Faculty Collaboration Database

Breaking the vicious cycle in sickle cell disease: Redox stress impairs red blood cell rheology and promotes lung vasocongestion. Free Radic Biol Med 2025 Oct;238:563-568

Date

07/12/2025

Pubmed ID

40645460

DOI

10.1016/j.freeradbiomed.2025.07.012

Scopus ID

2-s2.0-105010259048 (requires institutional sign-in at Scopus site)   1 Citation

Abstract

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.

Author List

Pant T, Li K, Jones DW, Day BW, Naylor S, Gupta K, Pritchard KA Jr

Authors

Tarun Pant Postdoctoral Researcher 4 in the Surgery department at Medical College of Wisconsin
Kirkwood A. Pritchard PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Anemia, Sickle Cell
Animals
Blood Viscosity
Disease Models, Animal
Erythrocyte Deformability
Erythrocytes
Hemoglobin, Sickle
Humans
Lung
Male
Mice
Oxidation-Reduction
Oxidative Stress
Reactive Oxygen Species