Therapeutic strategy for refractory Kawasaki disease in aspect of VEGF-VEGF receptor

p38丝裂原活化蛋白激酶（MAPK）信号通路在炎症性疾病的发病机制中起重要作用。p38 MAPK可被促炎细胞因子和血管内皮生长因子激活。然而，p38 MAPK在急性川崎（KD）中的作用尚不清楚，在KD中这些炎症介质升高。p38 MAPK在KD急性炎症期患者外周血单个核细胞中被强烈激活，在KD恢复期下调。此外，孵育人脐静脉内皮细胞（HUVEC）与KD血清之前，高剂量静脉注射免疫球蛋白（IVIG）诱导p38 MAPK磷酸化的快速增加。当HUVEC用来自对初始IVIG无反应且后来发生冠状动脉瘤（IVIG失败）的患者的IVIG后血清处理时，p38 MAPK的这种激活进一步增强，但当用来自对初始IVIG有反应且冠状动脉正常（IVIG反应者）的患者的IVIG后血清处理时，p38 MAPK的这种激活下调。与IVIG应答者或发热对照血清相比，IVIG失败血清不仅诱导HUVEC通透性增加，而且诱导HUVEC管形成活性降低。p38 MAPK抑制剂阻断IVIG失效血清诱导的血管通透性。同样的抑制剂恢复了IVIG失败血清诱导的HUVEC的管形成活性，这一发现伴随着Erk 1/2 MAPK活化的增强。结果表明，难治性KD患者血清诱导的体外内皮细胞功能障碍受p38 MAPK调节。

The p38 mitogen-activated protein kinase (MAPK) signaling pathway plays an important role in the pathogenesis of inflammatory diseases. p38 MAPK can be activated by proinflammatory cytokines and vascular endothelial growth factor. However, nothing is known about the role of p38 MAPK in acute Kawasaki disease (KD) where these inflammatory mediators are elevated. p38 MAPK was strongly activated in peripheral blood mononuclear cells from patients during acute KD inflammation and down-regulated in the convalescent phase of KD. Additionally, incubation of human umbilical vein endothelial cells (HUVEC) with KD sera before high-dose intravenous immune globulin (IVIG) induced a rapid increase in p38 MAPK phosphorylation. This activation of p38 MAPK was further enhanced when HUVEC were treated with post-IVIG sera from patients who failed to respond to initial IVIG and later developed coronary aneurysms (IVIG failure), but was down-regulated when treated with post-IVIG sera from patients who responded to initial IVIG and had normal coronaries (IVIG responder). Compared with sera from IVIG responders or febrile control, sera from IVIG failure induced not only the increase in HUVEC permeability but also the decrease in the tube forming activity of HUVEC. The p38 MAPK inhibitor blocked IVIG failure sera-induced vascular permeability. The same inhibitor restored the tube forming activity of HUVEC induced by sera from IVIG failure, a finding that was accompanied by enhancement of Erk1/2 MAPK activation. The findings suggest that in vitro endothelial cell dysfunction induced by serum from patients with refractory KD is modulated by p38 MAPK.