Kamegashira Akiko, Yanase Yuhki, Takahagi Shunsuke, Saito Ryo, Uchida Kazue, Kawaguchi Tomoko, Ishii Kaori, Tanaka Akio, Ozawa Koichiro, Hide Michihiro
Departments of, Department of, Dermatology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Department of, Pharmacotherapy, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
J Dermatol. 2020 Nov;47(11):1293-1300. doi: 10.1111/1346-8138.15516. Epub 2020 Aug 4.
The pathogenesis of chronic spontaneous urticaria (CSU), also called chronic idiopathic urticaria, has been considered to be associated with the activation of the extrinsic blood coagulation cascade. However, the trigger for the extrinsic coagulation cascade in patients with CSU remains unclear. We previously reported that histamine and lipopolysaccharide (LPS) synergistically induced the expression of tissue factor (TF), a trigger for the extrinsic coagulation cascade, in human umbilical vein endothelial cells (HUVEC). Because the elevation of tumor necrosis factor (TNF)-α, interleukin (IL)-33, IL-1β and vascular endothelial growth factor (VEGF) in serum has also been observed in patients with CSU, we examined the effects of LPS, TNF-α, IL-33, IL-1β, VEGF and histamine on TF expression in HUVEC by reverse transcription polymerase chain reaction and flow cytometry, as well as examining the activity that triggers the extrinsic coagulation cascade and induces intercellular gap formation of HUVEC in the presence of plasma by Actochrome TF activity assay and impedance sensor, respectively. The expression of TF mRNA and surface protein of TF on HUVEC in response to histamine or VEGF were synergistically enhanced by the treatment with LPS, TNF-α, IL-33 or IL-1β. Moreover, the activation of the extrinsic coagulation pathway and intercellular gap formation of HUVEC in response to histamine or VEGF were also synergistically increased in the presence of TNF-α and LPS. Thus, TF expression on vascular endothelial cells was strongly enhanced by co-stimulation with CSU-related molecules in blood. Blocking a common pathway of LPS, TNF-α, IL-33 and IL-1β, and/or that of VEGF and histamine may be an effective therapeutic measure for patients with severe and refractory CSU.
慢性自发性荨麻疹（CSU），也称为慢性特发性荨麻疹，其发病机制被认为与外源性凝血级联反应的激活有关。然而，CSU患者外源性凝血级联反应的触发因素仍不清楚。我们之前报道过，组胺和脂多糖（LPS）可协同诱导人脐静脉内皮细胞（HUVEC）中组织因子（TF）的表达，而TF是外源性凝血级联反应的触发因素。由于在CSU患者血清中也观察到肿瘤坏死因子（TNF）-α、白细胞介素（IL）-33、IL-1β和血管内皮生长因子（VEGF）水平升高，我们通过逆转录聚合酶链反应和流式细胞术检测了LPS、TNF-α、IL-33、IL-1β、VEGF和组胺对HUVEC中TF表达的影响，同时分别通过Actochrome TF活性测定和阻抗传感器检测了在血浆存在的情况下触发外源性凝血级联反应并诱导HUVEC细胞间间隙形成的活性。组胺或VEGF刺激后，LPS、TNF-α、IL-33或IL-1β处理可协同增强HUVEC上TF mRNA的表达和TF的表面蛋白表达。此外，在TNF-α和LPS存在的情况下，组胺或VEGF刺激后HUVEC的外源性凝血途径激活和细胞间间隙形成也协同增加。因此，血液中与CSU相关的分子共同刺激可强烈增强血管内皮细胞上的TF表达。阻断LPS、TNF-α、IL-33和IL-1β的共同途径，和/或VEGF和组胺的共同途径，可能是治疗重度难治性CSU患者的有效措施。
