Hiromu Kutsumi

Resolvin E1, an endogenous lipid mediator derived from eicosapentaenoic acid, prevents dextran sulfate sodium-induced colitis

Background: Resolvin E1 (RvE1), an endogenous lipid mediator derived from eicosapentaenoic acid, has been identified in local inflammation during the healing stage. RvE1 reduces inflammation in several types of animal models including peritonitis and retinopathy and blocks human neutrophil transendothelial cell migration. The RvE1 receptor ChemR23 is expressed on myeloid cells such as macrophages and dendritic cells. The aim of this study was to determine whether RvE1 regulates colonic inflammation when the innate immune response of macrophages plays a key role in pathogenesis and tissue damage. Methods: The RvE1 receptor ChemR23 was expressed in mouse peritoneal macrophages as defined by flow cytometry. Peritoneal macrophages were pretreated with RvE1, followed by lipopolysaccharide stimulation, whereupon transcriptional levels of proinflammatory cytokines were analyzed. Results: RvE1 treatment led to inhibition of proinflammatory cytokines including TNF‐&agr; and IL‐12p40. In HEK293 cells, pretreatment with RvE1 inhibited TNF‐&agr;‐induced nuclear translocation of NF‐&kgr;B in a ChemR23‐dependent manner. These results suggested that RvE1 could regulate proinflammatory responses of macrophages expressing ChemR23. Therefore, we investigated the beneficial effects of RvE1 in dextran sulfate sodium–induced colitis. RvE1 treatment led to amelioration of colonic inflammation. Conclusions: These results indicate that RvE1 suppresses proinflammatory responses of macrophages. RvE1 and its receptor may therefore be useful as therapeutic targets in the treatment of human inflammatory bowel disease and other inflammatory disorders. Inflamm Bowel Dis 2010

Retrospective study of technical aspects and complications of endoscopic submucosal dissection for laterally spreading tumors of the colorectum

BACKGROUND AND STUDY AIMS Laterally spreading tumors - non granular type (LST-NG) are more often considered candidates for endoscopic submucosal dissection (ESD) than laterally spreading tumors - granular type (LST-G), because of their higher potential for submucosal invasion. However, ESD for LST-NG can be technically difficult. The aim of our study was to compare our ESD results for LST-NG and for LST-G. PATIENTS AND METHODS Ninety-nine LST-NG and 169 LST-G measuring 20 mm in size or more were removed by ESD. We retrospectively evaluated the clinicopathological features of the tumors and treatment results (en bloc resection rate, procedure time and speed, rate of use of ancillary devices, and complication and recurrence rates). RESULTS Histopathology revealed that there were more submucosally invasive lesions in the LST-NG than in the LST-G group (28 % vs. 9 %; P < 0.0001). The en bloc resection rate, en bloc R0 resection rate, and en bloc curative resection rate of LST-NG were similar to those of LST-G (LST-NG: 99 %, 98 %, and 88 %; LST-G: 99 %, 98 %, and 91 %). In LST-NG, the median procedure time tended to be longer (LST-NG: 69 min; LST-G: 60 min) and the median procedure speed was slower (LST-NG: 0.15 cm (2)/min; LST-G: 0.25 cm (2)/min; P < 0.0001). Use of ancillary devices was higher for LST-NG (38 % vs. 15 % for LST-G; P < 0.0001), as was the perforation rate (5.1 % vs. 0.6 % for LST-G; P = 0.027). No recurrence was seen in either group. CONCLUSIONS ESD was an effective treatment method for both LST-NG and LST-G. However, the degree of technical difficulty appears higher for LST-NG than for LST-G lesions, as shown by the lower dissection speed and higher perforation rate. ESD for LST-NG should probably be performed by those with significant experience of colorectal ESD.

Endoscopic Pancreatic Duct Stents Reduce the Incidence of Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis in High-Risk Patients

BACKGROUND & AIMS Pancreatitis is the most common and potentially serious complication of post-endoscopic retrograde cholangiopancreatography (ERCP). Post-ERCP pancreatitis (PEP) is caused mostly by postprocedural papillary edema and retention of pancreatic juice. We conducted a randomized controlled trial to determine whether placement of a temporary-type, pancreatic duct stent prevents PEP and to identify risk factors for PEP. METHODS We analyzed data from 426 consecutive patients who underwent ERCP-related procedures at 37 endoscopic units. The patients were assigned randomly to groups that received stents (S group, n = 213) or did not (nS group, n = 213). The stent used was temporary, 5F in diameter, 3 cm long, and straight with an unflanged inner end. RESULTS The overall frequency of PEP was 11.3%. The frequencies of PEP in the S and nS groups were 7.9% and 15.2%, respectively; the lower incidence of PEP in the S group was statistically significant based on the full analysis set (P = .021), although there was no statistically significant differences in an intention-to-treat analysis (P = .076). There were significant differences in PEP incidence between groups in multivariate analysis for the following risk factors: pancreatography first, nonplacement of a pancreatic duct stent after ERCP, procedure time of 30 minutes or more, sampling of pancreatic tissue by any method, intraductal ultrasonography, and difficulty of cannulation (≥15 min). Patients with more than 3 risk factors had a significantly greater incidence of pancreatitis. CONCLUSIONS Placement of a pancreatic duct stent reduces the incidence of PEP. Several risk factors are associated with PEP.

A Role of the Aryl Hydrocarbon Receptor in Attenuation of Colitis

Background and AimsThe aryl hydrocarbon receptor (AhR), which is a member of the basic helix-loop-helix/Per-Arnt-Sim homology superfamily, plays an important role in multiple biological functions, and AhR knockout (AhR KO) animals suffer from a variety of organ disorders including a decline in the efficacy of their immune system. In addition, AhR activation is known to aid the maintenance of homeostasis in vivo. In this study, we investigated whether AhR is functionally associated with intestinal immunity.Methods and ResultsIn in vivo experiments, it was found that dextran sodium sulfate (DSS)-evoked colitis was more severe in AhR KO mice than in C57BL/6J wild type mice. It was also revealed that the administration of DSS increased the expression levels of AhR and CYP1A1 mRNA in the colon epithelium. In addition, oral administration of β-naphthoflavone (βNF), a non-toxic agonist of AhR, suppressed the pathogenesis of DSS-induced colitis. βNF also attenuated DSS-induced colitis. In cell culture experiments, downregulation of AhR in human colon carcinoma SW480 cells enhanced the inflammatory responses evoked by lipopolysaccharide (LPS), and furthermore, AhR activation attenuated LPS-induced inflammatory responses, suggesting that AhR expressing intestinal epithelial cells are involved in the prevention of colitis.ConclusionsOur findings about the potential role of AhR activators in epithelial immune regulation aid our understanding of mucosal homeostasis and inflammatory bowl disease (IBD) and suggest that AhR activation has therapeutic value for the treatment of IBD.

The performance of a novel ball-tipped Flush knife for endoscopic submucosal dissection: a case-control study

Aliment Pharmacol Ther 2010; 32: 908–915

GCMS‐based metabolomic study in mice with colitis induced by dextran sulfate sodium

Background: Metabolomics provides data about all the metabolic processes of a cell or organism. So far, the changes that occur in the levels of metabolites during the development of colitis have not been fully elucidated. Here we examined the changes of metabolite levels in the serum and colon tissue of colitis mice using gas chromatography mass spectrometry (GC/MS) with the aim of achieving a detailed understanding of the pathogenesis of inflammatory bowel disease (IBD). Methods: To induce colitis, C57BL/6J mice were administered 3.0% dextran sulfate sodium (DSS) in their drinking water for 5 days and were subsequently given drinking water alone. Results: A total of 77 and 92 metabolites were detected in serum and colon tissue, respectively, and among the metabolites the compositions of TCA cycle intermediates and amino acids changed depending on the degree of colitis. Then, partial least square discriminant analysis (PLS‐DA), a multiple classification analysis, showed distinct clustering and clear separation of the groups according to the degree of colitis. Furthermore, PLS‐DA loadings plots revealed that succinic acid, indole‐3‐acetic acid, glutamic acid, and glutamine were the main contributors to the separation of each stage of colitis. In addition, it was revealed that supplementation with glutamine, the level of which was significantly decreased in the acute phase of colonic inflammation, attenuated colitis induced by DSS. Conclusions: Our results suggest that metabolomics is capable of representing the various degrees of colitis, and our findings will aid in the discovery of therapeutic agents for IBD and other inflammatory disorders by metabolomic approaches. (Inflamm Bowel Dis 2011;)

THE NEW RESOURCES OF TREATMENT FOR EARLY STAGE COLORECTAL TUMORS: EMR WITH SMALL INCISION AND SIMPLIFIED ENDOSCOPIC SUBMUCOSAL DISSECTION

Introduction:  Early stage colorectal tumors can be removed by endoscopic mucosal resection (EMR) but larger tumors (≧20 mm) may require piecemeal resection. The development of endoscopic submucosal dissection (ESD) has enabled en‐bloc resection of lesions regardless of size and shape. However ESD of colorectal tumor is technically difficult. As the resources, we perform EMR with small incision (EMR with SI) for more reliable EMR, and also ESD with snaring (simplified ESD) for easier and safer ESD.

IgG transport across mucosal barriers by neonatal Fc receptor for IgG and mucosal immunity

Mucosal secretions of the human gastrointestinal, respiratory, and genital tracts contain significant quantities of IgG. The neonatal Fc receptor for IgG (FcRn) plays a major role in regulating host IgG levels and transporting IgG and associated antigens across polarized epithelial barriers. The FcRn can then recycle the IgG/antigen complex back across the intestinal barrier into the lamina propria for processing by dendritic cells and presentation to CD4+ T cells in regional organized lymphoid structures. FcRn, through its ability to secrete and absorb IgG, thus integrates luminal antigen encounters with systemic immune compartments and, as such, provides essential host defense and immunoregulatory functions at the mucosal surfaces.

Predictors of malignant intraductal papillary mucinous neoplasm of the pancreas.

Goals The predictors of malignant intraductal papillary mucinous neoplasm (IPMN) and invasive IPMN were investigated in this study to determine the optimal indicators of surgical resection for IPMN. Background Recently, international consensus guidelines have described the standard indicators of resection for IPMN. However, the indicators of surgical resection for IPMN, especially for branch duct IPMN, still remain controversial. Study Eighty-two patients with IPMN who underwent surgical resection during April 1998 to January 2009, were retrospectively reviewed and examined with regard to their preoperative factors and pathologic diagnosis. Results Multivariate analysis showed that main duct IPMN (P<0.01) and earlier diabetes (P=0.03) were independent predictors of malignant IPMN. In branch duct IPMN, the diameter of the main pancreatic duct (MPD) was found to be significantly associated with malignancy by univariate analysis (P=0.034). An elevated serum CA19-9 level (P<0.01) was an independent predictor of invasive IPMN. Conclusions Our observations suggest that main duct IPMN, branch duct IPMN with MPD dilatation, and IPMN with an elevated serum CA19-9 level should be considered as indications for surgical resection.

Autophagy in the intestinal epithelium reduces endotoxin-induced inflammatory responses by inhibiting NF-κB activation.

Autophagy is a lysosomal degradation pathway that is essential for survival, differentiation, development and homeostasis. There is growing evidence that impaired autophagy leads to the pathogenesis of diverse diseases. However, the role of autophagy in intestinal epithelium is not clearly understood, although previous studies have pointed out the possibility for the relationships of autophagy with bowel inflammation. In this study, we investigated the involvement of autophagy in intestinal epithelium with inflammatory responses. We generated the mice with a conditional deletion of Atg7, which is one of the autophagy regulated gene, in intestinal epithelium. In Atg7-deficient small intestinal epithelium, LPS-induced production of TNF-α and IL-1β mRNA was enhanced in comparison to the control small intestinal tissues. In addition, the degree of LPS-induced activation of NF-κB was promoted in Atg7-deficient intestinal epithelium. These results demonstrate that autophagy can attenuate endotoxin-induced inflammatory responses in intestinal epithelium resulting in the maintenance of intestinal homeostasis.