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i n t e r n a t i o n a l j o u r n a l o f s u r g e r y 6 ( 2 0 0 8 ) 4 0 – 4 4 Effect of mesalamine on healing in experimental colonanastomosis: A randomised experimental study Ahmet AslanMuhyittin TemizSibel HakverdiGurbuz Cemil Tumer,Abdulkerim TemiElif Canbolant aMustafa Kemal University, Faculty of Medicine, Department of General Surgery, Antakya-Hatay, TurkeybMersin University, Faculty of Medicine, Department of Biochemistry, Mersin, TurkeycMustafa Kemal University, Faculty of Medicine, Department of Pathology, Antakya-Hatay, Turkey Objective: We aimed to investigate the effect of mesalamine on healing of experimental colon anastomosis model.
Material/Methods: Forty adult male Wistar albino rats were performed segmentary colonicresection and end-to-end anastomosis. Animals were randomly divided into four groups: group I, anastomosis group, received no treatment (GI, n ¼ 8); group II, anastomosis þ oral mesalamine group (100 mg/kg/day); group III, anastomosis þ rectal mesalamine (2 mL) group, (GIII, n ¼ 8); group IV, anastomosis þ oral mesalamine þ rectal mesalamine (GIV, n ¼ 8) group. A sham group (n ¼ 8) was constituted and was performed laparotomy. Bursting pressure, hydroxyproline levels and histopathological characteristics of the anastomosis were analyzed.
Results: Although it was not statistically significant, there was an increase in the burst pres-sure of the mesalamine group. When hydroxyproline measurements were compared therewere statistically significant difference between the non-treated colon and all groups.
There were significant differences between GI and GIII–GIV, GII and GIV. The differencesbetween group I and II and group II and III were not statistically significant.
When we compared the median amount of the histopathological changes, we found signifi-cant difference between the anastomosis and the mesalamine groups (P < 0.05). But when me-salamine groups were compared with each other we did not observe a significant difference.
Conclusion: Mesalamine had positive effects which were not statistically significant onbursting pressure and statistically different significant effects on hydroxyproline (HP)levels based on the way of administration and statistically significant positive effects onhistopathologic anastomotic healing in experimental anastomosis model ª 2007 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
the field of general surgery. Although these operations aregenerally safe, leakage of the anastomosis is a serious compli- Colonic resection and subsequent anastomosis due to various cation and may even result in death.Factors reported to reasons are among the most widely performed operations in effect healing and integrity of the intestinal anastomosis are * Corresponding author. Tel.: þ90 326 214 06 49, 090532 6621100 (mobile); fax: þ90 326 214 49 77.
E-mail addresses: (A. Aslan), (M. Temiz), (S.
Hakverdi), (G. Polat), (C. Tumer), (A. Temiz), (E.
1743-9191/$ – see front matter ª 2007 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.ijsu.2007.09.003 i n t e r n a t i o n a l j o u r n a l o f s u r g e r y 6 ( 2 0 0 8 ) 4 0 – 4 4 blood supply, anastomotic technique and meticulous proce- The animals were randomly assigned into four groups: dure, colonic bacteria, inflammation, age, nutritional status, group I, anastomosis, received no treatment (GI, n ¼ 8); group associated disease, and Inadequate blood supply, bac- II, anastomosis þ oral mesalamine (100 mg/kg/day, Salofalk; terial count of colon, inflammation, technical errors, age, Ali Raif, Istanbul, Turkey); group III, anastomosis þ rectal nutritional status, associated diseases, and drugs such as mesalamine (Salofalk; Ali Raif, Istanbul, Turkey), 2 mL once chemotherapeutics, octreotide, suramine, irradiation, and a day via enema, (GIII, n ¼ 8); group IV, anastomosis þ oral dexamethasone impair the wound healing process.
mesalamine þ rectal mesalamine (GIV, n ¼ 8). Rats were killed 5-Aminosalicylic acid (5-ASA), sulfasalazine and mesal- by intracardiac puncture while under anesthesia at seventh amine, have been used for over 50 years, but the mechanisms postoperative day. Researchers were all blinded to the ran- of action of 5-ASA have remained elusive. 5-ASA compounds are capable of multiple effects that may protect the colon To assess the mechanical strength of the anastomosis, one from an inflammation-mediated damage. 5-ASA has been end of the excised segment was sealed with a suture. The free demonstrated to scavenge free radicals inhibit end was then catheterized with a polyurethane tube (2 mm leukotriene productioninhibit the chemotactic response to outer diameter), and a stay suture was tied circumferentially, leukotriene B4 (LTB4and inhibit cellular release of interleu- incorporating both tissue and tube to prevent air leakage. The kin-1 (IL-1) in cultured mucosal biopsy specimens from ulcera- external end of the tube was connected to an infusion pump tive colitis patientsDirect application of mesalamine via and a mercury manometer by way of a Y-shaped adapter.
enema or suppository is also effective in patients with distal The colon segment was then placed in a saline-filled container, colitis. The aim of topical treatment is to provide maximal mu- and air was pumped into the tube at a rate of 5 mL/min. The cosal anti-inflammatory effect and to decrease drug related side blood pressure reading at the instant the pressure decreased effects by minimal systemic effect. Rectal usage of mesalamine suddenly (caused by bursting of the anastomosis), or when is effective along the distal colon to level of splenic flexura bubbles were seen, was recorded as the ‘‘bursting pressure.’’ To date the effects of mesalamine on healing of colonic After measuring BP, a 5 mm-wide ring of tissue, including the anastomosis, was removed. Half of this removed tissue investigated the effects of mesalamine on the healing of was wrapped in aluminum foil and preserved at À20 C for later measurement of HP amount at the anastomosis site.
The other half was stored in 10% formaldehyde for later as-sessment of histopathologic features. When brought to room temperature, samples dry weights were recorded and, succes-sively, the amount of hydroxyproline was determined as de- Forty adult male Wistar albino rats, weighing between 260 and scribed previouslAbsorbance was read by a Shimadzu 290 g were used. The animals were acclimatized for 1 week to spectrophotometer (UV-120 À 02; Kyoto, Japan), and the colla- our laboratory conditions prior to experimental manipulation.
gen concentration was expressed as micrograms of hydroxy- They had free access to standard laboratory chow and water proline per gram of dry weight tissue. For histopathological ad libitum. The protocol of this study and animal experimen- assessment the tissues that were fixed in 10% formaldehyde tal procedures were approved by the Ethical committee of were stained with hematoxylin and eosin and were evaluated Mustafa Kemal University School of Veterinary.
at Â20 to Â200 magnification under the light microscope. The All of the animals were fasted overnight before surgery.
healing parameters and inflammatory changes, granulocytic Anesthesia was achieved with intra-peritoneal injection of cell infiltration, mononuclear cell infiltration, fibroblastic cell 10 mg/kg xylazine (Rompun; Bayer, Istanbul, Turkey) and infiltration, necrosis, exudate, and capillary formation were 50 mg/kg ketamine hydrochloride (Ketalar; Parke-Davis, Istan- assessed semiquantitatively by assigning a score of 0–3 to bul, Turkey). The surgical procedures were performed using each tissue specimen. Peritonitis was scored as being present clean and sterile instruments. Ten percentage of povidone- iodine solution was used for the disinfection of the skin. Afterplacing sterile drapes, a 3 cm midline incision was made.
Upon entering the abdominal cavity, the sigmoid colon wasidentified and the colon divided exactly 3 cm from the perito- The results were expressed as the mean Æ SEM. Differences neal reflection while preserving the vascular arcades. This among the groups were evaluated using one-way analysis of resected specimen was preserved at À20 C for later determi- variance (ANOVA), and multiple comparisons between the nation of the HP concentration in normal colon tissue. The groups were performed with a post-hoc test (Tukey’s HSD free ends of the colon inside the abdomen were anastomosed test). Differences were considered statistically significant with a single layer of interrupted inverting 6/0 polypropylene when P < 0.05. Data were analyzed by a statistical software sutures (Prolene; Ethicon, Scotland, United Kingdom) placed (SPSS for Windows 11.5; SPSS, Chicago, IL, USA).
1 mm apart. The fascia and skin layers were closed separatelywith running 4/0 silk sutures (Mersilk; Ethicon). To prevent de-hydration, 10 mL of 0.9% NaCl was administered subcutane- ously during the operation. All operative procedures wereperformed by the same investigator. Each animal was given In the GI anastomos group, one rat died on the fifth day of the free access to chow and water the morning after the study due to peritonitis caused by leakage from the anastomo- sis. The mean bursting pressures are shown in i n t e r n a t i o n a l j o u r n a l o f s u r g e r y 6 ( 2 0 0 8 ) 4 0 – 4 4 Table 1 – Bursting pressure measurements of theanastomoses Although it was not statistically significant, there was an in- crease in the burst pressures of the mesalamine group.
When hydroxyproline measurements were compared as in there were statistically significant difference betweenthe sham and all groups. There were significant differences between GI (anastomosis) and GIII–GIV (0.025 versus 0.00, re-spectively), GII and GIV (0.03). The differences between groupI and II and group II and III were not statistically significant.
Inflammatory changes such as mononuclear cell infiltra- tion, fibroblastic cell infiltration, epithelisation and capillary formation were evaluated as favourable changes while granu- locytic cell infiltration, necrosis and exudate formation were unfavourable. When we compared the median amount of the Fig. 1 – Hydroxyproline measurements according to histopathologic changes we found significant difference be- tween the anastomosis and the mesalamine groups (P < 0.05).
But when mesalamine groups were compared with each other xanthine oxidase may increase collagenolysis in the perianas- we did not observe a significant difference ( tomotic area, which delays wound healingIn our study weevaluated the histopathologic differences between groupsand we found more histologic findings favoring healing in the mesalamine groups in contrast to anastomosis group.
When we compare the mesalamine groups with each other Anastomotic healing is effected by the degree of primary we did not observe a significant difference.
inflammatory response; the rate of mucosal reepithelization; The precise mechanism of action of mesalamine is not the amount, strength, and maturation rate of new collagen; clear, but is likely due to a combination of anti-inflammatory and collagenolysis in the initial 3 days of the postanastomotic properties. Mesalamine has been shown to block the produc- period. Strength of an anastomosis is based on the collagen fi- tion of interleukin-1 (IL-1) and tumor necrosis factor-a bers and their maturation at the submucSynthesis of (TNF-a). Sulfasalazine has also been found to inhibit binding collagen is maximized in 5–7 days by proliferation of colla- of TNF-a to its receptor, thereby preventing signaling of subse- quent inflammatory Mesalamine is a potent When an anastomosis is constructed in the gastrointesti- inhibitor of the cyclooxygenase pathway, inhibiting the pro- nal tract, an inflammation occurs as a response to traumatic duction of prostaglandin E2 in inflamed intestinal specimens.
injury and foreign material such as sutures.This inflam- Its efficacy as an anti-inflammatory agent is also thought to be mation is a normal constituent of wound healing. If it is exag- due to effects on leukotrienes metabolism. Mesalamine is also gerated, however, wound healing is delayed because of one of the most potent known free radical scavengers and an- increased collagenolysis; this is why anastomotic healing is tioxidants.Many of the effects of 5-ASA may also be delayed in the presence of intra-abdominal explained by inhibition of activation of nuclear factor-kB The anastomotic area is already inflamed, and the endothe- (NF-kB), a central transcription regulatory factor involved in lium in the perianastomotic area is already activated during mediating the initiation and perpetuation of inflammatory the early phase of wound As a result of proinflam- processes. Activated NF-kB has been detected in macrophages matory and chemoattractant properties of the anastomosis, and epithelial cells in inflamed mucosa from Crohn’s disease activated circulating PMN leukocytes secondary to sepsis- and ulcerative colitis. Mesalamine has been demonstrated to induced injury may accumulate easily in the perianastomotic inhibit TNF-a stimulated NF-kB activation, NF-kB nuclear area, increase the inflammatory reaction, and delay healing.
translocation, and degradation of inhibitory kBa (IkBa).
Together with the proteolytic enzymes, oxygen-free radicals Mesalamine might also have some other subcelluler mecha- derived from activated PMN leukocytes and circulating nisms of action such as changing levels of mucosal and i n t e r n a t i o n a l j o u r n a l o f s u r g e r y 6 ( 2 0 0 8 ) 4 0 – 4 4 Table 3 – Histopathologic characteristics of the groups submucosal matrix metalloproteinases (MMP). It has been and statistically different significant effects on HP levels based shown that disturbances of the extracellular matrix play on the way of administration and statistically significant pos- a role in the pathogenesis of anastomotic leakage and that sig- itive effects on histopathologic anastomotic healing in exper- nificantly higher expressions of MMP occurred in the bowel wall of the leakage groups in studies.Whether mesalamineshowed its anti-inflammatory effect via changing levels of MMP is a potential future direction of this study.
The authors have no conflict of interest.
Collagen is important during all phases of wound healing and is critical for the return of tissue integrity and strength.
In this study, we determined the HP content in the anasto- motic tissue by means of a parameter of collagen synthesisand wound healing and observed that HP levels were increased significantly in the mesalamine group when com- Ethical committee of Mustafa Kemal University of Veterinary.
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