Activated protein C attenuates acute ischaemia reperfusion injury in skeletal muscle

Abstract

Activated protein C (APC) is an endogenous anti-coagulant with anti-inflammatory properties. The purpose of the present study was to evaluate the effects of activated protein C in the setting of skeletal muscle ischaemia reperfusion injury (IRI). IRI was induced in rats by applying rubber bands above the levels of the greater trochanters bilaterally for a period of 2 h followed by 12 h reperfusion. Treatment groups received either equal volumes of normal saline or activated protein C prior to tourniquet release. Following 12 h reperfusion, muscle function was assessed electrophysiologically by electrical field stimulation. The animals were then sacrificed and skeletal muscle harvested for evaluation.Activated protein C significantly attenuated skeletal muscle reperfusion injury as shown by reduced myeloperoxidase content, wet to dry ratio and electrical properties of skeletal muscle. Further in vitro work was carried out on neutrophils isolated from healthy volunteers to determine the direct effect of APC on neutrophil function. The effects of APC on TNF-u stimulated neutrophils were examined by measuring CD18 expression as well as reactive oxygen species generation. The in vitro work demonstrated a reduction in CD 18 expression and reactive oxygen species generation.We conclude that activated protein C may have a protective role in the setting of skeletal muscle ischaemia reperfusion injury and that this is in part mediated by a direct inhibitory effect on neutrophil activation.

Endothelial Glycocalyx Damage During Endotoxemia Coincides With Microcirculatory Dysfunction and Vascular Oxidative Stress

“…Beneficial effects of activated protein C involve inhibition of diverse molecular mechanisms of inflammation and cellular damage, including those related to overt generation of circulating and locally produced proinflammatory mediators, the presence of activated leukocytes, and endothelial cell activation (14,15,26). In vitro experiments also revealed that activated protein C may exert inhibitory effects on reactive oxygen species generation and lipid peroxidation (29,30). Overall, experimental evidence supports a role of activated protein C in maintaining the integrity of the endothelium through both direct and indirect mechanisms.…”

Comparison of Ischemic Preconditioning and Systemic Piracetam for Prevention of Ischemia-Reperfusion Injury in Musculocutaneous Flaps

“…Many medical treatment options such as recombinant human BCL2 protein, ethyl pyruvate, laser therapy, hydrogen sulfide, PJ 34, poloxamer 188, ketamine, recombinant human VEGF165 protein, activated protein C, adenosine A, bortezomib, MRS2693, hypertonic saline solution, cariporide, grape seed proanthocyanin extract, Wisconsin solution, ultrasound, erythropoietin, resveratrol, vitamin E, 12 amino acid peptides have been experimentally studied and all of them were reported to have positive effects at some degree. [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38] However, studies on all these agents remained experimental and these agents failed to find a place in clinical use.…”

Activated Protein C: An Emerging Therapeutic Agent in the Prevention of Ischemia-Reperfusion Injury

“…APC administration has also been shown to reduce the oxidative damage and edema associated with skeletal muscle ischemia-reperfusion injury. 90 In a rat model of hind limb ischemia-reperfusion injury, Dillon et al showed reduced myeloperoxidase levels and protected electrical muscle activity in animals treated with intravenous APC. In addition, through a series of in vitro experiments, they demonstrated that human neutrophils treated with APC exhibited reduced CD18 expression and ROS generation.…”

“…In addition, through a series of in vitro experiments, they demonstrated that human neutrophils treated with APC exhibited reduced CD18 expression and ROS generation. 90 Despite the evidence supporting the use of APC in several in vivo and in vitro models of ischemiareperfusion injury, there is little published regarding the clinical use of APC in microvascular surgery. Although the hind limb ischemia-reperfusion experiments of Dillon et al are particularly informative, no published studies to date have examined the use of APC in the prevention of ischemia-reperfusion injury in free or pedicled fasciocutaneous or musculocutaneous flap models.…”

“…Although the hind limb ischemia-reperfusion experiments of Dillon et al are particularly informative, no published studies to date have examined the use of APC in the prevention of ischemia-reperfusion injury in free or pedicled fasciocutaneous or musculocutaneous flap models. 90 The development of experiments to examine the efficacy of APC in preventing ischemia-reperfusion injury in free tissue transfers represents an important avenue of future research.…”