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

活化蛋白C（APC）是凝血系统的重要抑制剂，最近已被证明可以通过阻断白细胞的活化来防止组织损伤。为了确定APC是否也可以预防创伤后脊髓损伤（SCI），白细胞在其中发挥重要作用的条件下，我们测试了APC对大鼠压迫性创伤诱导的SCI的影响。在诱导SCI之前或之后给予APC，显著减少了这些动物的运动障碍。相比之下，无论是活化因子X（DEGR-Xa）的非活性衍生物，凝血酶生成的选择性抑制剂，也没有活性位点阻断APC（DIP-APC）减少运动障碍。组织学检查显示，在创伤后24小时观察到的髓内肿胀在施用APC的动物中显著减少。在接受APC的动物中，脊髓损伤节段中肿瘤坏死因子-a（TNF-α）的组织水平的增加和中性粒细胞的积聚被显著抑制，但这些在施用DIP-APC或DEGR-Xa的动物中没有被抑制。白细胞减少的诱导具有与APC相同的效果，因为它显著降低了运动障碍、组织中TNF-α的水平和遭受压迫性SCI.These研究结果表明，在SCI中，APC主要通过减少损伤部位的TNF-α的量来减少运动障碍，从而抑制中性粒细胞的积累和对内皮细胞的损伤。

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.