Histone deacetylase inhibitors decrease intra-abdominal adhesions with one intraoperative dose by reducing peritoneal fibrin deposition pathways.
BACKGROUND
We previously demonstrated that postoperative peritoneal injury and inflammation contribute to adhesiogenesis. Recent evidence suggests that in addition to their role of interfering with the acetylation status of nuclear histone proteins, histone deacetylase inhibitors (HDACIs) including valproic acid (VPA) can target nonhistone proteins to resolve inflammation and modulate immune cells. We hypothesized that HDACIs could reduce adhesions.


METHODS
Seventy-two rats underwent laparotomy with creation of 6 peritoneal ischemic buttons to induce adhesions. A single intraperitoneal (IP) dose of 50 mg/kg VPA was administered intraoperatively, whereas controls received vehicle. To evaluate the timing, 25 rats underwent ischemic button creation with either an intraoperative or a delayed IP dose of VPA at 1, 3, or 6 hours postoperatively. On postoperative day 7, adhesions were quantified. To investigate mechanisms, ischemic buttons were created in 24 rats and either VPA or saline was administered in 1 intraoperative dose. At 3 or 24 hours later, peritoneal fluid was collected and fibrinolytic activity measured. Alternatively, button tissue was collected 30 minutes postoperatively to measure tissue factor, fibrinogen, and vascular endothelial growth factor (VEGF) by real-time polymerase chain reaction or Western blot.


RESULTS
A single intraoperative dose of VPA reduced adhesions by 50% relative to controls (P < .001). Delayed dosing did not reduce adhesions. In operated animals, peritoneal fibrinolytic activity was not different between groups. Tissue factor mRNA was downregulated by 50% (P = .02) and protein by 34% (P < .01) in animals administered VPA versus saline. VPA decreased fibrinogen protein by 56% and VEGF protein by 25% compared with saline (P = .03).


CONCLUSIONS
These findings suggest that VPA rapidly reduces the extravasation of key adhesiogenic substrates into the peritoneum. A single, intraoperative intervention provides an ideal dosing strategy and indicates an exciting new role for HDACIs in adhesion prevention.
Department of Surgery, Boston University School of Medicine, Boston, MA.
Michael R
MR
Cassidy
Department of Surgery, Boston University School of Medicine, Boston, MA.
Alan C
AC
Sherburne
Department of Surgery, Boston University School of Medicine, Boston, MA.
Holly K
HK
Sheldon
Department of Surgery, Boston University School of Medicine, Boston, MA.
Melanie L
ML
Gainsbury
Department of Surgery, Boston University School of Medicine, Boston, MA.
Stanley
S
Heydrick
Department of Surgery, Boston University School of Medicine, Boston, MA. Electronic address: astucchi@bu.edu.
Arthur F
AF
Stucchi
D000818:Animals; D001549:Benzamides / Q000008:administration & dosage; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007422:Intestines / Q000601:surgery; D007430:Intraoperative Care; D008297:Male; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D013925:Thromboplastin / Q000378:metabolism; D000267:Tissue Adhesions / Q000378:metabolism / Q000517:prevention & control*; D014635:Valproic Acid / Q000008:administration & dosage*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000077337:Vorinostat; D014945:Wound Healing / Q000187:drug effects
D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; C118739:entinostat; D000077337:Vorinostat; D014635:Valproic Acid; D005337:Fibrin; D005340:Fibrinogen; D013925:Thromboplastin; D040301:Vascular Endothelial Growth Factor Receptor-2