Polynitroxyl albumin inhibits inflammation and vasoocclusion in transgenic sickle mice

Individuals with sickle-cell disease (SCD) and transgenic sickle mice expressing human β^S globin exhibit enhanced reactive oxygen species (ROS) production, vascular inflammation, and episodic vasoocclusion. We hypothesize that reduction of ROS will reduce endothelial-cell activation and adhesion-molecule expression, thereby inhibiting vasoocclusion. To test this hypothesis, we measured endothelial-cell activation, adhesion-molecule expression, and vasoocclusion in sickle mice after administering IV polynitroxyl albumin (PNA), a superoxide dismutase and catalase mimetic. Untreated sickle mice, compared with normal mice, showed increased activation of nuclear factor-κB (NF-κB), an oxidant-sensitive transcription factor, in their lungs, livers, and skin. NF-κB activation was increased further in the livers and skin of sickle but not normal mice after hypoxia-reoxygenation. IV administration of PNA inhibited NF-κB activation by 60% (P <. 01) in the lungs and by 33% (P <. 05) in the livers of sickle mice after hypoxia-reoxygenation. PNA also reduced the expression of vascular cell-adhesion molecule-1 (VCAM-1) by 57% in lung (P <. 05) and by 33% in liver (P <. 05) and reduced the expression of intercellular-adhesion molecule-1 (ICAM-1) by 40% in lung (P <. 05) and by 53% in liver (P <. 05). PNA inhibited a hypoxia-reoxygenation-induced increase in leukocyte rolling (P <. 01) and adhesion (P <. 05) in venules of the dorsal skin. Most importantly, PNA completely inhibited hypoxia-reoxygenation-induced vasoocclusion (P <. 001). Control albumin had no effect on NF-κB, VCAM-1, ICAM-1, rolling, adhesion, or vasoocclusion. We speculate that therapies to reduce oxidative stress will inhibit inflammation and vasoocclusion in SCD.