Activated protein C prevents deleterious effects of remote reperfusion injury caused by intestinal ischemia on wound healing in the left colonic anastomoses: an experimental study in the murine model.
BACKGROUND
Activated protein C (APC) is a serine protease with anticoagulant and antiinflammatory activities. The delaying effects of remote reperfusion injury on the wound-healing process in colonic anastomoses have been previously shown. In this study, we aimed to investigate whether APC protects against deleterious systemic effects of intestinal ischemia/reperfusion (I/R) injury on colonic anastomotic wound healing process.


METHODS
Male Wistar-albino rats were randomly allocated into 4 groups, and a left colonic anastomosis was performed in all animals: (1) sham-operated group, simultaneously with left colonic anastomosis, the superior mesenteric artery and collateral branches were divided from the celiac axis, and the inferior mesenteric artery were isolated but not occluded (group 1, n = 12), (2) sham + APC group, identical to group 1 except for APC treatment (100 microg/kg, intravenously, 15 minutes before construction of the colonic anastomosis), (group 2, n = 12), (3) intestinal I/R group, 60 minutes of superior mesenteric ischemia followed by reperfusion (group 3, n = 12), and (4) APC-treated group, (100 microg/kg, intravenously, 15 minutes before reperfusion) (group 4, n = 12). All animals were sacrificed, and colonic anastomotic bursting pressures were measured in vivo on day 7. Tissue samples were obtained for analysis of hydroxyproline contents, nitrate/nitrite levels, and activities of oxidative and antioxidative enzymes. The plasma levels of proinflammatory cytokines and D-dimer were also measured.


RESULTS
Intestinal I/R led to significant decreases in colonic anastomotic bursting pressures, tissue hydroxyproline contents, and activities of antioxidative enzymes, along with increases in tissue nitrate/nitrite levels, activities of oxidative enzymes, and plasma levels of proinflammatory cytokines and D-dimer (P < .05). However, APC treatment led to significant increases in colonic anastomotic bursting pressures, tissue hydroxyproline contents, and activities of antioxidative enzymes, along with decreases in tissue nitrate/nitrite levels, activities of oxidative enzymes, and plasma levels of proinflammatory cytokines and D-dimer (P < .05).


CONCLUSIONS
This study clearly showed that APC treatment prevented the delaying effects of remote I/R injury on colonic anastomotic wound healing process. Further clinical studies are required to determine whether APC has a useful role in the enhancement of colonic anastomotic wound healing after particular operations in which I/R injury occurs.
Teke
Zafer
Z
Department of General Surgery, Pamukkale University, School of Medicine, 20070, Kinikli, Denizli, Turkey. zteke_md@yahoo.com
Sacar
Mustafa
M
Yenisey
Cigdem
C
Atalay
A Ozgur
AO
Bicakci
Tuncay
T
Erdem
Ergun
E
D000704:Analysis of Variance; D000714:Anastomosis, Surgical; D000818:Animals; D016009:Chi-Square Distribution; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007422:Intestines / Q000098:blood supply* / Q000601:surgery*; D007511:Ischemia / Q000150:complications / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008638:Mesenteric Arteries / Q000601:surgery; D051379:Mice; D009566:Nitrates / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D011486:Protein C / Q000494:pharmacology*; D011897:Random Allocation; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*; D014969:Xanthine Oxidase / Q000378:metabolism
D015850:Interleukin-6; D009566:Nitrates; D009573:Nitrites; D011486:Protein C; D014409:Tumor Necrosis Factor-alpha; D008315:Malondialdehyde; D009195:Peroxidase; D014969:Xanthine Oxidase; D005980:Glutathione Reductase; D005978:Glutathione