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Michael R Cassidy1, Alan C Sherburne1, Holly K Sheldon1

  • 1Department of Surgery, Boston University School of Medicine, Boston, MA.

Surgery
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Summary

Valproic acid (VPA), a histone deacetylase inhibitor (HDACI), significantly reduced postoperative adhesions by 50% when given as a single intraoperative dose. This suggests VPA

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Area of Science:

  • Surgical research
  • Inflammation and immunology
  • Pharmacology

Background:

  • Postoperative peritoneal injury and inflammation are primary contributors to adhesion formation.
  • Histone deacetylase inhibitors (HDACIs), such as valproic acid (VPA), modulate immune cells and resolve inflammation by targeting both histone and nonhistone proteins.
  • HDACIs are hypothesized to reduce postoperative adhesions.

Purpose of the Study:

  • To investigate the efficacy of VPA in reducing postoperative peritoneal adhesions.
  • To determine the optimal timing for VPA administration in adhesion prevention.
  • To elucidate the underlying mechanisms by which VPA may prevent adhesions.

Main Methods:

  • Seventy-two rats underwent laparotomy with induced peritoneal adhesions.
  • A single intraoperative intraperitoneal (IP) dose of VPA (50 mg/kg) was administered, with controls receiving vehicle.
  • Adhesions were quantified on postoperative day 7; timing of VPA administration and molecular mechanisms (fibrinolytic activity, tissue factor, fibrinogen, VEGF) were also assessed.

Main Results:

  • A single intraoperative VPA dose reduced adhesions by 50% (P < .001), while delayed dosing showed no effect.
  • VPA administration led to significant downregulation of tissue factor mRNA (50%) and protein (34%).
  • VPA also decreased fibrinogen protein (56%) and vascular endothelial growth factor (VEGF) protein (25%) compared to controls.

Conclusions:

  • Intraoperative VPA administration effectively reduces postoperative peritoneal adhesions.
  • VPA appears to act by rapidly decreasing the peritoneal extravasation of key adhesiogenic substrates.
  • HDACIs represent a promising therapeutic strategy for adhesion prevention, with single intraoperative dosing being an effective approach.