A substance P receptor antagonist (SPRA) that reduces intraabdominal adhesion formation decreases peritoneal matrix metalloproteinase (MMP) activity

Abstract

Abstract Introduction: Intraabdominal adhesions remain a significant complication of abdominal surgery. Previous data from our laboratory demonstrate that administration of a SPRA (CJ-12,255, Pfizer) reduces adhesion formation. There is a growing body of evidence suggesting that dysregulation of extracellular matrix (ECM) degradation and remodeling by MMPs is a key element of adhesion formation. The aim of this study was to utilize the SPRA to determine if the proinflammatory peptide substance P (SP) modulates peritoneal MMP activity. Methods: Following laparotomy, 6 ischemic buttons were created on the peritoneum to induce adhesions in 46 rats. These rats were randomized to receive either intraperitoneal injections of a SPRA (5 mg/kg) or sterile water. Peritoneal fluid (PF) and peritoneal adhesion tissue (PT) was collected at 24 hours and 7 days and compared with 27 non-operated controls. Total MMP activity was determined by a quenched fluorescent substrate assay while the activity of MMP-2 and MMP-9 was assessed by gelatin zymography. Results: SPRA administration resulted in significant reductions in total MMP activity at 24 hours and 7 days in PF and PT compared with both non-operated controls and operated, untreated animals. In contrast, SPRA administration was ineffective in reducing the observed increase in MMP-2 and MMP-9 activities in PT and PF following laparotomy. ∗AssayPeritoneal sample24 hours7 days% of Non-operated control−SPRA+SPRA−SPRA+SPRATotal MMPPF101 ± 1266 ± 5∗ † 122 ± 734 ± 11∗ † PT171 ± 54149 ± 11409 ± 39∗273 ± 50∗ † MMP-2PF176 ± 11∗221 ± 17∗198 ± 94268 ± 78∗PTNot detectedNot detected194 ± 8∗205 ± 15∗MMP-9PF305 ± 43∗308 ± 29∗116 ± 4∗132 ± 20∗PT234 ± 26∗266 ± 36∗162 ± 10143 ± 20Data expressed as mean ± SEM.PF = peritoneal fluid; PT=peritoneal tissue.∗p Conclusions: By reducing the activation of MMPs, the SPRA may prevent early peritoneal ECM remodeling, thus reducing adhesion formation. These results suggest a prophylactic role for SPRA in adhesion prevention.