Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in rats

Abstract

To examine whether administration of activated protein C or antithrombin reduces local splanchnic derangement of coagulation and inflammation and attenuates intestinal dysfunction and injury following intestinal ischemia/reperfusion. Randomized prospective animal study. University research institute. Adult male Wistar rats, weighing 300–325 g (n = 72). Rats were subjected to superior mesenteric artery occlusion consisting of 20 or 40 mins of ischemia and 3 hrs of reperfusion. A randomized intravenous administration of vehicle (0.9% NaCl), heparin, antithrombin, or activated protein C was performed during ischemia, 15 mins before reperfusion. Coagulation and fibrinolysis variables obtained from portal blood were correlated with mucosal fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance), and intestinal injury (histologic evaluation by Park/Chiu score). Activated protein C- or antithrombin-treated animals demonstrated less ischemia/reperfusion-induced intestinal dysfunction and histologic changes compared with control animals, whereas intravenous administration of heparin only showed less histologic derangement. Activated protein C- or antithrombin-treated animals showed less thrombin generation, fibrin degradation products, and fibrin deposition compared with control animals, as confirmed by histologic examination, whereas heparin administration showed only a limited reduction of portal fibrin degradation product concentrations. Furthermore, activated protein C or antithrombin administration markedly inhibited the inflammatory response, as reflected by reduced interleukin-6 plasma concentrations to baseline values, whereas heparin had no effect. Administration of activated protein C or antithrombin inhibited local and systemic derangement of coagulation and inflammation following intestinal ischemia/reperfusion, diminished mucosal fibrin deposition, and attenuated ischemia/reperfusion-induced intestinal injury. These observations suggest that activated protein C or antithrombin reduces ischemia/reperfusion-induced intestinal injury, both through their anticoagulant and anti-inflammatory effects.