Effect of a Matrix Metalloproteinase Activity and TNF-Alpha Converting Enzyme Inhibitor on Intra-Abdominal Adhesions

Abstract

Background: Formation of intra-abdominal adhesions depends, in part, on the activity of serine proteinases. Matrix metalloproteinases (MMP) are required for epithelialization of skin wounds but their involvement in mesothelialization of peritoneal wounds and in adhesion pathogenesis is not known. Early tumor necrosis factor-α (TNF-α) levels have been proposed to reflect propensity to adhesion formation. Objective: The impact of MMP activity and secreted TNF-α on peritoneal adhesion formation and healing was investigated through systemic administration of the synthetic broad-spectrum MMP and TNF-α-converting enzyme (TACE) inhibitor GM 6001. Methods: Female Sprague-Dawley rats of 4–6 weeks of age were injected subcutaneously daily with GM 6001 100 mg/kg (n = 12) or vehicle (n = 10) starting two days before surgery. In each rat, two standardized peritoneal wounds, 20 mm × 5 mm, were made. One peritoneal wound was sutured whereas the contralateral wound healed by secondary intention. Adhesion formation and peritoneal healing, cell proliferation, and hydroxyproline concentrations were evaluated on postoperative day 7. Results: Total serum TNF-α levels increased in vehicle-treated rats (p = 0.019) while GM 6001 treatment effectively prevented the rise in the postoperative phase (p < 0.001). No significant differences were observed in the extent of adhesion formation (p = 0.67) between control (65.0%) and GM 6001-treated (61.5%) animals, or peritoneal wound healing or cell proliferation. Hydroxyproline levels increased in the wounds (p = 0.014) but were not different between the two groups (p = 0.14). Conclusions: Lack of a striking effect of the MMP and TACE antagonist GM 6001 on postoperative adhesions suggests that MMP activity and TNF-α might not be major adhesiogenic factors.