Background
Intraperitoneal adhesions occur in more than 94% of patients after abdominal surgery.
Mechanisms that decrease oxidative stress and upregulate peritoneal fibrinolysis reduce
adhesions. N-acetyl-l-cysteine (NAC) is a clinically relevant antioxidant whose effect on peritoneal fibrinolysis
and ability to decrease adhesions has not been established. The aims of this study
were to determine if NAC reduces adhesions and to characterize its potential mechanism(s)
of action.
Methods
Male Wistar rats (n = 92) received 0.9% saline (OP Control), intraperitoneal NAC (150 mg/kg, OP + NAC),
or oral NAC (1200 mg/kg) twice daily on preoperative day 1, day of operation, and
postoperative day 1. Adhesions were induced on the day of operation using our previously
described ischemic button model. Animals were killed on postoperative day 7 for adhesion
scoring. Peritoneal tissue and fluid from the intraperitoneal NAC group were measured
at 24 hours for fibrinolytic activity, tissue plasminogen activator (tPA), plasminogen
activator inhibitor-1 (PAI-1), total glutathione, and 8-isoprostane (8-IP). The effect
of NAC on tPA and PAI-1 production was tested in vitro in human mesothelial cells.
The effect of NAC on intestinal wound healing was measured using colonic anastomotic
burst pressures.
Results
Intraperitoneal NAC reduced adhesions by 53% (P < .001) compared to OP Controls without affecting anastomotic wound healing. NAC
increased the tPA/PAI-1 protein ratio and peritoneal fibrinolytic activity by 69%
and 127%, respectively, compared to OP Controls (P < .05). NAC did not restore total glutathione levels in peritoneal adhesion tissue
but decreased 8-IP by 46% and 65% (P < .05) in peritoneal tissue and fluid, respectively, compared to OP Controls. Human
mesothelial cells incubated with NAC exhibited a concentration-dependent increase
in the tPA/PAI-1 ratio, which supported in vivo observations (P < .05). Oral NAC did not decrease adhesions.
Conclusion
NAC administered intraperitoneally decreased adhesion formation while upregulating
peritoneal fibrinolytic activity and antioxidant defenses without affecting normal
anastomotic wound healing. These data suggest a potential new therapeutic use for
NAC in adhesion prevention.
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to SurgeryAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Peritoneal adhesions: etiology, pathophysiology, and clinical significance. Recent advances in prevention and management.Dig Surg. 2001; 18: 260-273
- Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomized, double-blind multicenter study.J Am Coll Surg. 1996; 183: 297-306
- Disorders of adhesions or adhesion-related disorder: monolithic entities or part of something bigger–CAPPS?.Semin Reprod Med. 2008; 26: 356-368
- The role of neutrophils and oxygen free radicals in post-operative adhesions.J Surg Res. 2006; 136: 45-52
- A neurokinin-1 receptor antagonist that reduces intra-abdominal adhesion formation decreases oxidative stress in the peritoneum.Am J Physiol Gastrointest Liver Physiol. 2007; 293: G544-G551
- Pharmacologic inhibition of adhesion formation and peritoneal tissue-type plasminogen activator activity.Semin Reprod Med. 2008; 26: 331-340
- Acute oxidative stress induces peritoneal hyperpermeability, mesothelial loss, and fibrosis.J Lab Clin Med. 2004; 143: 31-40
- The role of fibrinolysis in adhesion formation.Eur J Surg Suppl. 1997; 577: 24-31
- Cilostazol and pentoxifylline decrease angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal adhesion in mice.Life Sci. 2009; 84: 537-543
- A neurokinin 1 receptor antagonist decreases postoperative peritoneal adhesion formation and increases peritoneal fibrinolytic activity.Proc Natl Acad Sci USA. 2004; 101: 9115-9120
- Statins (HMG-CoA reductase inhibitors) decrease postoperative adhesions by increasing peritoneal fibrinolytic activity.Ann Surg. 2007; 245: 176-184
- An FDA approved neurokinin-1 receptor antagonist is effective in reducing intraabdominal adhesions when administered intraperitoneally, but not orally.J Gastrointest Surg. 2008; 12: 1754-1761
- Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options.Curr Neuropharmacol. 2009; 7: 65-74
- Glutathione dysregulation and the etiology and progression of human diseases.Biol Chem. 2009; 390: 191-214
- Intraperitoneal administration of methylene blue attenuates oxidative stress, increases peritoneal fibrinolysis, and inhibits intraabdominal adhesion formation.J Surg Res. 2007; 143: 311-319
- Allopurinol reduces the severity of peritoneal adhesions in mice.J Pediatr Surg. 1995; 30: 533-537
- The effects of melatonin on postoperative intraabdominal adhesion formation.Yonsei Med J. 2007; 48: 659-664
- Clinical policy: critical issues in the management of patients presenting to the emergency department with acetaminophen overdose.J Emerg Nurs. 2008; 34: e1-18
- N-acetylcysteine in cardiovascular-surgery-associated renal failure: a meta-analysis.Ann Thorac Surg. 2009; 87: 139-147
- The appropriate use of mucolytic agents.Am J Med. 1970; 49: 1-4
- The role of N-acetylcysteine in lower extremity ischemia/reperfusions.J Cardiovasc Surg (Torino). 2006; 47: 563-568
- N-acetylcysteine prevents deleterious effects of ischemia/reperfusion injury on healing of colonic anastomosis in rats.Eur Surg Res. 2009; 43: 8-12
- Prenatal N-acetylcysteine prevents cigarette smoke-induced lung cancer in neonatal mice.Carcinogenesis. 2009; 30: 1398-1401
- Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points.Carcinogenesis. 2001; 22: 999-1013
- The effect of inducible nitric oxide synthase on postoperative adhesion formation in rats.Eur J Obstet Gynecol Reprod Biol. 2004; 117: 64-69
- Neurokinin-1 receptor and substance P messenger RNA levels increase during intraabdominal adhesion formation.J Surg Res. 2002; 108: 165-172
- Effect of N-acetylcysteine route of administration on chemoprotection against cisplatin-induced toxicity in rat models.Cancer Chemother Pharmacol. 2008; 62: 235-241
- Effects of hyaluronic acid/carboxymethylcellulose gel on bowel anastomoses in the New Zealand white rabbit.J Gastrointest Surg. 1997; 1: 569-575
- A neurokinin 1 receptor antagonist decreases adhesion reformation after laparoscopic lysis of adhesions in a rat model of adhesion formation.Surg Endosc. 2007; 21: 1790-1795
- Intra-abdominal adhesions and their prevention by topical tissue plasminogen activator.J R Soc Med. 1989; 82: 534-535
- Dose dependency and wound healing aspects of the use of tissue plasminogen activator in the prevention of intra-abdominal adhesions.Am J Surg. 1993; 165: 229-232
- Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells.Thromb Res. 2009; 124: 439-446
- Plasminogen activator inhibitor 2 reduces peritoneal fibrinolytic activity in inflammation.Br J Surg. 1993; 80: 107-109
- Phenotypic and functional characteristics of porcine peritoneal mesothelial cells.Vitro Cell Dev Biol Anim. 1999; 35: 625-634
- Comparative effects of N-acetyl-L-cysteine and ramipril on arterial hypertension, insulin resistance, and oxidative stress in chronically glucose-fed rats.Can J Physiol Pharmacol. 2008; 86: 752-760
- N-acetylcysteine prevents glucose/glucose oxidase-induced oxidative stress, mitochondrial damage and apoptosis in H9c2 cells.Life Sci. 2009; 84: 328-336
- Human neutrophil oxidative bursts and their in vitro modulation by different N-acetylcysteine concentrations.Arzneimittelforschung. 2002; 52: 669-676
- Evaluation of thiol-based antioxidant therapeutics in cystic fibrosis sputum: focus on myeloperoxidase.Free Radic Res. 2011; 45: 165-176
- N-acetylcysteine inhibits RhoA and promotes apoptotic cell clearance during intense lung inflammation.Am J Respir Crit Care Med. 2010; 181: 374-387
- Peroxynitrite inactivates tissue plasminogen activator.Anesth Analg. 2004; 98 (table of contents): 1312-1317
- In vitro oxidative damage to tissue-type plasminogen activator: a selective modification of the biological functions.Cardiovasc Res. 1995; 30: 255-261
- Reactive oxygen species upregulate expression of PAI-1 in endothelial cells.Cell Mol Biol Lett. 2002; 7: 1065-1071
- Cyclic strain-induced plasminogen activator inhibitor-1 (PAI-1) release from endothelial cells involves reactive oxygen species.Biochem Biophys Res Commun. 1996; 225: 100-105
- Biosutures improve healing of experimental weak colonic anastomoses.Int J Colorectal Dis. 2010; 25: 1447-1451
- Methylene blue prevents surgery-induced peritoneal adhesions but impairs the early phase of anastomotic wound healing.Can J Surg. 2006; 49: 321-328
- Combined effects of tissue plasminogen activator and carboxymethylcellulose on adhesion reformation in rabbits.Int J Fertil Menopausal Stud. 1994; 39: 172-176
- Distribution of radio-labeled N-Acetyl-L-Cysteine in Sprague-Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage.Cutan Ocul Toxicol. 2007; 26: 113-134
- Prevention of intra-abdominal adhesions using the antiangiogenic COX-2 inhibitor celecoxib.Ann Surg. 2005; 242: 140-146
- Inhibition of intra-abdominal adhesion formation with the angiogenesis inhibitor sunitinib.J Surg Res. 2008; 149: 115-119
- Intraperitoneal administration of adenosine inhibits formation of abdominal adhesions.Dis Colon Rectum. 2004; 47: 1390-1396
- Prevention of peritoneal adhesions with an in situ cross-linkable hyaluronan hydrogel delivering budesonide.J Control Release. 2007; 120: 178-185
- The effects of intraperitoneal sildenafil administration on healing of left colonic anastomoses and intra-abdominal adhesion formation in the presence of intra-abdominal infection.Dis Colon Rectum. 2008; 51: 1837-1841
- Intraperitoneal administration of single dose type I collagen or low dose melatonin to prevent intraperitoneal adhesion formation: a comparative study.Eur J Obstet Gynecol Reprod Biol. 2009; 145: 209-213
- Local release of fibrinolytic agents for adhesion prevention.J Surg Res. 1995; 59: 759-763
- Adhesions: preventive strategies.Eur J Surg Suppl. 1997; 577: 32-39
Article info
Publication history
Accepted:
February 17,
2011
Footnotes
Supported in part by research grants from the Smithwick Endowment Fund, Department of Surgery, Boston University School of Medicine, and the Robert and Dana Smith Family Foundation.
Identification
Copyright
© 2011 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
