Rouschop Kasper M A, Roelofs Joris J T H, Claessen Nike, da Costa Martins Paula, Zwaginga Jaap-Jan, Pals Steven T, Weening Jan J, Florquin Sandrine
Department of Pathology, Academic Medical Center, P.O. Box 22660, 1100 DD, Amsterdam, The Netherlands.
J Am Soc Nephrol. 2005 Jul;16(7):2034-43. doi: 10.1681/ASN.2005010054. Epub 2005 May 18.
Inflammation contributes to renal ischemia reperfusion (I/R) injury, potentially causing renal dysfunction. The inflammatory infiltrate mainly consists of neutrophils, which are deleterious for the renal tissue. Because CD44 is expressed by neutrophils and is rapidly upregulated by capillary endothelial cells after I/R injury, it was hypothesized that CD44 might play an important role in the development of I/R injury. This study showed that rapid CD44 upregulation on renal capillary endothelial cells mediates neutrophil recruitment to the postischemic tissue. Hence, CD44 deficiency led to decreased influx of neutrophils regardless of comparable levels in chemotactic factors expressed in the kidney. The reduced influx of neutrophils was associated with preserved renal function and morphology. Adoptive transfer experiments of labeled neutrophils revealed that endothelial CD44 rather than neutrophil CD44 mediates neutrophil migration. Activation of neutrophils increased cell-surface expression of hyaluronic acid (HA). Altogether, a novel mechanism in the recruitment of neutrophils that involves interaction of endothelial CD44 and neutrophil HA was found. Either blocking endothelial CD44 or removal of neutrophil HA decreased rolling and adhesion of neutrophils. Administration of anti-CD44 to mice reduced the influx of neutrophils into the postischemic tissue, associated with renal function preservation. Therefore, anti-CD44-based therapies may contribute to prevent or reduce renal I/R injury.
炎症会导致肾缺血再灌注（I/R）损伤，可能引起肾功能障碍。炎症浸润主要由中性粒细胞组成，这些细胞对肾组织有害。由于中性粒细胞表达CD44，且在I/R损伤后毛细血管内皮细胞会迅速上调CD44的表达，因此推测CD44可能在I/R损伤的发生发展中起重要作用。本研究表明，肾毛细血管内皮细胞上CD44的快速上调介导了中性粒细胞向缺血后组织的募集。因此，无论肾脏中趋化因子的表达水平相当，CD44缺乏都会导致中性粒细胞流入减少。中性粒细胞流入减少与肾功能和形态的保留有关。标记中性粒细胞的过继转移实验表明，是内皮细胞的CD44而非中性粒细胞的CD44介导了中性粒细胞的迁移。中性粒细胞的激活增加了透明质酸（HA）的细胞表面表达。总之，发现了一种涉及内皮细胞CD44与中性粒细胞HA相互作用的中性粒细胞募集新机制。阻断内皮细胞CD44或去除中性粒细胞HA均可减少中性粒细胞的滚动和黏附。给小鼠注射抗CD44可减少中性粒细胞流入缺血后组织，同时保留肾功能。因此，基于抗CD44的疗法可能有助于预防或减轻肾I/R损伤。
