Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice.
In sickle cell anemia, the initiation, progression, and resolution of a vasoocclusive episode may present features of ischemia-reperfusion injury, with recurrent episodes of ischemia/hypoxia and reoxygenation promoting inflammation. Here, we have tested the hypothesis that hypoxia/reoxygenation triggers inflammation in the transgenic sickle mouse. In these mice, even at ambient air, peripheral leukocyte counts are elevated by 1.7-fold and neutrophil counts by almost 3-fold. Two hours of hypoxia, followed by reoxygenation, induced a greater than normal rolling flux and adhesion of leukocytes in these mice, but no leukocyte extravasation. When 3 hours of hypoxia was followed by reoxygenation, sickle mice, but not normal mice, showed a distinct inflammatory response characterized by an increased number of adherent and emigrated leukocytes. Because these events, which are exaggerated in sickle mice, are not seen in response to hypoxia alone, we conclude that they represent a form of reperfusion injury. Studies using an H(2)O(2)-sensitive probe revealed clear evidence of oxidant production in vascular endothelial cells after hypoxia/reoxygenation in sickle mice. Infusion of an anti-P-selectin antibody, but not an anti-E-selectin antibody, completely inhibited this inflammatory response and significantly increased wall shear rates. These findings suggest that leukocyte-endothelium interaction contribute to vasoocclusive events in the sickle mice and perhaps in human sickle disease.
Kaul
D K
DK
Albert Einstein College of Medicine, Bronx, New York 10461, USA. kaul@aecom.yu.edu
Hebbel
R P
RP
D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000503:physiopathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002448:Cell Adhesion; D002465:Cell Movement; D004195:Disease Models, Animal; D019040:E-Selectin / Q000276:immunology / Q000502:physiology; D006439:Hemodynamics; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000209:etiology* / Q000503:physiopathology; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009504:Neutrophils; D016877:Oxidants / Q000378:metabolism; D019007:P-Selectin / Q000276:immunology / Q000502:physiology; D015427:Reperfusion Injury / Q000097:blood / Q000150:complications* / Q000503:physiopathology
D000911:Antibodies, Monoclonal; D019040:E-Selectin; D016877:Oxidants; D019007:P-Selectin