Background: Matrix metalloproteinases (MMPs) catalyze the degradation of collagen and extracellular matrix. They play a role in pathologic states including malignancy, in which they facilitate invasion and metastasis. MMP inhibition has been shown to block neoplastic invasion and to improve survival in animal models of malignancy. Concern about the effects of MMP inhibitors on wound and anastomotic healing may limit their potential use in the perioperative period, when surgical manipulation may lead to local and systemic showering of cancer cells. We sought to assess the effect of perioperative administration of a MMP-inhibitor (BB-94) on skin and bowel healing in a rat model.
Methods: Male Sprague-Dawley rats were given an intraperitoneal injection with BB-94 (40 mg/kg) or carrier for 3 days or 14 days starting on the day of operation. Rats underwent distal small bowel resection and end-to-end anastomosis under ketamine/pentobarbital anesthesia. Animals were sacrificed at 4, 10, 14, 28, and 49 days and the bowel bursting pressure (BBP) was measured at the anastomosis. Skin and bowel specimens were formalin-fixed or snap-frozen in liquid nitrogen. Mallory's trichrome stain was used to assess collagen content and wound morphology. Frozen specimens were quantitatively assayed for hydroxyproline to determine collagen concentration.
Results: Absorption of BB-94 was confirmed through HPLC and mass spectroscopy of sera from treated animals. BBP in all animals increased almost 10-fold between 4 and 14 days (27± 2 mm Hg at 4 days to 269± 10 mm Hg at 14 days; p<0.001). Two-way ANOVA showed no significant difference in BBP between control and treatment animals over time. There was a significant increase in the collagen content of skin specimens of all animals combined between 4 and 28 days (increase from 9.1± 0.6 to 11.9± 1.3 mg collagen/g tissue; p<0.05). Similarly, for all animals, an increase in bowel collagen from 2.1± 0.2 to 4.9± 0.8 mg/g tissue was seen between 4 and 28 days (p<0.001). Two-way ANOVA showed no significant difference in skin or bowel collagen concentrations between control and treatment animals over time. Stained histologic sections showed no qualitative differences between control and treatment animals with regard to skin or bowel collagen content or wound organization.
Conclusion: Perioperative MMP-inhibition treatment does not impair wound or enteric healing in a rat model of laparotomy and small bowel resection. MMP-inhibitors may be used safely as adjuvants to cancer resection.
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