Individuals with
sickle-cell disease (SCD) and transgenic sickle mice expressing human betaS
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 i.v.
polynitroxyl albumin (PNA), a
superoxide dismutase and
catalase mimetic. Untreated sickle mice, compared with normal mice, showed increased activation of
nuclear factor-kappaB (
NF-kappaB), an
oxidant-sensitive
transcription factor, in their lungs, livers, and skin.
NF-kappaB activation was increased further in the livers and skin of sickle but not normal mice after
hypoxia-reoxygenation. IV administration of PNA inhibited
NF-kappaB 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-kappaB,
VCAM-1,
ICAM-1, rolling, adhesion, or vasoocclusion. We speculate that
therapies to reduce oxidative stress will inhibit
inflammation and vasoocclusion in SCD.