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 vas oocclusive episode may present Features of ischemia-reperfusion injury, wit h recurrent episodes of ischemia/hypoxia and reoxygenation promoting inflam mation. Here, we have tested the hypothesis that hypoxia/reoxygenation trig gers inflammation in the transgenic sickle mouse. In these mice, even at am bient air, peripheral leukocyte counts are elevated by 1.7-fold and neutrop hil counts by almost 3-fold. Two hours of hypoxia, followed by reoxygenatio n, induced a greater than normal rolling flux and adhesion of leukocytes in these mice, but no leukocyte extravasation, When 3 hours of hypoxia was fo llowed by reoxygenation, sickle mice, but not normal mice, showed a distinc t inflammatory response characterized by an increased number of adherent an d emigrated leukocytes. Because these events, which are exaggerated in sick le mice, are not seen in response to hypoxia alone, we conclude that they r epresent a Form of reperfusion injury. Studies using an H2O2-sensitive prob e revealed clear evidence of oxidant production in vascular endothelial cel ls after hypoxia/reoxygenation in sickle mice. Infusion of an anti-P-select in 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 vasoo cclusive events in the sickle mice and perhaps in human sickle disease.