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Rapid Increase in Serum Levels of Matrix Metalloproteinase-9 (MMP-9) Postoperatively is Associated With a Decrease in the Amount of Intracellular MMP-9

College of Physicians and Surgeons of Columbia University, Department of Surgery, BB1702, 630 West 168th Street, New York, NY 10032; belizon{at}nyc.rr.com

Irena Kirman, MD, PhD

Moshe Karten

Suvinit Jain, BA

Richard L. Whelan, MD

Department of Surgery, College of Physicians and Surgeons of Columbia University

We have previously demonstrated a significant decrease in the serum concentration of intact insulin-like growth factor-binding protein (IGFBP-3) after laparotomy. IGFBP-3, a major IGF binding protein, inhibits the growth of tumor cells via several mechanisms. Our goal was to determine, in a murine model, whether matrix metalloproteinase-9 (MMP-9), a known protease of IGFBP-3, is responsible for the postoperative decrease in serum IGFBP-3 levels. Six IGFBP-3 transgenic mice on a CD-1 background were used in this study. These mice over-express human IGFBP-3. Sham laparotomy, in the form of a midline abdominal incision, was the test procedure. General anesthesia was established using ketamine and xylazine immediately before a 30-minute sham laparotomy and before preoperative blood sampling, done via retro-orbital venipuncture, 48 hours before surgery. The animals were sacrificed and blood was drawn 24 hours postoperatively. Plasma MMP-9 activity was measured using zymography at each time point (48 hours before and 24 hours after operation). MMP-9 activity was also measured in mononuclear cell lysates at both time points. Zymography analysis demonstrated significantly higher plasma levels of MMP-9 postoperatively compared with preoperative levels (81 RU vs 40 RU; P < .05). In contrast, mononuclear cell levels of MMP-9 were significantly higher preoperatively compared with postoperative levels (37.5 RU vs. 0.75 RU, P < .05). Plasma levels of MMP-9, a known protease of IGFBP-3, are significantly elevated postoperatively. In addition, mononuclear cells that store MMP-9 are depleted of it postoperatively. This suggests that rapid MMP-9 release by mononuclear cells leads to an increase in serum levels of this protease postoperatively. Further studies will elucidate mechanisms of MMP-9–related IGFBP-3 depletion.

Key Words: insulin-like growth factor-binding protein • laparotomy • matrix metalloproteinase-9 • tumor growth

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