The Influence of Enzymes on Adhesive Processes in the Abdominal Cavity

Abstract

Introduction: Intraperitoneal adhesions remain a common problem after abdominal surgery. However, the advent of targeted, specific agents as a directed therapy against inflammatory and neoangiogenesis raises the prospect of a new approach for anti-adhesion strategies.

Methods: 70 adult rats were divided into two groups: an enzyme group (35 rats) and a control group (35 rats). Following laparotomy the visceral peritoneum of the cecum and inner layer the abdominal cavity were abraded. In the enzyme group the preparation Wobenzym (a combination of animal and vegetable proteases plus rutoside) dissolved in 2 ml of sterile 0.9% NaCl was administered to the rats through a gastric probe over a period of 21 days. The control animals received the same quantity of saline without the preparation. On the 1^st, 3^rd, 7^th and 21^st postoperative days 8 animals from each group were sacrificed. VEGF, bFGF and laminin were detected in the visceral and parietal peritoneum by immunohistochemistry.

Results: The mean adhesion grades of the enzyme group were significantly lower than in the control group. A comparison of the two groups showed that the expression of VEGF, bFGF and laminin in the enzyme group was lower than in the control group. Moreover, in the enzyme group the concentration of bFGF and laminin peaked on the 7^th day, while in the control group the maximum concentrations peaked on day 21.

Conclusions: Our study found that oral poly-enzyme therapy following laparotomy and abrasion of the visceral and parietal peritoneum reduces the extent of postoperative intestinal adhesions. This favorable effect can be explained by the lower levels of angiogenic agents (VEGF, bFGF) and laminin after the administration of hydrolytic enzymes.

peritoneal adhesions - VEGF - bFGF - laminin - prevention

References

• 1 Carmeliet P. Angiogenesis in health and disease.  Nature Medicine. 2003;  9 653-660
• 2 Beck DE, Opelka FG, Bailey HR. et al . Incidence of small-bowel obstruction and adhesiolysis after open colorectal and general surgery.  Dis Colon Rectum. 1999;  42 241-248
• 3 Bulbuller N, Ilhan YS, Kirkil C. et al . Can angiotensin converting enzyme inhibitors prevent postoperative adhesions?.  J Surg Res. 2005;  125 94-97
• 4 Cahill RA, Redmond HP. Cytokine orchestration in post-operative peritoneal adhesion formation.  World J Gastroenterol. 2008;  14 ((31)) 4861-4866
• 5 Coleman MG, McLain AD, Moran BJ. Impact of previous surgery on time taken for incision and division of adhesions during laparotomy.  Dis Colon Rectum. 2000;  43 1297-1299
• 6 Darmas B. Use of barrier products in the prevention of adhesion formation following surgery.  J Wound Care. 2008;  17 ((9)) 405-408
• 7 Diegelmann RF, Evans MC. Wound healing: An overview of acute, fibrotic and delayed healing.  Front Biosci. 2004;  9 283-289
• 8 Ellis LM, Liu W, Fan F. Role of angiogenesis inhibitors in cancer treatment.  Oncology. 2001;  15 ((Suppl 8)) 39-46
• 9 Haas TL, Milkiewicz M, Davis SJ. et al . Matrix metalloproteinase activity is required for activity-induced angiogenesis in rat skeletal muscle.  Am J Physiol Heart Circ Physiol. 2000;  279 H1540-H1547
• 10 Holland-Cunz S, Boelter AV, Waag KL. Protective fibrin-sealed plication of the small bowel in recurrent laparotomy.  Pediatr Surg Int. 2003;  19 540-543
• 11 Jaenigen BM, Weis C, Odermatt EK. et al . The new adhesion prophylaxis membrane A-part(R) – From in vitro testing to first in vivo results.  J Biomed Mater Res B Appl Biomater. 2008;  6 218-222
• 12 Jendresen MB, Qvist N. Postoperative peritoneal adhesions.  Ugeskr Laeger. 2008;  170 ((42)) 3321-3324
• 13 Kawanishi H, Ide K, Yamashita M. et al . Surgical techniques for prevention of recurrence after total enterolysis in encapsulating peritoneal sclerosis.  Adv Perit Dial. 2008;  24 51-55
• 14 Kohyama T, Liu X, Wen FQ. et al . IL-4 and IL-13 induce chemotaxis of human foreskin fibroblasts, but not human fetal lung fibroblasts.  Inflammation. 2004;  28 33-37
• 15 Kosaka H, Yoshimoto T, Yoshimoto T. et al . Interferon-gamma is a therapeutic target molecule for prevention of postoperative adhesion formation.  Nat Med. 2008;  14 437-441
• 16 Manhart N, Akomeah R, Bergmeister H. et al . Administration of proteolytic enzymes bromelain and trypsin diminishes the number of CD4+ cells and the interferon-γ response in Peyer's patches and spleen in endotoxemic balb/c mice.  Cell Immunology. 2002;  215 113-119
• 17 Mirastschijski U, Johannesson K, Jeppsson B. et al . Effect of a matrix metalloproteinase activity and TNF-alpha converting enzyme inhibitor on intra-abdominal adhesions.  Eur Surg Res. 2005;  37 68-75
• 18 Molinas CR, Campo R, Dewerchin M. et al . Role of vascular endothelial growth factor and placental growth factor in basal adhesion formation and in carbon dioxide pneumoperitoneum-enhanced adhesion formation after laparoscopic surgery in transgenic mice.  Fertil Steril. 2003;  80 ((Suppl 2)) 803-811
• 19 Neurath MF. Immunotherapy in inflammatory bowel disease: Current concepts and future perspectives.  Arch Immunol Ther Exp Warsz. 2000;  48 81-84
• 20 Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: Role of the HIF system.  Nat Med. 2003;  9 677-684
• 21 Rout UK, Oommen K, Diamond MP. Altered expressions of VEGF mRNA splice variants during progression of uterine-peritoneal adhesions in the rat.  Am J Reprod Immunol. 2000;  43 299-304
• 22 Salmi M, Jalkanen S. Human leukocyte subpopulations from inflamed gut bind to joint vasculature using distinct sets of adhesion molecules.  J Immunol. 2001;  166 4650-4657
• 23 Takahashi I, Kiyono H. Gut as the largest immunologic tissue.  JPEN. 1999;  23 S7-S12
• 24 Uguralp S, Akin M, Karabulut A. et al . Reduction of peritoneal adhesions by sustained and local administration of epidermal growth factor.  Pediatr Surg Int. 2008;  24 191-197
• 25 Van Der Krabben AA, Dijkstra FR, Nieuwenhuijzen M. et al . Morbidity and mortality of inadvertent enterotomy during adhesiotomy.  Br J Surg. 2000;  87 467-471
• 26 Wagoner LE, Merrill W, Jacobs J. et al . Angiogenesis protein therapy with human fibroblast growth factor (FGF-1): Results of a phase I open label.  Circulation. 2007;  116 443-446
• 27 Williams RS, Rossi AM, Chegini N. et al . Effect of transforming growth factor beta on postoperative adhesion formation and intact peritoneum.  J Surg Res. 1992;  52 65-70
• 28 Williams SG, Buscarini M, Stein JP. Molecular markers for diagnosis, staging, and prognosis of bladder Cancer.  Oncology. 2001;  15 1461-1484
• 29 Xu W, Niu A, Li Zh. et al . Effect of pingyangmycin emulsion on the microenvironment of infantile proliferating capillary hemangioma.  World J Pediatr. 2006;  3 217-222
• 30 Xu X, Rivkind A, Pappo O. et al . Role of mast cells and myofibroblasts in human peritoneal adhesion formation.  Ann Surg. 2002;  236 593-601
• 31 Zhenchevskii RA, Gumilevskaia EM. Pathogenesis of chronic productive peritonitis.  Vestn Khir Im I I Grek.. 1986;  136 ((5)) 24-28

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