Nishimura Misato, Nii Tokiko, Trimova Gulzhan, Miura Shuhei, Umezawa Kazuo, Ushiyama Akira, Kubota Tetsuo
Tokyo Medical and Dental University Graduate School of Health Care Sciences, Tokyo, Japan.
Department of Molecular Target Medicine Screening, Aichi Medical University School of Medicine, Aichi, Japan.
J Nephropathol. 2013 Apr;2(2):114-21. doi: 10.12860/JNP.2013.19. Epub 2013 Apr 1.
β2-glycoprotein I (β2GPI)-dependent antiphospholipid antibodies (aPLs) are considered to play a pivotal pathogenic role in antiphospholipid syndrome (APS) by inducing the expression of tissue factor, inflammatory cytokines, and chemokines, most of which are dependent upon the NF-κB pathway. Therefore, the NF-κB is regarded as a promising target for the development of a novel therapeutic strategy. However, progress has been limited owing to the fact that there are no widely-used in vivo models, or highly specific inhibitors.
This study aimed to test the effects of an NF-κB-specific inhibitor, DHMEQ, in preventing thrombus formation using an original mouse model of APS.
Specificity of a monoclonal aPL WB-6 was examined by ELISA. WB-6 was injected into normal BALB/c mice with or without DHMEQ treatment. A pulse laser was radiated to a cutaneous vein in the window of a dorsal skinfold chamber attached to the mouse and thrombus formation was observed and recorded under a microscope.
WB-6 bound preferentially to the caldiolipin (CL)-β2GPI complex rather than to CL alone, or β2GPI alone. WB-6, but not isotype-matched control antibody, induced a prothrombotic state in the mice by inducing tissue factor expression upon circulating monocytes, resulting in thrombus formation at the site of laser-induced endothelial injury. This diathesis was almost completely ameliorated by DHMEQ treatment.
Inhibition of the NF-κB pathway is a promising strategy for the development of a novel treatment for APS.
β2糖蛋白I（β2GPI）依赖性抗磷脂抗体（aPLs）被认为通过诱导组织因子、炎性细胞因子和趋化因子的表达，在抗磷脂综合征（APS）中发挥关键的致病作用，其中大多数因子依赖于核因子κB（NF-κB）信号通路。因此，NF-κB被视为开发新型治疗策略的一个有前景的靶点。然而，由于缺乏广泛应用的体内模型或高度特异性抑制剂，进展有限。
本研究旨在使用原始的APS小鼠模型，测试NF-κB特异性抑制剂DHMEQ预防血栓形成的效果。
通过酶联免疫吸附测定（ELISA）检测单克隆aPL WB-6的特异性。将WB-6注射到接受或未接受DHMEQ治疗的正常BALB/c小鼠体内。用脉冲激光照射附着在小鼠身上的背部皮肤褶皱腔窗口中的皮肤静脉，并在显微镜下观察和记录血栓形成情况。
WB-6优先结合心磷脂（CL）-β2GPI复合物，而不是单独的CL或单独的β2GPI。WB-6而非同型对照抗体通过诱导循环单核细胞上的组织因子表达，在小鼠体内诱导促血栓形成状态，导致激光诱导的内皮损伤部位形成血栓。DHMEQ治疗几乎完全改善了这种易患性。
抑制NF-κB信号通路是开发APS新型治疗方法的一种有前景的策略。
