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Valproic Acid (VPA), a Histone Deacetylase Inhibitor (HDACi) that reduces intraabdominal adhesions m
Matthew Brady, MD, Elizabeth King, MD, Michael Cassidy, MD, Stanley Heydrick, PhD, and Arthur Stucchi, PhD
Department of Surgery, Boston University School of Medicine, Boston, MA

Background: Intraabdominal adhesions occur in nearly 100% of patients following abdominopelvic surgery. We have shown that VPA administered intraperitoneally (IP) reduces adhesions in a rat model; however, the mechanism remains unclear. We hypothesize that VPA inhibits fibrin exudation at the adhesion site and limits plasma extravasation into the peritoneum in the immediate postoperative period. Methods: Rats (n=25) underwent laparotomy with creation of 4 peritoneal ischemic buttons as we have previously described. A single IP dose of 50mg/kg VPA or saline was administered intraoperatively. To measure plasma extravasation, Evans Blue (25mg/kg) was injected via the tail vein. Animals were sacrificed after 3 hr to quantify Evans Blue accumulation in peritoneal buttons and sidewall tissue. In additional experiments, ischemic button and peritoneal sidewall tissues were collected 3 hrs post-op for RNA extraction and real-time PCR analysis to measure mRNA levels of VEGF, which promotes vascular permeability, and thrombomodulin (TM) and tissue factor (TF), which influence fibrin accumulation by modulating thrombin activity. 4 untreated rats served as non-operated controls.

Results: VPA reduced plasma extravasation into inflamed peritoneal tissue at 3hrs postoperatively (Table) consistent with the significant reduction in VEGF mRNA levels. The reduction in TF and TM by VPA further contribute to adhesion reduction

Conclusion: These data suggest that fibrinolytic events in the early postoperative period play a key role in the regulation of adhesiogenesis and remain viable pharmacologic targets.


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