Prevention of peritoneal adhesions:A promising role for gene therapy

Adhesions are the most frequent complication of abdominopelvic surgery,yet the extent of the problem,and its serious consequences,has not been adequately recognized.Adhesions evolved as a life-saving mecha-nism to limit the spread of intraperitoneal inflammatory conditions.Three different pathophysiological mechanisms can independently trigger adhesion formation.Mesothelial cell injury and loss during operations,tissue hypoxia and inflammation each promotes adhesion formation separately,and potentiate the effect of each other.Studies have repeatedly demonstrated that interruption of a single pathway does not completely prevent adhesion formation.This review summarizes the pathogenesis of adhesion formation and the results of single gene therapy interventions.It explores the prom-ising role of combinatorial gene therapy and vector modif ications for the prevention of adhesion formation in order to stimulate new ideas and encourage rapid advancements in this field.

Peritoneal adhesions after laparoscopic gastrointestinal surgery

Although laparoscopy has the potential to reduce peritoneal trauma and post-operative peritoneal adhesion formation, only one randomized controlled trial and a few comparative retrospective clinical studies have addressed this issue. Laparoscopy reduces de novo adhesion formation but has no efficacy in reducing adhesion reformation after adhesiolysis. Moreover, several studies have suggested that the reduction of de novo post-operative adhesions does not seem to have a significant clinical impact. Experimental data in animal models have suggested that CO2 pneumoperitoneum can cause acute peritoneal inflammation during laparoscopy depending on the insufflation pressure and the surgery duration. Broad peritoneal cavity protection by the insufflation of a low-temperature humidified gas mixture of CO2, N2O and O2 seems to represent the best approach for reducing peritoneal inflammation due to pneumoperitoneum. However, these experimental data have not had a significant impact on the modification of laparoscopic instrumentation. In contrast, surgeons should train themselves to perform laparoscopy quickly, and they should complete their learning curves before testing chemical anti-adhesive agents and anti-adhesion barriers. Chemical anti-adhesive agents have the potential to exert broad peritoneal cavity protection against adhesion formation, but when these agents are used alone, the concentrations needed to prevent adhesions are too high and could cause major post-operative side effects. Anti-adhesion barriers have been used mainly in open surgery, but some clinical data from laparoscopic surgeries are already available. Sprays, gels, and fluid barriers are easier to apply in laparoscopic surgery than solid barriers. Results have been encouraging with solid barriers, spray barriers, and gel barriers, but they have been ambiguous with fluid barriers. Moreover, when barriers have been used alone, the maximum protection against adhesion formation has been no greater than 60%. A recent small, randomized clinical trial suggested that the combination of broad peritoneal cavity protection with local application of a barrier could be almost 100% effective in preventing post-operative adhesion formation. Future studies should confirm the efficacy of this global strategy in preventing adhesion formation after laparoscopy by focusing on clinical end points, such as reduced incidences of bowel obstruction and abdominal pain and increased fertility.

Evaluation of the effectiveness of alginate-based hydrogels in preventing peritoneal adhesions

Infertility and intestinal blockage are just two examples of the postoperative consequences that can arise from peritoneal damage,which can also result in severe peritoneal fibrosis and peritoneal adhesions.Peritoneal adhesions are still not effectively treated,and both pharmaceutical therapy and biomaterial barriers have only had modest preventative effects.In this work,we looked into the effectiveness of in-place injectable sodium alginate hydrogel for peritoneal adhesion prevention.The findings demonstrated that sodium alginate hydrogel promoted human peritoneal mesothelial cell proliferation and migration,prevented peritoneal fibrosis by suppressing the production of transforming growth factor-β1,and,most importantly,promoted mesothelium self-repair.These findings imply that this brand-new sodium alginate hydrogel is a good candidate material for peritoneal adhesion prevention.

Preventive effects of chitosan on peritoneal adhesion in rats

AIM： To study the effects of chitosan gel and blending chiston/gelatin film on preventing peritoneal adhesion in rats. METHODS： SD rats were randomly divided into 2 groups, group A treated with chitosan gel and group B with blending chiston/gelatin film. In group A, rats were randomly subdivided into 3 subgroups as groups A1, A2 and A3, and different methods were used to induce peritoneal adhesions at the dead end of vermiform process in each group as follows： Group A1 with trauma, A2 with talc powder and A3 with ligation of blood vessel. In each subgroup, rats were redivided into control group and experimental group whose treated vermiform processes were respectively coated with chitosan gel and normal saline immediately after the adhesioninduced treatments. In group B, all the rats received traumatic adhesion-induced treatments and then were randomly divided into 4 groups （groups B1, B2, B3, B4）. Group B1 served as control group and were coated with normal saline in the vermiform processes immediately after the treatments, and groups B2, B3 and B4 with 100% chitosan film, chitosan film containing 10% gelatin and chiston film containing 50% gelatin, respectively. At 2 and 4 wk after the above treatments, half of the rats in each terminal group were belly opened, and the peritoneal adhesive situation was graded and histopathological changes were examined. RESULTS： （1） In group A, regarding peritoneal adhesion situation： At both 2 and 4 wk after the treatments, for groups A1 and A3, the adhesive grades of experimental groups were significantly lower than those of the control group （2 wk： H = 4.305, P 〈 0.05 for A1, H = 6.743, P 〈 0.01 for A3; 4 wk： H = 4.459, P 〈 0.05 for A1, H =4.493, P 〈 0.05 for A3）. However, of group A2, there was no significant difference between the experimental and control groups （2 wk： H = 0.147, P 〉 0.05; 4 wk： H = 1.240, P 〉 0.05）. Regarding pathological changes： In groups A1 and A3, the main pathological change was fibroplasia. In group A2, the main changes were massive foreign-body giant cell reaction and granuloma formation with fibroplasia of different degrees. （2） In group B, regarding degradation of film： With increase of the blended gelatin concentration, degrading speed of the film accelerated significantly. Regarding peritoneal adhesion situation： At both 2 and 4 wk after the treatments, the adhesive grades of B1 were the lowest among the four subgroups of B （2 wk： H = 29.679, P 〈 0.05; 4 wk： H = 18.791, P 〈 0.05）. At 2 wk after the treatments, the grades of group B2 were significantly lower than that of groups B3 and B4 （H = 4.025, P 〈 0.05 for B2 vs B3; H = 4.361, P 〈 0.05 for B2 vs B4）. At 4 wk, there were no significant differences of the grades between groups B2, B3 and B4. Regarding pathological changes： Inflammatory cell infiltration and fibroplastic proliferation were observed in the local treated serous membranes, which was the mildest in group B1. Slight foreign-body giant cell reactions were also found in groups B2, B3, and B4. CONCLUSION： （1） Chitosan gel has preventive effect on traumatic or ischemic peritoneal adhesion, but no obvious effect on foreign body-induced peritoneal adhesion. （2） Chitosan film may exacerbate the peritoneal adhesion. Blending with gelatin to chitosan film can accelerate the degradation of the film, but can simultaneously facilitate the formation of peritoneal adhesion.

Cytokine orchestration in post-operative peritoneal adhesion formation

Peritoneal adhesions are a near inevitable occurrence after laparotomy and a major cause of both patient and physician misery. To date, clinical attempts at their amelioration have concentrated on manipulating the physical factors that affect their development despite a wealth of experimental data elucidating the molecular mechanisms that underlie their initiation, development and maturation. However, the advent of targeted, specific anti-cytokine agents as directed therapy for inflammatory and neoplastic conditions raises the prospect of a new era for anti-adhesion strategies. To harness this potential will require considerable cross-disciplinary collaboration and that surgeon-scientists propel themselves to the forefront of this emerging fi eld.

Effect of Monocyte Chemotactic Protein-1 on the Intraperitoneal Adhesion Formation

In order to study the role of monocyte chemotactic protein-1 (MCP-1) in the intra-peri- toneal adhesion formation, 23 infertile patients undergoing laparoscopic operation were divided into two groups: experimental group including 12 patients with intra-peritoneal adhesion and control group including 11 patients without intra-peritoneal adhesion. Peritoneal fluid (PF) and peritoneum were collected from these patients during laparoscopic examination. The expression levels of MCP-1 protein and MCP-1 mRNA were detected by using enzyme-linked immunosorbent assay (ELISA) and dot blot analysis method respectively. It was found that the levels of MCP-l protein in PF of the patients with peritoneal adhesion were significantly higher than in the control group (0.44±0. 11 ng/ ml vs 0. 19±0.09 ng/ml respectively, P<0. 01). The level of MCP-l mRNA in the peritoneum of the patients with peritoneal adhesion was significantly higher than in the control group (48. 61±3. 72 vs 19.87±2.54 respectively, P<0. 01). It was suggested that MCP-1 might play a role in the adhe- sion formation, and chemotactic cytokines expressing in the peritoneal mesothelial cells might be take part in the process.

Identification of candidate biomarkers correlated with pathogenesis of postoperative peritoneal adhesion by using microarray analysis

BACKGROUND Postoperative peritoneal adhesion(PPA),characterized by abdominal pain,female infertility,and even bowel obstruction after surgery,has always been a major concern.The occurrence and formation of adhesion are from complex biological processes.However,the molecular mechanisms underlying the basis of microarray data profile,followed by peritoneal adhesion formation,are largely unknown.AIM To reveal the underlying pathogenesis of PPA at the molecular level.METHODS The gene expression profile was retrieved from the Gene Expression Omnibus database for our analysis.We identified a panel of key genes and related pathways involved in adhesion formation using bioinformatics analysis methods.We performed quantitative PCR and western blotting in vivo to validate the results preliminarily.RESULTS In total,446 expressed genes were altered in peritoneal adhesion.We found that several hub genes(e.g.,tumor necrosis factor,interleukin 1 beta,interleukin 6,CX-C motif chemokine ligand 1,C-X-C motif chemokine ligand 2)were marked as significant biomarkers.Functional analysis suggested that these genes were enriched in the Toll-like receptor signaling pathway.According to the Kyoto Encyclopedia of Genes and Genomes pathway and published studies,TLR4,myeloid differentiation primary response protein 88(MyD88),and nuclear factor kappa B(NF-κB)played essential roles in Toll-like signaling transduction.Here,we obtained a regulatory evidence chain of TLR4/MyD88/NF-κB/inflammatory cytokines/peritoneal adhesion involved in the pathogenesis of postoperative adhesion.The results of the microarray analysis were verified by the animal experiments.These findings may extend our understanding of the molecular mechanisms of PPA.CONCLUSION The regulatory evidence chain of TLR4/MyD88/NF-κB/inflammatory cytokines/peritoneal adhesion may play key roles in the pathogenesis of PPA.Future studies are required to validate our findings.

Experimental Observation on the Effects of Different Chitosan on Preventing Traumatic Peritoneal Adhesion in Rats

objective:The effects of different chitosan on preventing traumatic peritoneal adhesion in rats was studied in this paper. METHODS: 96 SD rats with injured vermiform process were randomly divided into 4 groups as follows: group A without any treatment as control, group B treated with chitosan gel, group C treated with pure chitosan film and group D treated with chiston film containing 50% gelatin. 2 and 4 weeks after surgery, 12 rats in each group were respectively belly opened to observe chitosan degradation and evaluate peritoneal adhesion, and the adhesive vermiform processes tissues were histopathologically observed. RESULTS: 1.Degradation in the group D was faster than that in the group C but slower than that in the group B. 2. 2 weeks after surgery the adhesion in the group B was milder than that in the control group(goup A) (P<0.05), but that in the group C and D (both P<0.05) were more severe than that in the control group . 3. 4 weeks after surgery , the adhesion in the group B was milder than that in the control group (P<0.05), but that in the group C and D (both P<0.05) were more severe than that in the control group , whereas, there was no significant difference between adhesion in the group C and group D (P>0.05). 4.Histopathological examinaiton indicated that: 2 weeks after surgery ,inflammatory cell infiltration and fibroplastic proliferation dominated in local lesion and the response was most severe on the serous coat, furthermore, the response in the control group was more severe than that in the group B, but milder than that in the group C and D; 4 weeks after surgery, fibroplastic proliferation dominated in local lesion in each group , moreover, the response in the control group was more severe than that in the group B but milder than that in the group C and D. What’s more, integrated fibrous membrane formed around implanted materials in the group C and D, and the fibrous membranes were thinner in the group C than that in the group D. CONCLUSION: 1.Chitosan gel has perfect effect in protecting traumatic peritoneal adhesion in rats. 2.Pure chitosan film could exacerbate peritoneal adhesion and chitosan containing gelatin could exacerbate peritoneal adhesion further.

Conservative management of chronic gastric volvulus:44 cases over 5 years

AIM:To investigate clinical outcomes of patients with chronic gastric volvulus(GV)who were managed conservatively over a 5-year period.METHODS:A total of 44 consecutive patients with chronic GV,as diagnosed by barium study between October 2002 and July 2008 were investigated.All of these patients received conservative management initially without anatomical correction.Their clinical manifestations,diagnostic work-ups,and clinical outcomes were analyzed.We sought to identify independent risk factors for poor outcome by using the Cox proportional hazards model.RESULTS:The enrolled patients were predominantly male(n=37,84%)and of advanced age(median: 71 years old,interquartile range:57.5-78 years).Abdominal pain and fullness were the most common presentations.During the follow-up period(median:16 mo,up to 69 mo),there was no severe complication,but symptomatic recurrence was noted in 28 patients(64%).Only one patient turned to elective surgery for frequent symptoms.Peritoneal adhesion was the only independent risk factor associated with recurrence(hazard ratio:2.58,95%CI:1.08-6.13,P=0.033).CONCLUSION:Symptomatic recurrence of chronic GV is very common although serious complications infrequently occur with conservative management.Peritoneal adhesion is independently associated with recurrence.

Umbilical displacement: a mini review

Background:Umbilical displacement is a known disorder in folk medicine of different cultures.The various causes,clinical signs and symptoms are attributed to this disorder and different diagnostic and therapeutic methods are mentioned.Methods:To follow the aim of the study,Persian medicine literature,Google Scholar,Google,PubMed,Scopus and Web of Science were searched with no limit of the publication date and the article type(original papers and literature reviews).The searched terms were Navel,Umbilicus and other synonyms in Persian,Turkish,Russian,German,Chinese and Indian language,Dislocation,Sliding,Displacement,Deviation,Falling,Ptosis,Folk medicine and combination of these words.We also corresponded with several experts in traditional medicine via LinkedIn.All available descriptive evidence related to umbilical displacement was retrieved,and the contents were presented as categories including the disorder name,attributed signs and symptoms,and the diagnostic and therapeutic methods.Results:This disorder is called“Taharok-e-Sorre”in Persian medicine,“Nawikkatin”in Erbil(Iraq),“Dharan or Nabhi Sarakna”in Hindi,“Göbek düşmesi”in Turkish,Bēn tún in Chinese and“Cirro”in the people of Mayan community and Spanish,and“смещенпупок”in the folk medicine of the Kurgan Bashqir.Hard work,pregnancy,childbirth,fear,lifting heavy objects,rapid and sudden movements,trauma or fall and slipping of the foot are said to be causes of umbilical displacement.Umbilical displacement is associated with several symptoms such as diarrhea,constipation,abdominal pain,anorexia,anxiety,and depression.Conclusion:In this mini-review,umbilical displacement was expressed from the viewpoint of different cultures.New cases of umbilical displacement has been reported in new articles,and the pathology of umbilical displacement has been explained from the perspective of Persian medicine.

Berberine prevents primary peritoneal adhesion and adhesion reformation by directly inhibiting TIMP-1

Peritoneal adhesions are fibrous tissues that tether organs to one another or to the peritoneal wall and represent the major cause of postsurgical morbidity.Enterolysis at repeat surgeries induces adhesion reformation that is more difficult to prevent than primary adhesion.Here we studied the preventive effects of different approaches of berberine treatment for primary adhesion,and its effects on adhesion reformation compared to Interceed.We found the primary adhesion was remarkably prevented by berberine through intraperitoneal injection 30 min before abrasive surgery(pre-berberine)or direct addition into injured cecum immediately after the surgery(inter-berberine).Rats with adhesion reformation had a more deteriorative collagen accumulation and tissue injury in abrasive sites than rats with primary adhesion.The dysregulated TIMP-1/MMP balance was observed in patients after surgery,as well as adhesion tissues from primary adhesion or adhesion reformation rats.Inter-berberine treatment had a better effect for adhesion reformation prevention than Interceed.Berberine promoted the activation of MMP-3 and MMP-8 by directly blocking TIMP-1 activation core,which was reversed by TIMP-1 overexpression in fibroblasts.In conclusion,this study suggests berberine as a reasonable approach for preventing primary adhesion formation and adhesion reformation.