Norihiro Hamamoto

Therapeutic effect of intracolonically administered nuclear factor kappa B (p65) antisense oligonucleotide on mouse dextran sulphate sodium (DSS)-induced colitis.

Cytokines such as IL‐1, tumour necrosis factor‐alpha (TNF‐α), IL‐6 and IL‐8 are increased in inflamed colonic mucosa after administration of mouse DSS. Nuclear factor κB (NF‐κB) is a transcription factor which regulates the expression of these cytokine genes. The effect of intracolonically administered NF‐κB (p65) antisense phosphorothioate oligonucleotide was examined in mouse DSS‐induced colitis using drinking water containing 5% DSS. When antisense oligonucleotide was given on day 0, the disease activity index (DAI) representing clinical symptoms improved and the histological score decreased; furthermore, IL‐1, IL‐6, and TNF‐α concentrations in rectal mucosa were lower compared with the control group. Clinical and histological improvement was also observed when antisense oligonucleotide was begun on day 2 but not on day 7. In addition, the distribution of antisense oligonucleotides was investigated by confocal laser microscopy. In colonic mucosa, oligonucleotides were predominantly localized to cells in the lamina propria, but also in the epithelium. Western blot analysis using homogenized rectal mucosa showed the decreased expression of NF‐κB p65 in the antisense oligonucleotide‐treated group, although it was increased in the colitis group. These results suggest that intracolonic administration of NF‐κB antisense oligonucleotide may be effective in ulcerative colitis.

Inhibition of dextran sulphate sodium (DSS)-induced colitis in mice by intracolonically administered antibodies against adhesion molecules (endothelial leucocyte adhesion molecule-1 (ELAM-1) or intercellular adhesion molecule-1 (ICAM-1)).

We examined the effect of intracolonic administration of anti‐adhesion molecule antibodies on DSS‐induced colitis in mice. Immunohistochemical staining in mice with colitis showed increased expression of ELAM‐1 and ICAM‐1 on endothelial cells of vessels in the lamina propria and submucosa at sites of inflamed lesions. Intracolonic administration of anti‐ELAM‐1 or anti‐ICAM‐1 antibody decreased bloody stools, anaemia, and histologically evident damage, as well as myeloperoxidase activity and IL‐1β content. We concluded that adhesion molecule expression is important in the development of DSS‐induced colitis in mice and that intracolonic administration of anti‐adhesion molecule antibodies, especially anti‐ELAM‐1 antibody, effectively inhibits the colonic inflammation. Intracolonic administration of anti‐adhesion molecule antibodies may show therapeutic promise in ulcerative colitis.

Balloon-occluded retrograde transvenous obliteration of high risk gastric fundal varices.

OBJECTIVE:Balloon-occluded retrograde transvenous obliteration is an effective new method for treating gastric fundal varices, but subsequent occurrence of esophageal varices creates a problem. The relationship between portal hemodynamics and the occurrence of esophageal varices after prophylactic balloon-occluded retrograde transvenous obliteration was investigated.METHODS:Ten cirrhotic patients considered to have high risk gastric fundal varices underwent angiography. Six patients showed a communication between blood flow in gastric wall vessels and that in the gastrorenal shunt (type I), whereas the others (type II) did not. Depending on the flow direction in the left gastric vein, the two groups were further divided into hepatopetal (a) and hepatofugal (b) subgroups. The therapeutic effect on portal hemodynamics and the relationship between pretreatment portal hemodynamics and posttreatment occurrence of esophageal varices were investigated.RESULTS:Fundal varices disappeared endoscopically in all 10 patients and the gastrorenal shunt was also occluded after the procedure. No patient showed worsening of liver function or systemic complications during follow-up. The increase in portal blood flow was more significant in type Ib patients than in the others. Esophageal varices occurred in all type I patients, and as to those in type Ib, high risk varices developed within 6 months after treatment. On the other hand, esophageal varices did not occur in type II patients.CONCLUSIONS:This procedure was effective for treating gastric fundal varices. However, type Ib patients are likely to develop high risk esophageal varices after occlusion of the gastrorenal shunt.

Expression of the EP4 Prostaglandin E2 Receptor Subtype with Rat Dextran Sodium Sulphate Colitis: Colitis Suppression by a Selective Agonist, ONO-AE1-329

Expression of the EP4 receptor, a prostaglandin (PG)E2 receptor subtype, as well as disease suppression by the administration of a selective EP4 agonist (ONO‐AE1‐329) was investigated in the colorectal mucosa of rats with dextran sodium sulphate (DSS)‐induced colitis. Rats were given drinking water containing 3% DSS for 2 weeks. Expression of EP4 receptor mRNA was barely detectable under normal conditions according to reverse transcription‐polymerase chain reaction (RT‐PCR). By 1 week after the initial administration of DSS, the receptor mRNA was strongly expressed. After ONO‐AE1‐329 was administered intracolonically to rats with DSS colitis for 7 consecutive days, erosion and ulceration decreased. Peripheral white blood cell (WBC) counts became less elevated. Interleukin (IL)‐1β and growth‐regulated gene product/cytokine‐induced neutrophil chemoattractant (GRO/CINC‐1) concentrations in colorectal mucosa were lower than in colitis control group (IL‐1β: 12.8 ± 4.6 and 30.8 ± 6.2 µg/mg protein, P < 0.05; GRO/CINC‐1: 15.5 ± 3.0 and 39.2 ± 5.4 µg/mg protein, P < 0.05), and the expression of the corresponding cytokine mRNA was strongly suppressed. IL‐10 concentration was higher than in control group (14.5 ± 1.7 and 7.9 ± 1.2 µg/mg, P < 0.05), and the mRNA was more strongly expressed. These results suggest that the EP4 receptor is important in colonic inflammation, and that PGE2 suppresses DSS colitis at least partly via the EP4 receptor and the above cytokine changes. Intracolonic administration of selective EP4 agonist might have therapeutic applicability in inflammatory bowel disease such as ulcerative colitis.

Left gastric vein hemodynamics and variceal recurrence in patients undergoing prophylactic endoscopic ligation of high-risk esophageal varices.

BACKGROUND Early recurrence of esophageal varices remains problematic after endoscopic variceal ligation. To evaluate the efficacy of prophylactic endoscopic ligation for esophageal varices at high risk for bleeding, the relationship between left gastric vein hemodynamics and variceal recurrence was investigated. METHODS Thirty-five patients with cirrhosis underwent endoscopic variceal ligation. Angiography was performed in all patients before treatment and after eradication of varices to study left gastric vein hemodynamics. RESULTS Before treatment, 12 patients had hepatopetal flow in the left gastric vein (type I), 17 had hepatofugal flow (type II), and 6 had hepatofugal flow with an extra-esophageal shunt (type III). In type I and III patients, the direction of blood flow in the left gastric vein did not change after eradication of varices. Type II patients showed bi-directional flow in the left gastric vein after treatment. Varices recurred in all but one type II patient and in one type I patient during follow-up (mean 36.7 months). The 2-year recurrence-free rate was higher in type I patients (p = 0.0001) and type III patients (p = 0.0002) than in type II patients. CONCLUSIONS Prophylactic ligation seems to be a safe and useful procedure, especially in patients with type I or III hemodynamics in the left gastric vein before treatment.

Enprostil, a Prostaglandin‐E2 Analogue, Inhibits Interleukin‐8 Production of Human Colonic Epithelial Cell Lines

We previously reported that intracolonic administration of enprostil, a prostaglandin‐E2 (PGE2) analogue, had therapeutic effects on acute colitis induced in rodents by dextran sulfate sodium (DSS). In addition, production of growth‐regulated gene product/cytokine‐induced neutrophil chemoattractant‐1 [GRO/CINC‐1; an interleukin(IL)‐8 like cytokine] was suppressed in the inflamed tissues. In the present study we used a human colon cancer cell line (HT‐29) to investigate enprostil effects on the IL‐8 production of intestinal epithelial cells stimulated by various stimulants. In a MTT assay, concentrations of enprostil >10−5M had cytotoxitic effects on HT‐29 cells. Furthermore, 10−6 M enprostil suppressed IL‐8 production in HT‐29 cells, SW620 and CaCo2 stimulated with interleukin‐1β (IL‐1β) or lipopolysaccharide (LPS), but did not suppress this response when cells were stimulated with tumour necrosis factor (TNF)‐α. These results suggest that enprostil affects a point in the pathway between the IL‐1 receptor or LPS receptor and nuclear factor‐κB(NF‐κB), without affecting the pathway between the TNF receptor and NF‐κB, with the latter factor being required for the IL‐8 gene transcription. The therapeutic effect of exogenous enprostil on DSS colitis may involve the inhibition of IL‐8 production in colonic epithelial cells stimulated by IL‐1β or LPS.

USEFULNESS OF MULTI DETECTOR ROW COMPUTED TOMOGRAPHY FOR DETECTION OF FLAT AND DEPRESSED COLORECTAL CANCER

Background:  Recently, the clinical usefulness of colorectal cancer screening by CT colonography has been reported in Europe and the USA. However, in Japan, the diagnosis of flat or depressed colorectal cancer lesions has been emphasized, and the question of whether CT colonography facilitates visualization of these lesions remains to be answered. In the present study, we compared the visualization of flat and depressed colorectal cancer lesions by CT colonography with that of protruding lesions.

Prophylaxis of rebleeding from isolated gastric fundal varices by balloon-occluded retrograde transvenous obliteration

We describe a case of bleeding gastric fundal varices associated with a gastrorenal shunt that were successfully treated with balloon-occluded retrograde transvenous obliteration. Blood flow in the varices disappeared after treatment. Because of its safety and simplicity, balloon-occluded retrograde transvenous obliteration appears to be a feasible alternative to transjugular intrahepatic portosystemic shunt for the treatment of gastric fundal varices.