Regulatory Mechanisms of Airway Infiltration and Activation of Eosinophils by Cysteinyl Leukotriene and Adhesion Molecules

我们研究了半胱氨酸白蛋白（CysLT）是否调节嗜酸性粒细胞的迁移过程和功能。白三烯D4 （Leukotriene D4, LTD4）是一种Cys LT，可直接显著诱导嗜酸性粒细胞的跨内皮迁移、超氧阴离子的产生和特异性颗粒蛋白的释放。此外，这些参数均被白三烯受体拮抗剂（LTRA）或抗β -2整合素抗体阻断，表明cyslt -受体和β -2整合素粘附分子都至关重要。重组粘附分子ICAM-1和VCAM-1显著增强LTD4诱导的嗜酸性粒细胞超氧阴离子的生成。此外，这些粘附分子对ltd4刺激的嗜酸性粒细胞的增强激活被抗β 2-或抗α 4整合素抗体减弱。为了评估CysLT1的表面表达是否可以被嗜酸性粒细胞激活剂(s)修饰，我们用流式细胞术检测其表达。然而，没有一种激活剂能改变CysLT1在嗜酸性粒细胞上的表达。最后，我们研究了LTRA是否直接改变了嗜酸性粒细胞的迁移反应。Pranlukast，一种LTRA，阻断了嗜酸性粒细胞对LTD4的跨内皮迁移。另一方面，普鲁司特在C-C趋化因子或PAR的作用下不调节嗜酸性粒细胞跨内皮迁移，因此，普鲁司特对嗜酸性粒细胞迁移的抑制作用是高度特异性的，仅针对Cys-LT1依赖途径。

We examined as to whether cysteinyl leukotriens (CysLT) regulate the migrative process and functions of eosinophils. Leukotriene D4 (LTD4), a Cys LT, directly and significantly induced the transendothelial migration, superoxide anion generation, and release of specific granule-protein of eosinophils. Furthermore, these parameters were all blocked by leukotriene receptor antagonist (LTRA) or anti-beta2 integrin antibody, indicating that both CysLT-receptor and beta-2 integrin adhesion molecules are critically involved. Eosinophil superoxide anion generation provoked by LTD4 was significantly augmented by recombinant adhesion molecules both ICAM-1 and VCAM-1. Furthermore, the enhanced activation of LTD4-stimulated eosinophils by those adhesion molecules was attenuated by either anti-beta2- or anti-alpha4-integrin antibody. To evaluate whether the surface expression of CysLT1 can be modified by eosinophils activator(s), the expressions were examined using flow cytometry. However, none of activators examined modified the expression of CysLT1 on eosinophils. Finally, we examined whether LTRA directly modify the migrative response of eosinophils. Pranlukast, a LTRA, blocked the eosinophil transendothelial migration in response to LTD4. On the other hand, pranlukast did not modulate eosinophil transendothelial migration in response to C-C chemokines or PAR Therefore, the inhibitory effect of pranlukast on eosinophil transmigration is highly specific for the Cys-LT1 -dependent pathway.