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      Inhibition of cyclooxygenase-2 prevents intra-abdominal adhesions by decreasing activity of peritoneal fibroblasts

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          Abstract

          Background

          Postoperative intra-abdominal adhesions are common complications after abdominal surgery. The exact molecular mechanisms that are responsible for these complications remain unclear, and there are no effective methods for preventing adhesion formation or reformation. The aim of the study reported here was to investigate the preventive effects and underlying potential molecular mechanisms of selective cyclooxygenase-2 (COX-2) inhibitors in a rodent model of postoperative intra-abdominal adhesions.

          Materials and methods

          The expression of COX-2 in postoperative intra-abdominal adhe-sions and normal peritoneal tissue was examined by immunohistochemistry and Western blot analysis. Assays were performed to elucidate the effect of COX-2 inhibition on hypoxia-induced fibroblast activity in vitro and on intra-abdominal adhesion formation in vivo.

          Results

          Hypoxia-induced COX-2 expression in peritoneal fibroblasts was increased in postoperative intra-abdominal adhesions. Inhibition of COX-2 attenuated the activating effect of hypoxia on normal peritoneal fibroblasts in vitro. Data indicate that selective COX-2 inhibitor prevents in vivo intra-abdominal adhesion by inhibition of basic fibroblast growth factor and transforming growth factor-beta expression, but not through an antiangiogenic mechanism. Furthermore, using selective COX-2 inhibitors to prevent intra-abdominal adhesions did not adversely affect the weight, bowel motility, or healing of intestinal anastomoses in a rat model.

          Conclusion

          These results show that hypoxia-induced COX-2 expression in peritoneal fibroblasts is involved in the formation of intra-abdominal adhesions. Inhibition of COX-2 prevents postoperative intra-abdominal adhesions through suppression of inflammatory cytokines.

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          Most cited references 34

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          Burden of adhesions in abdominal and pelvic surgery: systematic review and met-analysis

          Objective To estimate the disease burden of the most important complications of postoperative abdominal adhesions: small bowel obstruction, difficulties at reoperation, infertility, and chronic pain. Design Systematic review and meta-analyses. Data sources Searches of PubMed, Embase, and Central, from January 1990 to December 2012, without restrictions to publication status or language. Study selection All types of studies reporting on the incidence of adhesion related complications were considered. Data extraction and analysis The primary outcome was the incidence of adhesive small bowel obstruction in patients with a history of abdominal surgery. Secondary outcomes were the incidence of small bowel obstruction by any cause, difference in operative time, enterotomy during adhesiolysis, and pregnancy rate after abdominal surgery. Subgroup and sensitivity analyses were done to study the robustness of the results. A random effects model was used to account for heterogeneity between studies. Results We identified 196 eligible papers. Heterogeneity was considerable for almost all meta-analyses. The origin of heterogeneity could not be explained by study design, study quality, publication date, anatomical site of operation, or operative technique. The incidence of small bowel obstruction by any cause after abdominal surgery was 9% (95% confidence interval 7% to 10%; I2=99%). the incidence of adhesive small bowel obstruction was 2% (2% to 3%; I2=93%); presence of adhesions was generally confirmed by emergent reoperation. In patients with a known cause of small bowel obstruction, adhesions were the single most common cause (56%, 49% to 64%; I2=96%). Operative time was prolonged by 15 minutes (95% confidence interval 9.3 to 21.1 minutes; I2=85%) in patients with previous surgery. Use of adhesiolysis resulted in a 6% (4% to 8%; I2=89%) incidence of iatrogenic bowel injury. The pregnancy rate after colorectal surgery in patients with inflammatory bowel disease was 50% (37% to 63%; I2=94%), which was significantly lower than the pregnancy rate in medically treated patients (82%, 70% to 94%; I2=97%). Conclusions This review provides detailed and systematically analysed knowledge of the disease burden of adhesions. Complications of postoperative adhesion formation are frequent, have a large negative effect on patients’ health, and increase workload in clinical practice. The quantitative effects should be interpreted with caution owing to large heterogeneity. Registration The review protocol was registered through PROSPERO (CRD42012003180).
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            Pathophysiology and prevention of postoperative peritoneal adhesions.

            Peritoneal adhesions represent an important clinical challenge in gastrointestinal surgery. Peritoneal adhesions are a consequence of peritoneal irritation by infection or surgical trauma, and may be considered as the pathological part of healing following any peritoneal injury, particularly due to abdominal surgery. The balance between fibrin deposition and degradation is critical in determining normal peritoneal healing or adhesion formation. Postoperative peritoneal adhesions are a major cause of morbidity resulting in multiple complications, many of which may manifest several years after the initial surgical procedure. In addition to acute small bowel obstruction, peritoneal adhesions may cause pelvic or abdominal pain, and infertility. In this paper, the authors reviewed the epidemiology, pathogenesis and various prevention strategies of adhesion formation, using Medline and PubMed search. Several preventive agents against postoperative peritoneal adhesions have been investigated. Their role aims in activating fibrinolysis, hampering coagulation, diminishing the inflammatory response, inhibiting collagen synthesis or creating a barrier between adjacent wound surfaces. Their results are encouraging but most of them are contradictory and achieved mostly in animal model. Until additional findings from future clinical researches, only a meticulous surgery can be recommended to reduce unnecessary morbidity and mortality rates from these untoward effects of surgery. In the current state of knowledge, pre-clinical or clinical studies are still necessary to evaluate the effectiveness of the several proposed prevention strategies of postoperative peritoneal adhesions.
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              SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway.

              In our previous study, we found that blockade of SDF-1/CXCR4 signaling inhibits pancreatic cancer cell migration and invasion in vitro. However, the mechanism governing the downstream regulation of SDF-1/CXCR4-mediated invasion remains unclear. Here we report the role of SDF-1/CXCR4 in pancreatic cancer and the possible mechanism of SDF-1/CXCR4-mediated pancreatic cancer invasion. We show that there is a cross-talk between SDF-1/CXCR4 axis and non-canonical Hedgehog (Hh) pathway in pancreatic cancer. Furthermore, our data demonstrate that the ligand of CXCR4, SDF-1 induces CXCR4-positive pancreatic cancer invasion, epithelial-mesenchymal transition (EMT) process and activates the non-canonical Hh pathway. Moreover, we also demonstrate that the invasion of a pancreatic cancer and EMT resulting from the activation of SDF-1/CXCR4 axis is effectively inhibited by Smoothened (SMO) inhibitor cyclopamine and siRNA specific to Gli-1. Collectively, these data demonstrate that SDF-1/CXCR4 modulates the non-canonical Hh pathway by increasing the transcription of SMO in a ligand-independent manner. Taken together, SDF-1/CXCR4 axis may represent a promising therapeutic target to prevent pancreatic cancer progression. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2015
                15 June 2015
                : 9
                : 3083-3098
                Affiliations
                [1 ]Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, People’s Republic of China
                [2 ]Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, Xi’an, People’s Republic of China
                [3 ]Department of General Surgery, First People’s Hospital of Xianyang City, Xianyang, People’s Republic of China
                Author notes
                Correspondence: Xuqi Li, Department of General Surgery, First Affiliated Hospital of Xi’an Jiaotong University College of Medicine, 277 West Yanta Road, Xi’an, Shaanxi 710061, People’s Republic of China, Tel +86 29 8532 3899, Fax +86 29 8532 3899, Email lixuqi@ 123456163.com
                Article
                dddt-9-3083
                10.2147/DDDT.S80221
                4474398
                © 2015 Wei et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License

                The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                postoperative adhesions, cox-2, hypoxia, cox-2 inhibitors

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