Polynitroxyl albumin inhibits inflammation and vasoocclusion in transgenic sickle mice.
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.
Mahaseth
Hemchandra
H
Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis 554455, USA.
Vercellotti
Gregory M
GM
Welch
Thomas E
TE
Bowlin
Paul R
PR
Sonbol
Khalid M
KM
Hsia
Carleton J C
CJ
Li
Ma
M
Bischof
John C
JC
Hebbel
Robert P
RP
Belcher
John D
JD
D000418:Albumins / Q000494:pharmacology*; D000755:Anemia, Sickle Cell / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D005260:Female; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation / Q000187:drug effects; D009589:Nitrogen Oxides / Q000494:pharmacology*; D018384:Oxidative Stress; D014652:Vascular Diseases / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology
D000418:Albumins; D000975:Antioxidants; D009589:Nitrogen Oxides; C117059:polynitroxyl-albumin