Simvastatin Improves Wound Strength after Intestinal Anastomosis in the Rat

Background  Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor commonly known as a cholesterol-lowering drug with additional pleiotropic effects. Also, it is demonstrated that it prevents postoperative peritoneal adhesions in rat. This study was designed to assess its effects on the healing process of colonic anastomosis. Methods  Thirty-two male Wistar albino rats were randomized into two groups and subjected to colonic anastomosis. The study group was treated with simvastatin and the control group received only tap water instead. The rats were killed 3 and 7 days postoperatively. Wound complications, intra-abdominal abscesses, and anastomotic leaks and stenosis were recorded. Four types of assessment were performed: bursting pressure, hydroxyproline content, histopathology, and biochemical analysis. Results  Compared to the control group, simvastatin-treated rats displayed a higher bursting pressure (p < 0.001) and anastomotic hydroxyproline content (p < 0.05). Simvastatin treatment leads to a significant decrease in malondealdehyde levels (p < 0.05) and increase in paraoxonase activity (p < 0.001) at both time points. Histopathological analysis revealed that simvastatin administration leads to a better anastomotic healing in terms of reepithelialization, decreased granuloma formation, reduced ischemic necrosis, and inflammatory infiltration to muscle layer. Conclusion  Clinically relevant doses of simvastatin do not have a negative impact on colonic anastomosis but improve intestinal wound healing in rats. Oral presentation at the “Turkish National Surgery Congress”, Antalya, Turkey, May 2008.     

The Pig as an Experimental Model for Colonic Healing Study of Leakage and Ischemia in Colonic Anastomosis

Background: The object of this experimental study was to develop a model of anastomotic failure due to primary leakage and ischemia in porcine large bowel anastomosis. Methods: End-to-end anastomosis was constructed at descending colon in 12 pigs. The pigs were randomly divided into three groups. In Group A, the anastomosis was applied with a leak of 18 mm. In Group B, in addition to primary leakage, an artificial ischemia of the proximal anastomotic bowel segment was created by ligation of supplying vessels over 5 cm. In Group C, an artificial ischemia was created in the same manner at the proximal and distal anastomotic segment and the anastomosis was applied with an intentional leakage as in Groups A and B. The animals were sacrificed immediately in case of clinical signs of anastomotic dehiscence, sepsis, peritonitis, or ileus. The animals were sacrificed on day 28. The peritoneal cavity was examined for peritonitis, anastomotic wound dehiscence, and pericolic abscess formation. Results: Distinct fibrinous coverings and adhesions at the anastomotic area were found in all animals. In cases of primary leakage without ischemia, only one of the four animals developed abscess at anastomotic side with clinical sepsis. In cases of primary leakage with ischemia of the proximal anastomotic bowel segment, one of the four animals presented generalized peritonitis with sepsis. In Group C, there were no signs of leakage or peritonitis, although three of the four animals developed colonic ileus due to obturation of the colonic lumen by a clot of necrotic bowel wall. Conclusion: Large anastomotic dehiscence and local ischemia of the bowel wall are not reliable factors for the development of intra-abdominal abscess, peritonitis, or sepsis in the pig model.     

The Effect of Exogenous Melatonin on Experimental Colonic Anastomosis

In this study we investigated the role of exogenous melatonin administration on the healing of colonic anastomoses.

Materials and methods: Rats were divided into four groups: control, vehicle, 1 mg/kg and 10 mg/kg melatonin, which was administered postoperatively on days 0, 1, and 2. Following colon resection and anastomosis, the rats were sacrificed on the 3^rd and 7^th days to measure bursting pressure and hydroxyproline content of the anastomoses. Results: Bursting pressure significantly increased on the 7^th day compared with the 3^rd day in all groups. Hydroxyproline levels did not show any significant change on the 3^rd day compared with the 7^th day in any of the groups. Hydroxyproline levels were significantly higher in control groups than in melatonin groups.

Conclusion: Results suggest that exogenous melatonin has no beneficial effect on the healing of colonic anastomosis.     

砂仁对大鼠小肠吻合口愈合的影响

目的：探讨砂仁对大鼠小肠吻合口愈合的影响。方法：90只SD大鼠,随机分为模型组、砂仁组和普鲁本辛组,每组30只,均行小肠端端吻合。砂仁组在造模后灌胃给予砂仁溶液（按生药计,0.25g/kg）,普鲁本辛组在造模后灌胃给予普鲁本辛（3.5mg/kg）溶液。术后3、5、7d观察小肠吻合口病理学改变、吻合口爆破压、羟脯氨酸含量 术后7d测量小肠系膜微静脉血流流速。结果：砂仁组吻合口局部炎症轻于其他两组,胶原纤维排列较好 术后5,7d吻合口羟脯氨酸、爆破压高于模型组和普鲁本辛组（P〈0.05） 术后7d肠系膜微静脉血流流速高于模型组和普鲁本辛组（P〈0.05）。结论：砂仁口服能够促进大鼠小肠吻合口的愈合。     

Stable Gastric Pentadecapeptide BPC 157 in Trials for Inflammatory Bowel Disease (PL-10, PLD-116, PL14736, Pliva, Croatia) Heals Ileoileal Anastomosis in the Rat

Purpose Gastric pentadecapeptide BPC 157 (BPC 157), which has been shown to be safe in clinical trials for inflammatory bowel disease (PL-10, PLD-116, PL14736, Pliva, Croatia), may be able to cure intestinal anastomosis dehiscence. This antiulcer peptide shows no toxicity, is limit test negative, and a lethal dose is not achieved. It is stable in human gastric juice. In comparison with other standard treatments it is more effective for ulcers and various wounds, and can be used without a carrier needed for other peptides, both locally and systemically (i.e., perorally, parenterally). We studied the effectiveness of BPC 157 for ileoileal anastomosis healing in rats. Methods We assessed ileoileal anastomosis dehiscence macroscopically, histologically, and biomechanically (volume [ml] infused through a syringe-perfusion pump system (1 ml/10 s), and pressure [mmHg] to leak induction [catheter connected to a chamber and a monitor, at 10 cm proximal to anastomosis]), at 1, 2, 3, 4, 5, 6, 7, and 14 days. BPC 157 (10 μg, 10 ng, 10 pg/kg i.p. (or saline [5 ml/kg]) was first administered after surgery, while it was last given 24 h before either assessment or sacrifice. Results Throughout the experiment, both higher doses of BPC 157 were shown to improve all parameters of anastomotic wound healing. The formation of adhesions remained slight, the blood vessels were filled with blood, and a mild intestinal passage obstruction was only temporarily observed. Anastomosis without leakage induces markedly higher volume and pressure values, with a continuous increase toward healthy values. From day 1, edema was markedly attenuated and the number of granulocytes decreased, while from days 4 or 5 necrosis decreased and granulation tissue, reticulin, and collagen formation substantially increased, thus resulting in increased epithelization. Conclusion This study showed BPC 157 to have a beneficial effect on ileoileal anastomosis healing in the rat.     

Influence of Hydroxyethyl Starch on Healing of Colonic Anastomosis in a Rat Model of Peritonitis

Background: This study was designed to evaluate the role of different intravascular volume replacement regimens of HES 130/0.4 on wound healing process in left colonic anastomoses in the presence of intra-abdominal sepsis induced by murine model of cecal ligation and puncture (CLP). Methods: The left colonic anastomosis was performed in 40 rats that were divided into five groups (n = 8/group): saline controls (30 ml/kg); CLP plus saline (30 ml/kg); CLP plus HES (7.5, 15, or 30 ml/kg, respectively). Saline or HES was treated before the construction of left colonic anastomosis and on a regular daily basis. Anastomotic bursting pressures were measured in vivo on day 5. Tissue samples were obtained for analyses of hydroxyproline (HP) contents, myeloperoxidase (MPO) acivity, malondialdehyde (MDA), reduced glutathione (GSH) levels, and nuclear factor-κ B (NF-κ B) activation. The plasma levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were also measured. Results: Intra-abdominal sepsis led to significant decreases in colonic anastomotic bursting pressures, and perianastomotic tissue HP contents and GSH levels, along with increases in perianastomotic tissue MPO activity, MDA levels and NF-κ B activation and plasma levels of TNF-α and IL-6. After treated with HES, these provoked perianastomotic tissue MPO activity, MDA levels, NF-κ B activation, and plasma levels of TNF-α and IL-6 were suppressed and GSH levels were restored, especially in 15 ml/kg HES group. Without obvious influence on systemic nutritional condition, HES 15 ml/kg but not HES 7.5 ml/kg significantly increased anastomotic bursting pressures, and perianastomotic tissue HP contents. However, HES 30 ml/kg even led to adverse effects on anastomotic bursting pressures. Conclusions: This study showed that moderate doses (15 ml/kg) of HES 130/0.4 administration significantly prevented this intraperitoneal sepsis-induced impaired anastomotic healing of the left colon. It also suggested the possibility of poorer anastomotic healing receiving HES at higher doses (30 ml/kg). Clearly, HES 130/0.4 now should not be recommended to use at a high doses postoperatively in sepsis.     

大鼠肠系膜血管吻合式小肠移植模型建立及其意义

报告采用大鼠系膜血管吻合式小肠移植模型的制作方法,依此法共施小肠移植手术96只,模型稳定后的51只手术成功率达87.4%。该方法所建立大鼠自体移植模型不仅为利用远交系大鼠研究小肠移植免疫反应提供可靠的阴性对照,而且可做为移植小肠保存、缺血后再灌注损伤等多方面研究的较好模型。     

The Effects of Endothelin Receptor Blockade by Bosentan on the Healing of a Bowel Anastomosis in an Experimental Crohn’s Disease Model

Objective  It was previously described that endothelins may contribute to the pathogenesis of Crohn’s disease. In this study, it was aimed to investigate the effects of endothelin receptor blockade by bosentan on the healing of a bowel anastomosis in an experimental Crohn’s disease model. Material and Methods  Twenty-eight Sprague–Dawley rats were divided into four groups. Groups I and II were used as sham-operated and control groups, respectively. Bowel inflammation induced by intrajejunal injection of iodoacetamide in groups III and IV. Rats in group IV were treated with oral preparation of bosentan 60 mg/kg/day. Three days after induction of the inflammation, partial resection of test loop and anastomosis was performed. Re-laparotomy was performed, anastomosis bursting pressures and peritonitis scores were measured, and tissue samples were obtained for the measurements of tissue hydroxylproline level and mucosal damage index 4 days later. Results  The mean mucosal damage index and peritonitis score of group IV were significantly lower, and the mean tissue hydroxyproline level and anastomotic bursting pressure of group IV were significantly higher than those of group III. Conclusion  The blockade of endothelin receptors by bosentan decreases the severity of iodoacetamide induced intestinal inflammation, increases the wound healing in the inflamed intestinal tissue, and decreases the severity of peritonitis. This study was supported by The Coordination Committee of Scientific Researches and Projects of Fırat University.     

表皮生长因子对肠吻合口愈合影响的实验研究

目的　探讨重组人表皮生长因子 (rhEGF)对家兔小肠吻合口愈合的促进作用。方法　将 4 8只实验兔随机均分为实验组及对照组 ,均行近端小肠部分切除再吻合术 ,实验组动物于吻合时行rhEGF黏膜下注射。行外周血WBC计数 ,观察吻合口胶原纤维及羟脯氨酸的合成以及吻合口漏发生率。结果　两组术后 3d、5d及 7d与术前比较WBC略有升高 ,但差异无显著性意义 (P>0 .0 5 )。实验组吻合口漏发生率为 4 .3% ,而对照组为16 .7%。实验组术后 3d、5d及 7d胶原纤维面积密度较对照组明显增多 ,吻合口周围成纤维细胞明显增多 ,核大、浓染且胞浆丰富。实验组吻合口组织新生血管较多且有正常腺管结构 ,而对照组黏膜细胞结构破坏重。羟脯氨酸生成在术后 5d及 7d实验组与对照组相比差异有显著性意义 (P<0 .0 5 )。结论　炎症反应存在于创伤修复的全过程 ,但EGF局部应用对全身炎性反应的影响不大。rhEGF有促进创伤愈合、细胞向创面迁移的作用 ,使成纤维细胞增多 ,胶原纤维合成及转运加快 ,同时促进创面新生血管产生 ,可有效促进吻合口的愈合 ,防止吻合口漏的发生。     

Effect of Massive Small Bowel Resection on Gastric Acid Secretion in the Rat

The phenomenon of a transitory gastric acid hypersecretory state after extensive bowel resection is well established. Its time of onset, however, is unknown. The purpose of this study was to determine the immediate effect of massive small bowel resection (MSBR) on gastric acid secretion (GAS). An anesthetized innervated rat model was prepared with gastric and jugular cannulae. Three groups of animals were studied: group I (n = 12), basal unstimulated state; group II (n = 12). pentagastrin (Ps) 16 pg/kg h-¹ stimulated: and group III (n = 16), 5% liver extract meal (LEM) stimulated. Each group consisted of experimental animals that underwent 95% MSBR from proximal jejunum to terminal ileum and control animals that remained intact. Acid output was determined by extragastric titration with 0.1 M NaOH. Blood was taken for basal and postprandial serum gastrin levels. Basal acid output (peq/10 min) significantly increased immediately after MSBR in all groups (p <. 01). Ninety minutes following MSBR, acid outputs were significantly elevated in basal and Pg-stimulated but not LEM-stimulated rats. Serum gastrin increased from 30 ± 1 to 56 ± 6 pg/mL (p <. 01) in group I rats and from 81 ± 28 to 129 ± 13 pg/mL in group III rats (p = NS). We conclude that GAS increases immediately after MSBR in group I and II rats. This increase in GAS may be mediated by gastrin release.     

Effects of Hyperbaric Oxygen and Preconditioning on Wound Healing in Colonic Anastomoses

Aim: The purpose of this study was to evaluate the effects of hyperbaric oxygen (HBO) and HBO preconditioning (pre-HBO) on experimental wound healing and tensile strength in the colonic anastomosis of rats. Materials and Methods: A total of 21 Sprague–Dawley rats were divided into three random groups of equal numbers: sham operation, pre-HBO, and HBO. Sham group was given standard left colon resection and end-to-end anastomosis; pre-HBO group received HBO as one dose + colonic resection + anastomosis; HBO group was given colonic resection + anastomosis + HBO. HBO was administrated at 24-hr intervals and relaparatomy was performed on the fifth day. Malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), interleukin (IL)-10, IL-6, tumor necrosis factor-alpha (TNF-α), and hydroxy (OH)-proline levels and anastomotic burst pressure were evaluated. Results: Burst pressure and OH-proline levels markedly increased in the HBO group compared with the sham and pre-HBO groups. When compared with the sham group, MDA and MPO levels were significantly decreased in the HBO and pre-HBO groups. In contrast to these findings, SOD and GSH-Px levels were increased in the HBO group as compared with the sham and pre-HBO groups. TNF-α, IL-6, and IL-10 values were detected at low levels in the HBO group as compared with other groups. Conclusions: HBO administration accelerated wound healing and strengthened the anastomotic tissue. In the light of these results, the HBO administration has beneficial effects and contributed to wound healing in colonic anastomosis. But, as expected, pre-HBO did not alter the results significantly.     

The Effects of Resveratrol on the Healing of Left Colonic Anastomosis

Introduction: Resveratrol (RSV) is a natural polyphenolic compound found in grape skins and the red wine which improves histological reorganization of the regenerating tissue in dermal wound healing. Since anastomotic healing possesses paramount importance to prevent complications in colorectal surgery, the present study is aimed to evaluate the effect of RSV on the healing of experimental left colonic anastomoses. Methods: Thirty-two male Wistar albino rats were randomized into two groups and subjected to colonic anastomosis. The study group was treated with RSV and the control group received tap water instead. The rats were sacrificed 3 and 7 days postoperatively. Wound complications, intra-abdominal abscesses, and anastomotic leaks and stenosis were recorded. Four types of assessment were performed: bursting pressure, hydroxyproline (OHP) content, histopathology, and biochemical analysis. Results: Compared to the control group, the RSV-treated rats displayed a higher bursting pressure (p <. 001) and anastomotic OHP content (p <. 05)]. RSV treatment leads to significant increase in PON activity at both time points and decrease in malondialdehyde levels on postoperative day 3 (p <. 001). Histopathological analysis revealed that RSV administration leads to a better anastomotic healing in terms of mucosal ischemia, neovascularization, reepithelialization, fibroblast, and lymphocyte infiltration. Conclusion: The study results suggest that exogenous RSV administration exerts a positive effect on experimental colonic wound healing in the rat. Although the precise cellular mechanisms by which RSV enhances anastomotic wound healing is not clear, stimulation of neovascularization, generation of collagen synthesis, inhibition of overinflammation, and restriction of oxidative injury seems to be of paramount importance.     

Treatment with Chlorhexidine Modifies the Healing of Colon Anastomosis in Rats

ABSTRACT

Purpose: To investigate the effects of chlorhexidine on the healing of colon anastomosis in the presence of peritonitis. Methods: Peritonitis was induced in male Wistar rats by cecal ligation and puncture (CLP). The abdominal cavities of experimental animals were irrigated with warm solutions containing 0.9% saline (SAL group; n = 8) or 0.05% chlorhexidine (CHD group; n = 8), following which colon anastomosis was performed. Rats of the control group (n = 8) were submitted to colon anastomosis but not to CLP. Animals were euthanized seven days after surgery, and healing was assessed by histopathological examination and by measuring anastomotic burst pressure. Results: Post-operative survival rates were 100, 87.5 and 75% for the control, SAL, and CHD groups, respectively. The degree of inflammation was significantly lower (ρ = 0.01) in the CHD group compared with the other groups, whilst the anastomotic burst pressure within the CHD group (156.7 ± 53.2 mmHg) was lower than, but not significantly different from, those of the control and SAL groups (196.3 ± 49.8, 208.6 ± 72.7 mmHg, respectively). Conclusions: Peritoneal irrigation with chlorhexidine solution is effective in the control of inflammation promoted by peritonitis but does not improve healing of colon anastomosis in rats.     

The effect of remote ischemic preconditioning on healing of colonic anastomoses

BACKGROUND: We aimed to investigate the potential protective effect of remote ischemic preconditioning (IPC) on delayed colonic anastomotic healing induced by remote ischemia and reperfusion (I/R) injury. MATERIALS AND METHODS: Forty male Wistar rats were randomly assigned into four groups, each consisting of 10 rats: the control group (C), the remote I/R group [I/R, 40 min of superior mesenteric artery (SMA) occlusion], the preconditioned I/R group (IPC, two cycles of 5 min temporary occlusion of SMA before an ischemic insult of 40 min), and the preconditioned group (PC, two cycles of 5 min temporary occlusion of SMA). Colonic anastomosis was performed immediately after the ischemic insult. Anastomotic healing was assessed on postoperative day 7 by determining anastomotic bursting pressure (ABP), tissue hydroxyproline content, histopathological examination, malondialdehyde (MDA), and nitric oxide levels. RESULTS: Remote I/R injury resulted with significant impairment in anastomotic healing in terms of mean ABP (P = 0.004), hydroxyproline content (P = 0.002), histopathological healing score (P = 0.001), nitric oxide level (P = 0.010), and MDA levels (P = 0.0001) when compared with the control group, but remote IPC did not improve all above mentioned parameters (P = NS for all), except MDA level (P = 0.011) when compared with I/R group. PC alone impaired the ABP (P = 0.0001), but it did not significantly change the other parameters measured (P = NS). CONCLUSIONS: The results of this study showed that remote IPC did not prevent I/R-induced delaying in colonic anastomotic healing.     

The Effect of Platelet-Rich-Plasma on the Healing of Left Colonic Anastomosis in a Rat Model of Intra-Abdominal Sepsis

Objective: The aim of this study was to investigate the effect of platelet-rich plasma (PRP) on the healing of colonic anastomosis in the presence of sepsis. Materials and Method: Fifty Wistar-albino male rats were used. Ten healthy rats were euthanized to prepare PRP, the rest were subjected to colonic anastomosis and randomly allocated into four groups of 10 rats each as anastomosis without PRP (C), without PRP in sepsis (SC), anastomosis with PRP (C-PRP), and with PRP in sepsis (S-PRP). Sepsis was induced by cecal ligation and puncture procedure. All animals were euthanized on postoperative day 7. The body weight change, anastomotic bursting pressure (ABP), tissue hydroxyproline (TH) and histopathological examination of each group were analyzed by using one-way analysis of variance (ANOWA) and Tukey's HSD post-hoc test to assess the differences between the groups. Results: There was no statistical difference among the groups in terms of body weight changes. The ABP was measured at a mean value of 179.5 ± 10.3, 129.3 ± 14.2, 209 ± 14.4, and 167.5 ± 7.5 mm-Hg, in group C, SC, C-PRP, and S-PRP, respectively. The ABP and TH of C-PRP group was significantly higher than three groups (p < .05, for each comparison). In sepsis, PRP significantly raised the mean ABP and TH levels up to the levels of C group. Tissue regeneration was significant with increased collagen formation in C-PRP group than the other groups (p < .05). The healing effect of PRP in the presence of sepsis was significant than S-group (p < .05), while similar to C group (p = .181). Conclusion: PRP application to colonic anastomosis promotes the healing process in rats with intra-abdominal sepsis.     

Effect of Peritoneal Lavage with Taurolidine on Primary Colonic Anastomosis in a Rat Model of Secondary Peritonitis

Purpose The reported antibacterial, antiendotoxic, and antiadhesive effects of taurolidine prompted us to study the benefits of intraperitoneal lavage with taurolidine on primary colonic anastomosis in a rat model of secondary peritonitis. Methods We induced peritonitis in 40 rats by injecting Escherichia coli isolate intraperitoneally. We performed colonic resection and primary anastomosis 5 h later, after lavage with either taurolidine or saline solution. After the rats were killed, on postoperative day (POD) 3 (n = 10) or 7 (n = 10), we measured the bursting pressures and hydroxyproline levels, then examined the resected specimens histologically. Results Bursting pressures and tissue hydroxyproline levels were significantly higher in the taurolidine group than in the control group on PODs 3 and 7 (P < 0.05). Histopathological examination revealed significantly higher fibroblastic activity in the taurolidine group. Conclusions The higher bursting pressures and tissue hydroxyproline levels in the rats given taurolidine showed the positive effect of taurolidine on anastomotic strength in secondary peritonitis. Taurolidine is a novel antibiotic with both antibacterial and antiendotoxic effects. Intraperitoneal lavage with taurolidine solution may reduce the risks associated with performing primary colonic anastomosis in patients with secondary peritonitis.