Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration
Junctional adhesion molecule-A deficiency increases hepatic ischemia-reperfusion injury despite reduction of neutrophil transendothelial migration
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DOI：
10.1182/blood-2004-11-4416
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发表时间：
2005-07-15
期刊：
影响因子：
20.3
通讯作者：
Krombach, F
中科院分区：
文献类型：
--
作者：
Khandoga, A;Kessler, JS;Krombach, F
尚未确定控制缺血后肝脏中白细胞迁移的内皮受体。我们研究了连接粘附分子-A (JAM-A)（一种在内皮紧密连接、白细胞和血小板中表达的受体）在体内肝缺血再灌注 (I/R) 期间白细胞迁移中的作用。我们发现再灌注期间肝小静脉内皮细胞中 JAM-A 上调。在 JAM-A(-/-) 和内皮 JAM-A(-/-) 小鼠以及用抗 JAM-A 抗体处理的小鼠中，I/R 诱导的中性粒细胞迁移均减弱，而 T 细胞的迁移与 JAM-A 无关。 JAM-A(-/-) 和内皮 JAM-A(-/-) 小鼠缺血后白细胞滚动不受影响，而血管内白细胞粘附增加。 JAM-A-/-血小板与缺血后内皮细胞的相互作用程度与JAM-A(+/+)血小板相当。 JAM-A-/-小鼠中I/R诱导的丙氨酸转氨酶（ALT）/天冬氨酸转氨酶（AST）活性增加和肝窦灌注衰竭并未减少，而末端脱氧核苷酸转移酶介导的脱氧尿苷三磷酸缺口末端标记（TUNEL）阳性肝细胞的数量显着增加。因此，我们首次证明 JAM-A 在肝小静脉中上调，并作为中性粒细胞迁移的内皮受体，但它不介导白细胞滚动、粘附或血小板-内皮细胞相互作用。 JAM-A 缺乏不会减少缺血再灌注引起的微血管和肝细胞坏死损伤，但会增加肝细胞凋亡，尽管中性粒细胞浸润减弱。
The endothelial receptors that control leukocyte transmigration in the postischemic liver are not identified. We investigated the role of junctional adhesion molecule-A (JAM-A), a receptor expressed in endothelial tight junctions, leukocytes, and platelets, for leukocyte transmigration during hepatic ischemia-reperfusion (I/R) in vivo. We show that JAM-A is up-regulated in hepatic venular endothelium during reperfusion. I/R-induced neutrophil transmigration was attenuated in both JAM-A(-/-) and endothelial JAM-A(-/-) mice as well as in mice treated with an anti-JAM-A antibody, whereas transmigration of T cells was JAM-A independent. Postischemic leukocyte rolling remained unaffected in JAM-A(-/-) and endothelial JAM-A(-/-) mice, whereas intravascular leukocyte adherence was increased. The extent of interactions of JAM-A-/- platelets with the postischemic endothelium was comparable with that of JAM-A(+/+) platelets. The I/R-induced increase in the activity of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and sinusoidal perfusion failure was not reduced in JAM-A-/- mice, while the number of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive hepatocytes was significantly higher. Thus, we show for the first time that JAM-A is up-regulated in hepatic venules and serves as an endothelial receptor of neutrophil transmigration, but it does not mediate leukocyte rolling, adhesion, or platelet-endothelial cell interactions. JAM-A deficiency does not reduce I/R-induced microvascular and hepatocellular necrotic injury, but increases hepatocyte apoptosis, despite attenuation of neutrophil infiltration.