Article

Preservation of peritoneal fibrinolysis owing to decreased transcription of plasminogen activator inhibitor-1 in peritoneal mesothelial cells suppresses postoperative adhesion formation in laparoscopic surgery

Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
Surgery (Impact Factor: 3.38). 12/2012; 153(3). DOI: 10.1016/j.surg.2012.07.037
Source: PubMed

ABSTRACT

Background:
Postoperative adhesion formation is regulated by peritoneal fibrinolysis, which is determined by tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1). This study compared peritoneal fibrinolysis and adhesion formation after laparoscopic surgery (LAP) and open surgery (OP).

Methods:
We divided 154 male rats into 3 groups after cecal cauterization: Control, no treatment; LAP, CO2 pneumoperitoneum at 5 mmHg for 60 minutes; and OP, laparotomy for 60 minutes. Adhesions were quantified at day 7. The activity and mRNA level of tPA and PAI-1 were determined by enzyme-linked immunosorbent assay in plasma and peritoneal lavage and by real-time polymerase chain reaction in peritoneal mesothelial cells from omentum. We also examined peritoneal fibrinolysis in human gastric cancer patients treated with LAP (n = 14) or OP (n = 10).

Results:
In the animal study, adhesion scores, PAI-1 activity in peritoneal lavage fluid, and PAI-1 mRNA levels in peritoneal mesothelium were significantly greater in the OP group than the control and LAP groups. In the human study, postoperative PAI-1 mRNA levels were significantly greater in the OP group than the LAP group. Additionally, PAI-1 mRNA levels and subsequent adhesion formation were induced by prolonged operative time in the OP group, but not the LAP group.

Conclusion:
Preservation of peritoneal fibrinolysis owing to decreased PAI-1 expression at the transcriptional level in peritoneal mesothelial cells is associated with suppression of postoperative adhesion formation in LAP. PAI-1 mRNA levels and subsequent adhesion formation were not induced by prolonged operative time in LAP. These results highlight the less invasiveness nature of LAP.

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    • "The difficulty partially resides in understanding the exact pathogenesis of adhesion formation so that reversal of the mechanisms responsible does not impede normal healing processes or result in excessive bleeding. Although the etiology is complex, a unifying concept proposes that surgically induced trauma and microvascular ischemia evoke a robust inflammatory response leading to activation of the coagulation system with subsequent development of fibrin deposits [3–5]. Although there are numerous therapies, including solid and fluid/gel barriers, no FDA-approved device or pharmacologic agent appears to decrease the clinical consequences of adhesions [2, 6, 7]. "
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    ABSTRACT: Intraperitoneal adenosine reduces abdominal adhesions. However, because of the ultra-short half-life and low solubility of adenosine, optimal efficacy requires multiple dosing. Here, we compared the ability of potential adenosine prodrugs to inhibit post-surgical abdominal adhesions after a single intraperitoneal dose. Abdominal adhesions were induced in mice using an electric toothbrush to damage the cecum. Also, 20 μL of 95 % ethanol was applied to the cecum to cause chemically induced injury. After injury, mice received intraperitoneally either saline (n = 18) or near-solubility limit of adenosine (23 mmol/L; n = 12); 5'-adenosine monophosphate (75 mmol/L; n = 11); 3'-adenosine monophosphate (75 mmol/L; n = 12); 2'-adenosine monophosphate (75 mmol/L; n = 12); 3',5'-cyclic adenosine monophosphate (75 mmol/L; n = 19); or 2',3'-cyclic adenosine monophosphate (75 mmol/L; n = 20). After 2 weeks, adhesion formation was scored by an observer blinded to the treatments. In a second study, intraperitoneal adenosine levels were measured using tandem mass spectrometry for 3 h after instillation of 2',3'-cyclic adenosine monophosphate (75 mmol/L) into the abdomen. The order of efficacy for attenuating adhesion formation was: 2',3'-cyclic adenosine monophosphate > 3',5'-cyclic adenosine monophosphate ≈ adenosine > 5'-adenosine monophosphate ≈ 3'-adenosine monophosphate ≈ 2'-adenosine monophosphate. The groups were compared using a one-factor analysis of variance, and the overall p value for differences between groups was p < 0.000001. Intraperitoneal administration of 2',3'-cAMP yielded pharmacologically relevant levels of adenosine in the abdominal cavity for >3 h. Administration of 2',3'-cyclic adenosine monophosphate into the surgical field is a unique, convenient and effective method of preventing post-surgical adhesions by acting as an adenosine prodrug.
    Full-text · Article · Apr 2014 · Digestive Diseases and Sciences
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    • "Surgery results in abrasion of the mesothelium, thereby eliminating the source of tPA, exposing the submesothelial layer and increasing the source of PAI-1 (Holmdahl, 1997). As a result, after surgery, there is a decrease in the degradation and an increase in the production of fibrin, which may result in the formation of abdominal adhesions (Shimomura, 2012). D-dimer is a fragment that is exclusively released during fibrin lysis via the action of plasmin. "

    Full-text · Dataset · Feb 2014
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    • "Surgery results in abrasion of the mesothelium, thereby eliminating the source of tPA, exposing the submesothelial layer and increasing the source of PAI-1 (Holmdahl, 1997). As a result, after surgery, there is a decrease in the degradation and an increase in the production of fibrin, which may result in the formation of abdominal adhesions (Shimomura, 2012). D-dimer is a fragment that is exclusively released during fibrin lysis via the action of plasmin. "
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    ABSTRACT: Study rationale: Heparin is routinely administered postoperatively in abdominal surgery to prevent the formation of adhesions; however, there is no consensus in the literature indicating the effectiveness of such use. Objectives: This study sought to assess peritoneal fibrinolytic activity post-enterotomy of the small colon in equines treated with heparin. Methods: In the present study, 10 adult equines were divided into 2 groups of 5 animals each: the control group (CG) and treated group (TG). Both groups underwent laparotomy and enterotomy of the small colon through the right paralumbar fossa in quadrupedal position. In addition, the animals received combinations of flunixin meglumine, gentamicin and penicillin. The TG also received subcutaneous heparin (150 IU/kg, bwt q. 12 hours, 5 days). The animals were evaluated for the peritoneal concentrations of tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1) and D-dimer at the following time-points: prior to enterotomy (M0); 12 hours after (M1); 1 day after (M2); 2 days after (M3); 4 days after (M4); 6 days after (M5); 10 days after (M6) and 14 days after enterotomy (M7). Results: A significant difference in tPA level was observed between the groups when all time-points were combined, with a median value of 2.59 IU/mL for the CG and 2.03 IU/mL for the TG. Although no significant difference was observed when the groups were compared at different time-points, smaller tPA and D-dimer values were observed for the TG during heparin treatment. Conclusions: In addition to the finding that the TG showed a lower tPA concentration and reduced D-dimer formation, it was concluded that heparin treatment decreased the formation of fibrin clots and peritoneal fibrinolytic activity.Relevance: Because elevated D-dimer levels are directly related to a poor prognosis and high mortality rate, this study reinforced the relevance of the use of heparin in hypercoagulable states and following abdominal surgery.
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