Role of free radicals in the pathogenesis of acute chest syndrome in sickle cell disease

Abstract

Acute chest syndrome (ACS) of sickle cell disease (SCD) is characterized pathologically by vaso-occlusive processes that result from abnormal interactions between sickle red blood cells (RBCs), white blood cells (WBCs) and/or platelets, and the vascular endothelium. One potential mechanism of vascular damage in ACS is by generation of oxygen-related molecules, such as superoxide (O2-), hydrogen peroxide (H2O2), peroxynitrite (ONOO-), and the hydroxyl (*OH) radical. The present review summarizes the evidence for alterations in oxidant stress during ACS of SCD, and the potential contributions of RBCs, WBCs and the vascular endothelium to this process.

Figure 1

Mechanisms of oxidant production in sickle RBCs. Sickle RBCs, through the auto-oxidation of hemoglobin (Hb)S, produce O₂^-, which is metabolized to H₂O₂ by superoxide dismutase (SOD). H₂O₂ is then metabolized to O₂ and H₂O by catalase and GPx. Deficiencies in SOD, catalase, and GPx in sickle RBCs lead to increased O₂^- and H₂O₂ production. GSSG, oxidized glutathione.

Figure 2

Mechanism by which free radicals alter NO bioavailability and endothelial cell biology. Under conditions of increased O₂^- production, NO preferentially forms ONOO^-. Both O₂^- and ONOO^- can alter endothelial cell (EC) gene expression via activation and nuclear translocation of second messengers such as NF-κB.