Hu Guochang, Ye Richard D, Dinauer Mary C, Malik Asrar B, Minshall Richard D
Department of Pharmacology, University of Illinois College of Medicine, 835 South Wolcott Ave., Chicago, IL 60612, USA.
Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L178-86. doi: 10.1152/ajplung.00263.2007. Epub 2007 Nov 9.
Caveolin-1 present in immune cells may be involved in regulation of the inflammatory response. Here, using caveolin-1-null (Cav-1(-/-)) mice, we addressed the role of caveolin-1 in polymorphonuclear neutrophils (PMNs) in regulating PMN activation-mediated lung injury. In lungs of wild-type (Cav-1(+/+)) mice perfused at constant flow with Krebs-Henseleit solution, addition of Cav-1(+/+) PMNs (4 x 10(6) cells) into the perfusate followed by their activation with formyl-Met-Leu-Phe (fMLP, 1.0 muM) plus platelet-activating factor (1.0 nM) increased pulmonary microvessel filtration coefficient by 150% and wet-to-dry lung weight ratio by 50% as well as PMN accumulation in lungs. These responses were markedly reduced in lungs perfused with Cav-1(-/-) PMNs followed by addition of the same activating agents. fMLP-stimulated adhesion of Cav-1(-/-) PMNs to pulmonary microvascular endothelial cells and migration of Cav-1(-/-) PMNs across endothelial monolayers were also impaired compared with Cav-1(+/+) PMNs. Cav-1(-/-) PMNs showed 50-80% reduction in PMA- or fMLP-stimulated superoxide production compared with Cav-1(+/+) PMNs. In addition, Cav-1(-/-) PMNs had decreased migratory activity (50%) and adhesion to fibrinogen (40%) in response to fMLP. Rac1 and Rac2 were activated in Cav-1(+/+) PMNs after stimulation of fMLP but not in Cav-1(-/-) PMNs. Exogenous expression of caveolin-1 in COS-phox cells augmented the fMLP-induced Rac1 activation and superoxide production, indicating a direct role of caveolin-1 in the mechanism of superoxide production. Thus caveolin-1 expression in PMNs plays a key role in mediating PMN activation, adhesion, and transendothelial migration and in PMN activation-induced lung inflammation and vascular injury.
免疫细胞中存在的小窝蛋白-1可能参与炎症反应的调节。在此，我们使用小窝蛋白-1基因敲除（Cav-1(-/-)）小鼠，探讨了小窝蛋白-1在多形核中性粒细胞（PMN）中对PMN活化介导的肺损伤调节作用。在以恒定流量用Krebs-Henseleit溶液灌注的野生型（Cav-1(+/+)）小鼠肺中，向灌注液中加入Cav-1(+/+) PMN（4×10⁶个细胞），随后用甲酰甲硫氨酸-亮氨酸-苯丙氨酸（fMLP，1.0 μM）加血小板活化因子（1.0 nM）激活，可使肺微血管滤过系数增加150%，肺湿重与干重之比增加50%，同时肺内PMN积聚增加。在用Cav-1(-/-) PMN灌注并加入相同激活剂后，这些反应明显减弱。与Cav-1(+/+) PMN相比，fMLP刺激的Cav-1(-/-) PMN与肺微血管内皮细胞的黏附以及Cav-1(-/-) PMN跨内皮单层的迁移也受损。与Cav-1(+/+) PMN相比，Cav-1(-/-) PMN在佛波酯（PMA）或fMLP刺激下超氧化物生成减少50 - 80%。此外，Cav-(-/-) PMN对fMLP的迁移活性降低（50%），对纤维蛋白原的黏附减少（40%）。fMLP刺激后，Cav-1(+/+) PMN中的Rac1和Rac2被激活，而Cav-1(-/-) PMN中未被激活。在COS-phox细胞中外源表达小窝蛋白-1可增强fMLP诱导的Rac1激活和超氧化物生成，表明小窝蛋白-1在超氧化物生成机制中起直接作用。因此，PMN中小窝蛋白-1的表达在介导PMN活化、黏附、跨内皮迁移以及PMN活化诱导的肺部炎症和血管损伤中起关键作用。
