35 - Neutrophils in sickle cell disease: the missing candidate – myeloperoxidase

Abstract

Sickle cell disease (SCD) is caused by a single point mutation of the β-globin gene that increases the polymerization of hemoglobin under hypoxia and subsequent sickling of red blood cells (RBCs). Sickled RBCs occlude capillaries, inducing ischemic attacks in the lungs of affected individuals. Increased hemolysis and repeated bouts of ischemia-reperfusion injury lead to chronic states of oxidative stress and inflammation. Previously, we reported that sickle disease increases neutrophil activation and release of myeloperoxidase (MPO), which generates toxic oxidants that impair vascular function in SCD mice. In the present study, we determine if N-acetyl lysyltyrosylcysteine amide (KYC), a tripeptide inhibitor of MPO prevents toxic oxidant production and oxidative damage to sickle RBCs in SCD mice. KYC treatment of SCD mice reduced NO2-Tyr and Cl-Tyr, both markers of MPO-mediated damage, on sickle RBC membranes. Interestingly, the number of sickled RBCs in the lungs in KYC-treated SCD mice were reduced, which correlated with a reduction in the number of occluded blood vessels in the lungs of perfused SCD mice. KYC treatment also reduced MPO deposition, Cl-Tyr formation, and IgG deposition in the interstitium of the lungs of SCD mice. These data indicate KYC reduces oxidative damage to sickle RBCs which decreases sickling, vaso-occlusion, and ischemic injury of the lungs in sickle animals. KYC-dependent reductions in MPO-dependent oxidative damage to the lungs correlated with decreased vascular leakage in the lungs of SCD mice and reductions in SCD-related lung pathology. In conclusion, inhibitors that target MPO, such as KYC, may be an effective strategy for reducing vaso-occlusive events in SCD.