Histone deacetylase inhibitors decrease intra-abdominal adhesions with one intraoperative dose by reducing peritoneal...

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.