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


METHODS
Randomized prospective animal study.


METHODS
University research institute.


METHODS
Adult male Wistar rats, weighing 300-325 g (n = 72).


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Schoots
Ivo G
IG
Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands.
Levi
Marcel
M
van Vliet
Arlène K
AK
Maas
Adrie M
AM
Roossink
E H Paulina
EH
van Gulik
Thomas M
TM
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000991:Antithrombins / Q000008:administration & dosage / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D005337:Fibrin / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology; D007275:Injections, Intravenous; D015850:Interleukin-6 / Q000097:blood; D007422:Intestines / Q000098:blood supply* / Q000502:physiology; D008297:Male; D011446:Prospective Studies; D011486:Protein C / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology; D013917:Thrombin / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D000991:Antithrombins; D005338:Fibrin Fibrinogen Degradation Products; D015850:Interleukin-6; D011486:Protein C; D005337:Fibrin; D006493:Heparin; D013917:Thrombin