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 a...

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Veröffentlicht in:Blood Jg. 125; H. 8; S. 1339
Hauptverfasser: Dinarvand, Peyman, Hassanian, Seyed Mahdi, Weiler, Hartmut, Rezaie, Alireza R
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 19.02.2015
Schlagworte:
Animals
Cytokines - genetics
Cytokines - metabolism
Drug Evaluation, Preclinical
Inflammation - drug therapy
Inflammation - genetics
Inflammation - metabolism
Inflammation Mediators - metabolism
Infusions, Parenteral
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Peritoneal Diseases - genetics
Peritoneal Diseases - metabolism
Peritoneal Diseases - prevention & control
Peritonitis - drug therapy
Peritonitis - genetics
Peritonitis - metabolism
Postoperative Complications - genetics
Postoperative Complications - metabolism
Postoperative Complications - prevention & control
Protein C - administration & dosage
Tissue Adhesions - genetics
Tissue Adhesions - metabolism
Tissue Adhesions - prevention & control
ISSN:1528-0020, 1528-0020
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1528-0020
1528-0020
DOI:10.1182/blood-2014-10-609339