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Introduction: Postoperative (postop) adhesions are a formidable source of morbidity, and previous studies in our laboratory have shown that peritoneal inflammation and reduced peritoneal fibrinolysis contribute to adhesiogenesis. Histone deacetylase inhibitors (HDACIs) including valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA), and MS-275 modulate protein acetylation and gene transcription, and have anti-inflammatory and anti-proliferative properties that we hypothesized could reduce postop adhesions.
Methods: 42 male rats underwent laparotomy with creation of 6 peritoneal ischemic buttons to induce adhesions. A single intraperitoneal (IP) dose of 50mg/kg VPA, 50mg/kg SAHA, or 10mg/kg MS-275 was administered intraoperatively (intraop). Control animals received vehicle alone. To evaluate for a critical window of opportunity for intervention, an additional 25 rats underwent ischemic button creation with either an intraop or a delayed IP dose of VPA at 1, 3, or 6 hours postop. On postop day 7, adhesions were quantified as percent of ischemic buttons with adhesions. To investigate mechanism, ischemic buttons were created in 24 rats and either VPA or saline was administered in one intraop dose. 8 untreated rats served as non-operated controls. 3 or 24 hours later, peritoneal fluid was collected and fibrinolytic activity was measured in a kinetic assay for tissue plasminogen activator, and peritoneal tissue was collected for RNA extraction and real-time PCR.
Results: A single intraop dose of VPA significantly reduced adhesions by 45% relative to vehicle controls (39.4±4.1% vs 71.3±4.4%, p<0.001). Similarly, single intraop doses of SAHA and MS-275 reduced postoperative adhesions by 48% (44.4±8.2% vs 86.1±5.1%) and by 45% (47.2±5.1% vs 86.1±5.1%), respectively (p<0.001). Delayed doses of VPA at 1, 3, or 6 hours postop did not reduce adhesions (73.3±4.1%, 66.7±9.1%, 63.3±6.2% vs 73.3±4.1%). In operated animals, peritoneal fibrinolytic activity at 3 and at 24 hours postop was not significantly different between animals administered saline and VPA (6.99U/ml vs 6.75U/ml and 2.61U/ml vs 2.08U/ml). There was no differential regulation of gene transcription for IL-6, HIF-1a, tissue factor, or PAI-1 at 3 or at 24 hours postop with administration of VPA versus saline.
Conclusions: Three different HDACIs significantly reduce postop adhesions with very comparable efficacy, suggesting a similar mechanism of action. That the efficacy of VPA is limited to intraop administration only, with delayed administration of even 1 hour postop having no effect, suggests that HDACIs target very early events in adhesiogenesis that are unrelated to previously described mechanisms such as fibrinolytic activity or transcription of inflammatory regulators. These data further indicate that HDACIs reduce adhesions by a novel mechanism needing further investigation.