Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation

Paraplegia is a serious complication that can occur after surgical repair of thoracoabdominal aortic aneurysms. 1,2 This complication has been attributed to temporary or permanent ischemia of the spinal cord caused by interruption of the blood supply during aortic cross-clamping. 1,2 Lintott et al 3 have reported that dissection, rupture, and prolonged clamp times are closely related to an increased incidence of paraplegia. Although various interventions, such as temporary shunts, have been performed to maintain perfusion of the spinal cord, this complication remains unpredictable and unpreventable. 3–5 Additional damage to the spinal cord may occur during the reperfusion period. 5 Recently, it has been shown that neutrophils play a central role in development of the pathologic condition of ischemia/reperfusion-induced tissue injury. 6–8 Although the role of the neutrophils in ischemia/reperfusion-induced injury of the central nervous system is not fully understood, previous studies have shown that either administration of antiintercellular adhesion molecule-1 antibody 9 or inhibition of monocyte function 10 reduced spinal cord injury after transient ischemia in animal models. Activated protein C (APC) is an important physiologic anticoagulant that inactivates factors Va and VIIIa. 11,12 APC is generated from protein C by the action of the thrombin–thrombomodulin complex on the endothelial cells. 11 We have previously demonstrated that APC prevents pulmonary vascular injury by inhibiting neutrophil activation through inhibiting tumor necrosis factor-α (TNF-α) production in rats given lipopolysaccharide. 13,14 Thus, it is possible that APC may be effective in reducing ischemia/reperfusion-induced spinal cord injury in which activated neutrophils play an important role. The purpose of the present study was to evaluate the efficacy of APC in the prevention of spinal cord injury after transient ischemia of the spinal cord in rats. The therapeutic mechanisms of APC in this animal model of spinal cord injury were further investigated.