Taoka Y, Okajima K, Uchiba M, Johno M
Department of Laboratory Medicine, Kumamoto University School of Medicine, Japan.
Thromb Haemost. 2000 Mar;83(3):462-8.
We examined whether recombinant human soluble thrombomodulin (rhs-TM) reduces compression trauma-induced spinal cord injury through protein C activation in rats. Administration of rhs-TM, either before or after the induction of spinal cord injury (SCI), markedly reduced the resulting motor disturbances. However, neither rhs-TM pretreated with an anti-rhs-TM monoclonal antibody (MAb) F2H5, which inhibits thrombin binding to rhs-TM, nor those pretreated with MAb R5G12, which selectively inhibits protein C activation by rhs-TM, prevented the motor disturbances. Intramedullary hemorrhages, observed 24 h after trauma, were significantly reduced in animals given rhs-TM. The increase in the tissue levels of tumor necrosis factor-alpha (TNF-alpha), TNF-alpha mRNA expression, and the accumulation of leukocytes in the damaged segment of the spinal cord were significantly inhibited in animals receiving rhs-TM, but these effects were not observed following administration of rhs-TM pretreated with MAb R5G12 or MAb F2H5. Leukocytopenia and activated protein C all produced effects similar to those of rhs-TM. These findings suggest that rhs-TM prevents compression trauma-induced SCI by inhibiting leukocyte accumulation by reducing the expression of TNF-alpha mRNA and such therapeutic effects of rhs-TM could be dependent on its protein C activation capacity. Findings further suggest that thrombomodulin can be implicated not only in the coagulation system but in regulation of the inflammatory response.
我们研究了重组人可溶性血栓调节蛋白（rhs-TM）是否通过激活蛋白C来减轻大鼠压迫性创伤诱导的脊髓损伤。在脊髓损伤（SCI）诱导之前或之后给予rhs-TM，均能显著减轻由此产生的运动障碍。然而，用抑制凝血酶与rhs-TM结合的抗rhs-TM单克隆抗体（MAb）F2H5预处理的rhs-TM，以及用选择性抑制rhs-TM激活蛋白C的MAb R5G12预处理的rhs-TM，均不能预防运动障碍。创伤后24小时观察到的脊髓内出血，在给予rhs-TM的动物中显著减少。接受rhs-TM的动物，脊髓损伤节段中肿瘤坏死因子-α（TNF-α）的组织水平升高、TNF-α mRNA表达以及白细胞积聚均受到显著抑制，但在用MAb R5G12或MAb F2H5预处理的rhs-TM给药后未观察到这些效应。白细胞减少和活化蛋白C均产生了与rhs-TM类似的效果。这些发现表明，rhs-TM通过降低TNF-α mRNA的表达来抑制白细胞积聚，从而预防压迫性创伤诱导的SCI，且rhs-TM的这种治疗效果可能依赖于其激活蛋白C的能力。研究结果进一步表明，血栓调节蛋白不仅与凝血系统有关，还与炎症反应的调节有关。
