Top

Digestive Diseases and Sciences

Published in:

01-06-2010 | Original Article

Activated Protein C Improves the Severity of Severe Acute Pancreatitis via Up-Regulating the Expressions of Endothelial Cell Protein C Receptor and Thrombomodulin

Authors: Chen Ping, Zhang Yongping, Qiao Minmin, Yao Weiyan, Yuan Yaozong

Published in: Digestive Diseases and Sciences | Issue 6/2010

Abstract

Background and Aims

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 μg/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 α (TNF-α) 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 μg/kg-treated group, serum TNF-α, 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.

Raraty MG, Connor S, Criddle DN, Sutton R, Neoptolemos JP. Acute pancreatitis and organ failure: pathophysiology, natural history, and management strategies. Curr Gastroenterol Rep. 2004;6:99–103.CrossRefPubMed

Maeda K, Hirota M, Ichihara A, et al. Applicability of disseminated intravascular coagulation parameters in the assessment of the severity of acute pancreatitis. Pancreas. 2006;32:87–92.CrossRefPubMed

Salomone T, Tosi P, Palareti G, et al. Coagulative disorders in human acute pancreatitis: role for the D-dimer. Pancreas. 2003;26:111–116.CrossRefPubMed

Nomura F, Ihara A, Yoshitatsu M, Tamura K, Katayama A, Ihara K. Relationship between coagulation cascade, cytokine, adhesion molecule and aortic aneurysm. Eur J Cardiothorac Surg. 2003;23:1034–1038.CrossRefPubMed

Esmon CT. Coagulation and inflammation. J Endotoxin Res. 2003;9:192–198.PubMed

Dahlback B, Villoutreix BO. The anticoagulant protein C pathway. FEBS Lett. 2005;579:3310–3316.CrossRefPubMed

Rijneveld AW, Weijer S, Florquin S, et al. Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide. Blood. 2004;103:1702–1709.CrossRefPubMed

Taylor FB Jr, Peer GT, Lockhart MS, Ferrell G, Esmon CT. Endothelial cell protein C receptor plays an important role in protein C activation in vivo. Blood. 2001;97:1685–1688.CrossRefPubMed

Stearns-Kurosawa DJ, Kurosawa S, Molloca JS, Ferrell GL, Esmon CT. The endothelial cell protein C receptor augments protein C activation by the thrombin–thrombomodulin complex. Proc Natl Acad Sci USA. 1996;93:10212–10216.CrossRefPubMed

10.

Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation. Arterioscler Thromb Vasc Biol. 2004;24:1374–1383.CrossRefPubMed

11.

Yuksel M, Okajima K, Uchiba M, Horiuchi S, Okabe H. Activated protein C inhibits lipopolysaccharide-induced tumor necrosis factor-alpha production by inhibiting activation of both nuclear factor-kappa B and activator protein-1 in human monocytes. Thromb Haemost. 2002;88:267–273.PubMed

12.

Shimizu S, Gabazza EC, Taguchi O, et al. Activated protein C inhibits the expression of platelet-derived growth factor in the lung. Crit Care Med. 2003;167:1416–1426.CrossRef

13.

Bernard GR, Vincent JL, Laterre PF, et al. Recombinant human protein C worldwide evaluation in severe sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709.CrossRefPubMed

14.

Grewal HP, Mohey el Din A, Koth M, Gaber AO. Amelioration of the physiologic and biochemical changes of acute pancreatitis using an anti-TNF-alpha polyclonal antibody. Am J Surg. 1994;167:214–218.CrossRefPubMed

15.

Ottesen LH, Bladbjerg EM, Osman M, et al. Protein C activation during the initial phase of experimental acute pancreatitis in the rabbit. Dig Surg. 1999;16:486–495.CrossRefPubMed

16.

Radenkovic D, Bajec D, Karamarkovic A, et al. Disorders of hemostasis during the surgical management of severe necrotizing pancreatitis. Pancreas. 2004;29:152–156.CrossRefPubMed

17.

Liaw PC, Esmon CT, Kahnamoui K, et al. Patients with severe sepsis vary markedly in their ability to generate activate protein C. Blood. 2004;104:3958–3964.CrossRefPubMed

18.

Lindstrom O, Kylanpaa L, Mentula P, et al. Upregulated but insufficient generation of activated protein C is associated with development of multiorgan failure in severe acute pancreatitis. Crit Care. 2006;10:R16.CrossRefPubMed

19.

Akay S, Ozutemiz O, Yenisey C, Genc Simsek N, Yuce G, Batur Y. Use of activated protein C has no avail in the early phase of acute pancreatitis. HPB (Oxford). 2008;10:459–463.

20.

Yamanel L, Mas MR, Comert B, et al. The effect of activated protein C on experimental acute necrotizing pancreatitis. Crit Care. 2005;9:184–190.CrossRef

21.

Chen P, Zhao GM, Zhang Y, Qiao M, Yuan Y. Effect of activated protein C on hemodynamic changes of liver in severe acute pancreatitis. Chin J Pancreatol. 2007;5:321–324.

22.

Weiler H, Isermann BH. Thrombomodulin. J Thromb Haemost. 2003;1:1515–1524.CrossRefPubMed

23.

Uchiba M, Okajima K, Murakami K, Johno M, Okabe H, Takatsuki K. Recombinant thrombomodulin prevents endotoxin-induced lung injury in rats by inhibiting leukocyte activation. Am J Physiol. 1996;271:470–475.

24.

Sohn RH, Deming CB, Johns DC, et al. Regulation of endothelial thrombomodulin expression by inflammatory cytokines is mediated by activation of nuclear factor-kappa B. Blood. 2005;105:3910–3917.CrossRefPubMed

25.

Kim AY, Walinsky PL, Kolodgie FD, et al. Early loss of thrombomodulin expression impairs vein graft thromboresistance: implications for vein graft failure. Circ Res. 2002;90:205–212.CrossRefPubMed

26.

Gu JM, Katsuura Y, Ferrell GL, Grammas P, Esmon CT. Endotoxin and thrombin elevate rodent endothelial cell protein C receptor mRNA levels and increase receptor shedding in vivo. Blood. 2000;95:1687–1693.PubMed

27.

Liaw PC, Neuenschwander PF, Smirnov MD, Esmon CT. Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. J Biol Chem. 2000;275:5447–5452.CrossRefPubMed

28.

Franscini N, Bachli EB, Blau N, Leikauf MS, Schaffner A, Schoedon G. Gene expression profiling of inflamed human endothelial cells and influence of activated protein C. Circulation. 2004;110:2903–2909.CrossRefPubMed

29.

Mayer J, Rau B, Gansauge F, Beger HG. Inflammatory mediators in human acute pancreatitis: clinical and pathophysiological implications. Gut. 2000;47:546–552.CrossRefPubMed

30.

Wright KM, Friedland JS. Regulation of monocyte chemokine and MMP-9 secretion by proinflammatory cytokines in tuberculous osteomyelitis. J Leukoc Biol. 2004;75:1086–1092.CrossRefPubMed

31.

Chen P, Yuan Y, Wang S, Zhan L, Xu J. Serum matrix metalloproteinase 9 as a marker for the assessment of severe acute pancreatitis. Tohoku J Exp Med. 2006;208:261–266.CrossRefPubMed

32.

Alsfasser G, Warshaw AL, Thayer SP, et al. Decreased inflammation and improved survival with recombinant human activated protein C treatment in experimental acute pancreatitis. Arch Surg. 2006;141:670–676.CrossRefPubMed

33.

34.

Chen P, Zhang Y, Qiao M, Yuan Y. Activated protein C, an anticoagulant polypeptide, ameliorates severe acute pancreatitis via regulation of mitogen-activated protein kinases. J Gastroenterol. 2007;42:887–896.CrossRefPubMed

35.

Hoffmann JN, Vollmar B, Laschke MW, Fertmann JM, Jauch KW, Menqer MD. Microcirculatory alterations in ischemia-reperfusion injury and sepsis: effects of activated protein C and thrombin inhibition. Crit Care. 2005;S4:33–37.CrossRef

Title: Activated Protein C Improves the Severity of Severe Acute Pancreatitis via Up-Regulating the Expressions of Endothelial Cell Protein C Receptor and Thrombomodulin
Authors: Chen Ping
Zhang Yongping
Qiao Minmin
Yao Weiyan
Yuan Yaozong
Publication date: 01-06-2010
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 6/2010
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-009-0909-y

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background and Aims

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 6/2010

Rifaximin for Inflammatory Bowel Disease

Elevated Serum Matrix Metalloproteinase-3 and -7 in H. pylori-Related Gastric Cancer Can Be Biomarkers Correlating with a Poor Survival

Is the Benefit of Granulocyte Monocyte Adsorptive Apheresis in Ulcerative Colitis Overstated?

Caustic Ingestion and Upper Digestive Tract Injury

Relationship Between Low-Dose Aspirin-Induced Gastric Mucosal Injury and Intragastric pH in Healthy Volunteers

Ascertainment of Colonoscopy Indication Using Administrative Data

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials