Activated protein C reduces the severity of compression-induced spinal cord injury in rats by inhibiting cytokine production

活化蛋白C(APC)是一种重要的凝血系统抑制物，最近被证明通过阻断白细胞的激活来预防组织损伤。为了确定APC是否也能预防创伤后脊髓损伤(SCI)，在这种情况下，白细胞起着重要作用，我们测试了APC对挤压伤大鼠脊髓损伤的影响。无论是在脊髓损伤诱导前还是在脊髓损伤诱导后给药，APC都能显著减少这些动物的运动障碍。相反，激活因子X的非活性衍生物(DECR-Xa)和活性位点阻断的APC(DIP-APC)都不能减少运动障碍。组织学检查显示，给予APC的动物伤后24小时脊髓内出血明显减少。给予APC的动物脊髓损伤节段肿瘤坏死因子-α(TNF-a)组织水平的升高和中性粒细胞的聚集明显受到抑制，而DIP-APC或DIGR-Xa的这些作用不受抑制。诱导白细胞减少具有与APC相同的效果，因为它显著减少了受压脊髓损伤动物的运动障碍、组织中肿瘤坏死因子-α的水平和中性粒细胞的聚集。这些发现表明，在脊髓损伤中，APC主要通过减少损伤部位的肿瘤坏死因子-α的数量来减少运动障碍，从而抑制中性粒细胞的聚集和由此对内皮细胞的损伤。

Activated protein C (APC), an important inhibitor of the coagulation system, has recently been shown to prevent tissue injury by blocking the activation of leukocytes. To determine whether APC can also prevent post-traumatic spinal cord injury (SCI), a condition in which leukocytes play an important role, we tested the effects of APC on SCI induced in rats by compression trauma. Administration of APC,either before or after the induction of SCI,markedly reduced the motor disturbances in these animals. In contrast, neither an inactive derivative of activated factor X (DEGR-Xa), a selective inhibitor of thrombin generation, nor active site-blocked APC (DIP-APC) reduced the motor disturbances. Histologic examination revealed that intramedullary hemorrhages, observed 24 hours after trauma, were significantly reduced in the animals administered APC.The increase in the tissue level of tumor necrosis factor-a (TNF-a) and the accumulation of neutrophils in the damaged segment of the spinal cord were significantly inhibited in the animals that had received APC,but these were not inhibited in those administered with DIP-APC or DEGR-Xa. The induction of leukocytopenia had the same effect as APC,in that it significantly reduced motor disturbances, tissue levels of TNF-a, and neutrophil accumulation in the animals subjected to compressive SCI.These findings suggest that in SCI,APC reduces motor disturbances primarily by reducing the amount of TNF-a at the site of injury, thus inhibiting neutrophil accumulation and the resultant damage to the endothelial cells.