Activated protein C improves the severity of severe acute pancreatitis via up-regulating the expressions of endothelial cell protein C receptor and thrombomodulin.
OBJECTIVE
Activated protein C (APC) is increasingly understood to have diverse regulatory functions in inflammation. However, the exact mechanism of action remains unclear in severe acute pancreatitis (SAP). The aim of this study was to demonstrate the effects of APC on expressions of thrombomodulin (TM) and endothelial cell protein C receptor (EPCR), and its subsequent effect on the severity of SAP.


METHODS
Sprague-Dawley rats were randomly divided into four groups. The rats were given intravenous injections of APC (50, 10 microg/kg, respectively, treated groups) or saline (SAP group) just before induction of SAP. One group of rats underwent only sham operation as control group. Experimental samples were harvested at 16 h after induction. The protein and mRNA levels of matrix metalloprotease 9 (MMP-9), TM, and EPCR in pancreatic tissue were investigated. Serum tumor necrosis factor alpha (TNF-alpha) and interleukin-8 (IL-8) levels were determined. The severity of disease was evaluated by histological score of pancreatic injury, wet/dry weight ratio of pancreatic tissue, and serum amylase.


RESULTS
In the APC 50 microg/kg-treated group, serum TNF-alpha, IL-8, and pancreatic MMP-9 levels were decreased and the levels of pancreatic EPCR and TM were up-regulated compared with the SAP group. A significant dose-dependent relationship was found between the decreased levels of serum IL-8 and the APC-treated dosage. Furthermore, the severity of SAP was ameliorated by APC treatment.


CONCLUSIONS
APC could augment the anti-coagulation and anti-inflammatory activity by up-regulating EPCR and TM expressions, thus attenuating the severity of SAP.
Ping
Chen
C
Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Yongping
Zhang
Z
Minmin
Qiao
Q
Weiyan
Yao
Y
Yaozong
Yuan
Y
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D001779:Blood Coagulation Factors / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D011486:Protein C / Q000008:administration & dosage / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D012720:Severity of Illness Index; D013656:Taurocholic Acid; D018180:Thrombomodulin / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation
D001779:Blood Coagulation Factors; D016209:Interleukin-8; D011486:Protein C; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; C091963:activated protein C receptor; D013656:Taurocholic Acid; D000681:Amylases; D020780:Matrix Metalloproteinase 9
Crit Care. 2005 Jun;9(3):R184-90
15987389
J Biol Chem. 2000 Feb 25;275(8):5447-52
10681521
N Engl J Med. 2001 Mar 8;344(10):699-709
11236773
Am J Respir Crit Care Med. 2003 May 15;167(10):1416-26
12738599
Dig Surg. 1999;16(6):486-95
10805548
Arch Surg. 2006 Jul;141(7):670-6; discussion 676-7
16847238
Blood. 2004 Dec 15;104(13):3958-64
15319291
J Gastroenterol. 2007 Nov;42(11):887-96
18008033
Blood. 2000 Mar 1;95(5):1687-93
10688825
Blood. 2001 Mar 15;97(6):1685-8
11238108
Blood. 2005 May 15;105(10):3910-7
15677570
Gut. 2000 Oct;47(4):546-52
10986216
Thromb Haemost. 2002 Aug;88(2):267-73
12195699
Eur J Cardiothorac Surg. 2003 Jun;23(6):1034-8; discussion 1038-9
12829084
Am J Physiol. 1996 Sep;271(3 Pt 1):L470-5
8843797
Am J Surg. 1994 Jan;167(1):214-8; discussion 218-9
8311136
Blood. 2004 Mar 1;103(5):1702-9
14592828
Pancreas. 2004 Aug;29(2):152-6
15257107
J Thromb Haemost. 2003 Jul;1(7):1515-24
12871287
HPB (Oxford). 2008;10(6):459-63
19088933
Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10212-6
8816778
Pancreas. 2006 Jan;32(1):87-92
16340749
Circulation. 2004 Nov 2;110(18):2903-9
15505101
Arterioscler Thromb Vasc Biol. 2004 Aug;24(8):1374-83
15178554
J Leukoc Biol. 2004 Jun;75(6):1086-92
14982951
J Endotoxin Res. 2003;9(3):192-8
12831462
Tohoku J Exp Med. 2006 Mar;208(3):261-6
16498235
FEBS Lett. 2005 Jun 13;579(15):3310-6
15943976
Pancreas. 2003 Mar;26(2):111-6
12604906
Crit Care. 2006 Feb;10(1):R16
16420659
Curr Gastroenterol Rep. 2004 Apr;6(2):99-103
15191686
Circ Res. 2002 Feb 8;90(2):205-12
11834714
Crit Care. 2005;9 Suppl 4:S33-7
16168073