells (RBCs), oxidative stress, and microvascular dysfunction reinforce one another to perpetuate tissue injury. Currently, there is an urgent need for new therapies to improve RBC rheology.

Objectives: Here, we investigate whether N-acetyl-lysyltyrosylcysteine amide (KYC), a redox-modulating end-capped tripeptide, improves red blood cell (RBC) rheology by reducing oxidative stress.

Design/Methods: 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.

Results: Treatment with the redox-modulating agent KYC improved RBC deformability, reduced oxidative burden, and normalized blood viscosity in both normoxic and H/R conditions. KYC also significantly decreased sickle cell counts and plasma markers of oxidative protein damage. Histologic analyses showed that KYC attenuated RBC trapping and congestion in the pulmonary microvasculature following H/R exposure.

Conclusions: These findings highlight the mechanistic link between erythrocyte dysfunction and pulmonary vascular pathology and support a systems-level understanding of SCD as a vicious cycle. Interventions targeting the rheologic and redox properties of RBCs may offer a novel therapeutic strategy for disrupting this cycle and mitigating end-organ damage.