Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice
Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice
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DOI：
10.1172/jci9225
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发表时间：
2000-08-01
影响因子：
15.9
通讯作者：
Hebbel, RP
中科院分区：
文献类型：
--
作者：
Kaul, DK;Hebbel, RP
在镰状细胞性贫血中，血管闭塞发作的开始、进展和缓解可能呈现缺血再灌注损伤的特征，反复发作的缺血/缺氧和复氧促进炎症。在这里，我们测试了低氧/复氧在转基因镰刀鼠中触发炎症的假设。在这些小鼠中，即使在环境空气中，外周血白细胞计数也增加了1.7倍，中性粒细胞计数增加了近3倍。低氧2小时，复氧后，这些小鼠的白细胞滚动通量和粘附率高于正常，但没有白细胞外溢。当低氧3小时，复氧后，镰刀鼠表现出明显的炎症反应，其特征是粘附性和迁移性白细胞数量增加。因为这些事件在镰刀鼠身上被夸大了，并不只是对缺氧的反应，所以我们得出结论，它们代表了一种再灌注损伤的形式。使用过氧化氢敏感探针的研究显示，镰刀鼠在缺氧/复氧后血管内皮细胞产生氧化剂的明显证据。输注抗P-选择素抗体，但不输注抗E-选择素抗体，可完全抑制这种炎症反应，并显著增加壁剪切率。这些发现表明，白细胞-内皮细胞的相互作用有助于镰刀鼠血管闭塞事件的发生，可能在人类镰刀病中也是如此。
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 H2O2-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.