Using protease inhibitors to prevent intraperitoneal adhesions: effects of nafamostat mesylate, UAMC-00050, GM6001, and enoxaparin in the cecal ligation and puncture model and the ischemic button model

Purpose Intraperitoneal adhesions, a major cause of post-surgical intestinal obstruction, arise from an imbalance between proteases of the coagulation and fibrinolysis pathways. This study aimed to reduce early adhesion formation by using the protease inhibitors, nafamostat mesylate (NFM), UAMC-00050, enoxaparin, and GM6001, in the cecal ligation and puncture (CLP) model and the ischemic button (IB) model in mice. Methods Mice subjected to CLP received NFM (1, 10, or 20 mg/kg), UAMC-00050 (1 or 5 mg/kg), enoxaparin (1, 5, or 10 mg/kg), or GM6001 (100 mg/kg) in preventive, delayed, and combined setups. Adhesion severity was assessed 48 h post-CLP based on the extent, tenacity, and surgical access time. NFM and enoxaparin were tested further for 7 days in the IB model. Protease activity and gene expression were analyzed in NFM-treated mice. Results CLP induced adhesions more strongly than the sham procedure. Preventive NFM reduced the adhesion extent by 49.8%. Repeated enoxaparin administration reduced the extent, tenacity, and access time (-46%). UAMC-00050 and GM6001 had no effect. In the IB model, enoxaparin, but not NFM, reduced the adhesion surface area and tenacity. Conclusions Enoxaparin and NFM reduced adhesions effectively, suggesting that coagulation inhibition plays a key role. These findings suggest that selective protease inhibitors, when administered in a timely manner, could reduce intraperitoneal adhesions.