Intraperitoneal administration of activated protein C prevents postsurgical adhesion band formation.

Postsurgical peritoneal adhesion bands are the most important causes of intestinal obstruction, pelvic pain, and female infertility. In this study, we used a mouse model of adhesion and compared the protective effect of activated protein C (APC) to that of the Food and Drug Administration-approved antiadhesion agent, sodium hyaluronate/carboxymethylcellulose (Seprafilm) by intraperitoneal administration of either APC or Seprafilm to experimental animals. Pathological adhesion bands were graded on day 7, and peritoneal fluid concentrations of tissue plasminogen activator (tPA), d-dimer, thrombin-antithrombin complex, and cytokines (IL-1β, IL-6, interferon-γ, tumor necrosis factor-α, transforming growth factor-β1) were evaluated. Inflammation scores were also measured based on histologic data obtained from peritoneal tissues. Relative to Seprafilm, intraperitoneal administration of human APC led to significantly higher reduction of postsurgical adhesion bands. Moreover, a markedly lower inflammation score was obtained in the adhesive tissues of the APC-treated group, which correlated with significantly reduced peritoneal concentrations of proinflammatory cytokines and an elevated tPA level. Further studies using variants of human APC with or without protease-activated receptor 1 (PAR1) signaling function and mutant mice deficient for either endothelial protein C receptor (EPCR) or PAR1 revealed that the EPCR-dependent signaling activity of APC is primarily responsible for its protective activity in this model. These results suggest APC has therapeutic potential for preventing postsurgical adhesion bands.

[1]  L. O. Mosnier,et al.  Novel mechanisms for activated protein C cytoprotective activities involving noncanonical activation of protease-activated receptor 3. , 2013, Blood.

[2]  M. Soleimani,et al.  Novel approach to reduce postsurgical adhesions to a minimum: administration of losartan plus atorvastatin intraperitoneally. , 2013, The Journal of surgical research.

[3]  M. Pisarska,et al.  Pathogenesis, consequences, and control of peritoneal adhesions in gynecologic surgery: a committee opinion. , 2013, Fertility and sterility.

[4]  J. Li,et al.  Activated protein C modulates cardiac metabolism and augments autophagy in the ischemic heart , 2012, Journal of thrombosis and haemostasis : JTH.

[5]  J. Madon,et al.  Protease‐activated receptor‐1 cleaved at R46 mediates cytoprotective effects , 2012, Journal of thrombosis and haemostasis : JTH.

[6]  M. Soleimani,et al.  Function of poly (lactic-co-glycolic acid) nanofiber in reduction of adhesion bands. , 2012, The Journal of surgical research.

[7]  M. Mitka.  Drug for severe sepsis is withdrawn from market, fails to reduce mortality. , 2011, JAMA.

[8]  G. Saed,et al.  Macrophages induce the adhesion phenotype in normal peritoneal fibroblasts. , 2011, Fertility and sterility.

[9]  A. Rezaie.  Regulation of the protein C anticoagulant and antiinflammatory pathways. , 2010, Current medicinal chemistry.

[10]  T. Yılmazlar,et al.  A Comparison of Three Fibrinolytic Agents in Prevention of Intra-Abdominal Adhesions , 2010, Acta chirurgica Belgica.

[11]  A. Al-Hendy,et al.  Adenovirus-mediated overexpression of human tissue plasminogen activator prevents peritoneal adhesion formation/reformation in rats. , 2009, Surgery.

[12]  F. Castellino,et al.  The protein C pathway and pathologic processes , 2009, Journal of thrombosis and haemostasis : JTH.

[13]  N. Chegini.  TGF-beta system: the principal profibrotic mediator of peritoneal adhesion formation. , 2008, Seminars in reproductive medicine.

[14]  Nigel Mackman,et al.  Endotoxemia and sepsis mortality reduction by non-anticoagulant–activated protein C , 2007, The Journal of experimental medicine.

[15]  J. Griffin,et al.  The cytoprotective protein C pathway. , 2007, Blood.

[16]  M. Matthay,et al.  Bench-to-bedside review: The role of activated protein C in maintaining endothelial tight junction function and its relationship to organ injury , 2006, Critical care.

[17]  G. Saed,et al.  Modulation of the expression of tissue plasminogen activator and its inhibitor by hypoxia in human peritoneal and adhesion fibroblasts. , 2001, Fertility and sterility.

[18]  E. Rosen,et al.  Mice with a Severe Deficiency of the Endothelial Protein C Receptor Gene Develop, Survive, and Reproduce Normally, and Do not Present with Enhanced Arterial Thrombosis after Challenge , 2002, Thrombosis and Haemostasis.

[19]  G. Saed,et al.  Transforming growth factor-beta1 modulates expression of adhesion and cytoskeletal proteins in human peritoneal fibroblasts. , 2002, Fertility and sterility.

[20]  W. Ruf,et al.  Activation of Endothelial Cell Protease Activated Receptor 1 by the Protein C Pathway , 2002, Science.

[21]  Kavic Sm.  Adhesions and adhesiolysis: the role of laparoscopy. , 2002 .

[22]  S. Kavic,et al.  Adhesions and Adhesiolysis: The Role of Laparoscopy , 2002, JSLS : Journal of the Society of Laparoendoscopic Surgeons.

[23]  C. Dervenis,et al.  Peritoneal Adhesions: Etiology, Pathophysiology, and Clinical Significance , 2001, Digestive Surgery.

[24]  A. Rezaie.  Vitronectin Functions as a Cofactor for Rapid Inhibition of Activated Protein C by Plasminogen Activator Inhibitor-1 , 2001, The Journal of Biological Chemistry.

[25]  G. Saed,et al.  Molecular characterization of fibroblasts isolated from human peritoneum and adhesions. , 2001, Fertility and sterility.

[26]  J Ean,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis. , 2001, The New England journal of medicine.

[27]  J. Helterbrand,et al.  Efficacy and safety of recombinant human activated protein C for severe sepsis , 2003 .

[28]  G. Gabella,et al.  Growth of nerve fibres into murine peritoneal adhesions , 2000, The Journal of pathology.

[29]  C. V. van Blitterswijk,et al.  Effects of five different barrier materials on postsurgical adhesion formation in the rat. , 2000, Human reproduction.

[30]  G D Hooker,et al.  Prevention of adhesion formation with use of sodium hyaluronate-based bioresorbable membrane in a rat model of ventral hernia repair with polypropylene mesh--a randomized, controlled study. , 1999, Surgery.

[31]  M. Diamond,et al.  Reduction of postsurgical adhesion formation in the rabbit uterine horn model with use of hyaluronate/carboxymethylcellulose gel. , 1998, Fertility and sterility.

[32]  P. A. Peterson,et al.  Biological Consequences of Thrombin Receptor Deficiency in Mice , 1996, Thrombosis and Haemostasis.

[33]  S. Stryker,et al.  Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomized, double-blind multicenter study. , 1996, Journal of the American College of Surgeons.

[34]  Robert V Farese,et al.  Role of the thrombin receptor in development and evidence for a second receptor , 1996, Nature.

[35]  I. Chaudry,et al.  Prevention of peritoneal adhesions by administration of sodium carboxymethyl cellulose and oral vitamin E. , 1993, Surgery.

[36]  D. Menzies.  Peritoneal adhesions. Incidence, cause, and prevention. , 1992, Surgery annual.

[37]  H. Ellis,et al.  Intestinal obstruction from adhesions--how big is the problem? , 1990, Annals of the Royal College of Surgeons of England.

[38]  A. Chang,et al.  Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. , 1987, The Journal of clinical investigation.

[39]  C. Esmon,et al.  Generation of fibrinolytic activity by infusion of activated protein C into dogs. , 1981, The Journal of clinical investigation.

[40]  A. Aurora,et al.  Role of proteolytic enzyme in the prevention of postoperative intraperitoneal adhesions. , 1974, Archives of surgery.