Document Type : Original Article
- Behzad Pourreza 1
- Seyed Mehdi Ghamsari 1
- Farhang Sasani 2
- frajollah Adib hashemi 1
- Hamed Mansoor Lakooraj 3
1 Department of Surgery and Radiology, Faculty of Veterinary Medicine, University of Tehran, Tehran- Iran
2 Department of Pathology, Faculty of Veterinary Medicine, Tehran University, Tehran, Tehran-Iran
3 Department of Internal Medicine, Faculty of Veterinary Medicine, University of Tehran, Tehran- Iran
Objective- Mechanisms that decrease oxidative stress and enhance peritoneal fibrinolysis reduce adhesions. N-acetyl-L-cysteine (NAC) is an antioxidant whose effect on peritoneal fibrinolysis in large animal model has not been established. The aims of this study were to investigate the ability of NAC to decreased adhesion in stablished model of serosal trauma in sheep.
Design- Experimental study
Animals- Eight healthy male sheep weighting 42.67 ± 2.31 kg were used in this study.
Procedures- Established model of serosal trauma were used for adhesion induction. Each sheep intreated group (n=4) received NAC (150 mg/kg) intraperitonealy on operative day and Intravenous infusion during 7days after surgery. Animals in untreated group received normal saline instead of NAC. Blood samples for evaluation of the CBC, total protein and fibrinogen were obtained on perioperative day and at days 1, 2, 4, 7, 11 and 14 after surgery. Animals were killed 14 days postoperatively and Adhesion formation was scored macroscopically and histopathologically.
Results- Evaluation of CBC showed inflammation in 75% of animals in untreated group. CBC of animals in treated group was normal during the study. Measuring the fibrinogen concentration revealed significant differences between untreated and treated groups. Extensive of adhesion formation was 100% in all sheep in both 2 groups. Macroscopic evaluation of severity of adhesion and histopathological assessment of inflammation and fibrosis showed significant reduction in adhesion formation in treated animals.
Conclusions and Clinical Relevance- Results of our study suggest a potential therapeutic use for N-Acetylcysteine in adhesion reduction and prevention in human and veterinary medicine.
- Becker JM, Dayton MT, Fazio VW, Beck DE, Stryker SJ, Wexner SD, Wolff BG, Roberts PL, Smith LE, Sweeney SA and Moore M. Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomized, double-blind multicenter study. Journal of the American College of Surgeons, 1996; 183:297-306.
- Wiseman DM. Disorders of adhesions or adhesionrelated disorder: monolithic entities or part of something bigger–CAPPS? Seminars in Reproductive Medicine, 2008; 26:356-368.
- Jackson EK. Intraperitoneal administration of adenosine inhibits formation of abdominal adhesions. Diseases of the Colon & Rectum, 2004; 47:1390.
- Duron JJ. Postoperative intraperitoneal adhesion pathophysiology. Colorectal Disease, 2007; 9:14-24.
- Mendes JB, Campos PP, Rocha MA and Andrade SP. Cilostazol and pentoxifylline decrease angiogenesis, inflammation, and fibrosis in sponge-induced intraperitoneal adhesion in mice. Life Science, 2009; 84: 537-543.
- Rijhwani A, Sen S, Gunasekaran S, Ponnaiya J, Balasubramanian Ka and Mammen KE. Allopurinol reduces the severity of peritoneal adhesions in mice. Journal of Pediatric Surgery, 1995; 30:533.
- Nigwekar SU and Kandula P. N-acetylcysteine in cardiovascularsurgery associated renal failure: a metaanalysis. The Annals of Thoracic Surgery, 2009; 87:139-147.
- Zafarullah M, Li WQ, Sylvester J and Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cellular and Molecular Life Sciences, 2003; 60:6-20.
- Lieberman J. The appropriate use of mucolytic agents. The American Journal of Medicine, 1970; 49: 1-4.
- Cotgreave IA. N-acetylcysteine: pharmacological considerations and experimental and clinical applications. Advances in Pharmacology, 1997; 38:205.
- Kabali B, Girgin S, Gedik E, Ozturk H, Kale E and Buyukbayram H. N-acetylcysteine prevents deleterious effects of ischemia/ reperfusion injury on healing of colonic anastomosis in rats. European Surgical Research, 2009; 43:8-12.
- Pata O, Yazici G, Apa DD, Tok E, Oz U, Kaplanoğlu M, Aban M and Dilek S. The effect of inducible nitric oxide synthase on postoperative adhesion formation in rats. European Journal of Obstetrics and Gynecology, 2004; 117:64-69.
- Chu DI, Lim R, Heydrick S, Gainsbury ML, Abdou R, D'Addese L, Reed KL, Stucchi AF and Becker JM. N-acetyl-l-cysteine decreases intra-abdominal adhesion formation through the upregulation of peritoneal fibrinolytic activity and antioxidant defenses. Surgery, 2011; 149(6):801-812.
- Moll H, Schumacher J and Wright JC. Evaluation of sodium carboxymethylcellulose for prevention of experimentally induced abdominal adhesion in ponies. American Journal of Veterinary Research,1991; 52:88-91.
- Zühlke HV, Lorenz EMP, Straub EM and Savvas V. Pathophysiologie und klassifikation von Adhäsionen. Arch Chir Supplement.1990; 2:1009-1016.
- Hooker GD, Taylor BM and Driman DK. Prevention of adhesion formation with use of sodium hyaluronatebased bioresorbable membrane in a rat model of ventral hernia repair with polypropylene mesh - a randomized, controlled study. Surgery. 1999; 125:211-216.
- Festing M. Doing better animal experiments; together with notes on genetic nomenclature of laboratory animals. ANZCCART News, 2000; 13:1-8.
- Gulden VD, Beynen AC and Bosland MC. Animal Models. In: van Zutphen LFM, Baumans V and Beynen AC, eds. Principles of Laboratory Animal Science. 2nd ed.Amsterdam: Elsevier 2000;189-196.
- Menzies D and Ellis H. Intra-abdominal adhesions and their prevention by topical tissue plasminogen activator. Journal of the Royal Society of Medicine, 1989; 82: 534-535.
- Evans DM, McAree K, Guyton DP, Hawkins N and Stakleff K. Dose dependency and wound healing aspects of the use of tissue plasminogen activator in the prevention of intraabdominal adhesions. American Journal of Surgery. 1993; 165:229-232.
- Lowry OH, Rosebrough NJ, Farr AL and Randall RJ. Protein measurement with the Folin phenol reagent. The Journal of Biological Chemistry, 1951; 193: 265.
- Scott-Coombes D, Whawell S and Vipond MN, Thompson, J. Human intraperitoneal fibrinolytic response to elective surgery. British Journal of Surgery, 1995; 82:414.
- D’Angelo A, Kluft C, Verheijen JH, Rijken DC, Mozzi E and Mannucci PM. Fibrinolytic shut-down after surgery: Impairment of the balance between tissue-type plasminogen activator and its specific inhibitor. European Journal of Clinical Investigation, 1985; 15:308.
- Bakkum EA, Emeis JJ, Dalmeijer RA, van Blitterswijk CA, Trimbos JB and Trimbos-Kemper TC. Long-term analysis of peritoneal plasminogen activator activity and adhesion formation after surgical trauma in the rat model. Fertility and Sterility, 1999; 66:1018.
- Jaulmes A, Sansilvestri-Morel P, Rolland-Valognes G, Bernhardt F, Gaertner R, Lockhart BP, Cordi A, Wierzbicki M, Rupin A and Verbeuren TJ. Nox4 mediates the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells. Thrombosis Research, 2009; 124:439-446.
- Whawell SA, Vipond MN, Scott-Coombes DM and Thompson JN. Plasminogen activator inhibitor 2 reduces peritoneal fibrinolytic activity in inflammation. British Journal of Surgery, 1993; 80: 107-109.
- Ohan J, Gilbert MA, Brouland JP, Rougier JP, Trugnan G, Wassef M, Leseche G and Drouet L. Phenotypic and functional characteristics of porcine peritoneal mesothelial cells. In Vitro Cellular & Developmental Biology Animal, 1999; 35:625-634.
- Cheong YC, Laird SM, Shelton JB, Ledger WL, Li TC and Cooke ID. The correlation of adhesions and peritoneal fluid cytokine concentrations: A pilot study. Human Reproduction, 2002; 17:1039.
- Gotloib L, Wajsbrot V, Cuperman Y and Shostak A. Acute oxidative stress induces peritoneal hyperpermeability, mesothelial loss, and fibrosis. Journal of Laboratory and Clinical Medicine, 2004; 143:31.
- de la Portilla F, Ynfante I, Bejarano D, Conde J, Fernández A, Ortega JM and Carranza G. Prevention of peritoneal adhesions by intraperitoneal administration of vitamin E: An experimental study in rats. Diseases of Colon and Rectum, 2004; 47: 2157.
- Kagoma P, Burger SN, Seifter E, Levenson SM and Demetriou AA. The effect of vitamin E on experimentally induced peritoneal adhesions in mice. Archives of Surgery, 1985; 120:949.
- Galili Y, Ben-Abraham R, Rabau M, Klausner J and Kluger Y. Reduction of surgeryinduced peritoneal adhesions by methylene blue. American Journal of Surgery, 1998; 175:30.
- Tsimoyiannis EC, Tsimoyiannis JC, Sarros CJ, Akalestos GC, Moutesidou KJ, Lekkas ET and Kotoulas OB. The role of oxygen-derived free radicals in peritoneal adhesion formation induced by ileal ischaemia/reperfusion. Acta chirurgica Scandinavica, 1989; 155:171.
- Nielsen VG, Crow JP, Zhou F and Parks DA. Peroxynitrite inactivates tissue plasminogen activator. Anesthesia & Analgesia, 2004; 98:1312-1317.
- Feng YH and Hart G. In vitro oxidative damage to tissue-type plasminogen activator: a selective modification of the biological functions. Cardiovascular Research, 1995; 30: 255-261.
- Swiatkowska M, Szemraj J, Al-Nedawi KN and Pawłowska Z. Reactive oxygen species upregulate expression of PAI-1 in endothelial cells. Cellular and Molecular Biology Letters, 2002; 7:1065-1071.
- Cheng JJ, Chao YJ, Wung BS and Wang DL. Cyclic straininduced plasminogen activator inhibitor-1 (PAI-1) release from endothelial cells involves reactive oxygen species. Biochemical and Biophysical Research Communications, 1996; 225:100-105.
- Te Velde AA, Huijbens RJ and Heije K. Interleukin-4 (IL-4) inhibits secretion of IL-1 beta, tumor necrosis factor alpha, and IL-6 by human monocytes. Blood, 1990; 76: 1392-1397.
- Holschneider CH, Cristoforoni PM, Ghosh K, Punyasavatsut M, Abed E and Montz FJ. Endogenous versus exogenous IL-10 in postoperative intraperitoneal adhesion formation in a murine model. Journal of Surgery Research, 1997; 70:138-143.
- Coleman MG, McLain AD and Moran BJ. Impact of previous surgery on time taken for incision and division of adhesions during laparotomy. Diseases of Colon and Rectum. 2000; 43:1297-1299.
- Van Der Krabben AA, Dijkstra FR, Nieuwenhuijzen M, Reijnen MM, Schaapveld M and Van Goor H. Morbidity and mortality of inadvertent enterotomy during adhesiotomy. British Journal of Surgery, 2000; 87: 467-471.
- DeWilde RL and Trew G. Postoperative abdominal adhesions and their prevention in gynaecological surgery. Expert consensus position. Part 2—Steps to reduce adhesions. Gynecolgical Surgery, 2007; 4: 243-253.
- Harris ES, Morgan RF and Rodeheaver GT. Analysis of the kinetics of peritoneal adhesion formation in the rat and evaluation of potential antiadhesive agents. Surgery, 1995; 117: 663-669.