N-acetyl-L-Cysteine (NAC) Reduces Intraabdominal Adhesion Formation Through the Upregulation of Peritoneal Fibrinolytic Activity and Antioxidant Defenses
Daniel I-Hsin Chu, MD, Rizal Liam, MD, Stanley Heydrick, PhD, Melanie L. Grainsbury, MD, Karen L. Reed, PhD, Arthur Stucchi, PhD, James M. Becker, MD, FACS
Boston University Medical Center, Boston, MA
PURPOSE OF STUDY
Intraabdominal adhesions are a major source of morbidity and efforts to prevent them remain limited. Our laboratory has shown that adhesions are reduced by mechanisms that upregulate peritoneal fibrinolysis and antioxidant capacity. NAC is a clinically relevant antioxidant whose ability to reduce adhesions is unknown. We hypothesized that NAC would reduce adhesions and characterized its effects on peritoneal fibrinolysis and antioxidant defenses.
Abdominal adhesions were induced using our ischemic button model. Male Wistar rats (n = 40) were randomized to three groups: non-operative controls (NON-OP), operative controls (OP+Saline) or operative treatment with NAC (OP+NAC). Operated animals were administered either 1-mL normal saline (vehicle) or NAC (150mg/kg) intraperitoneally BID on pre-op day 1, operative day and post-op day 1. Animals were sacrificed at 7 days for adhesion scoring or at 24hrs to evaluate peritoneal fluid for fibrinolytic activity and tissue for tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) mRNA by RT-PCR, PAI-1 protein by Western blot, glutathione (GSH) and the oxidative stress marker, 8-isoprostane (8-IP), by ELISA.
SUMMARY OF RESULTS
NAC reduced adhesions by 53% (p<0.001) and increased peritoneal fibrinolytic activity over two-fold (p=0.002). Peritoneal tissue tPA mRNA levels increased by two-fold with NAC (p=0.007) while PAI-1 protein levels decreased by 30% (p=0.047). Surgery reduced peritoneal GSH levels by 92% but NAC did not reconstitute GSH levels. NAC decreased 8-IP, however, by 46% (p=0.009).
NAC administered intraperitoneally reduces adhesion formation while upregulating peritoneal fibrinolytic activity and antioxidant defenses. These data suggest a potentially new therapeutic use for NAC in adhesion prevention.