Takeshi Takajo

Toll-like receptor (TLR) 2 agonists ameliorate indomethacin-induced murine ileitis by suppressing the TLR4 signaling.

Few drugs have been found satisfactory in the treatment of nonsteroidal anti‐inflammatory drugs (NSAIDs)‐induced enteropathy. Toll‐like receptor (TLR) 4 and aberrant leukocyte migration to the intestinal mucosa are reported to be involved in the pathology of intestinal enteropathy and TLR2 agonists have been found to evoke hyposensitivity to TLR4 stimulation in vitro. In this study, we investigated whether and how lipoarabinomannan (LAM) or lipoteichoic acid (LTA), TLR2 agonists, attenuated indomethacin (IND)‐induced intestinal damage.

Platelet interaction with lymphatics aggravates intestinal inflammation by suppressing lymphangiogenesis.

Lymphatic failure is a histopathological feature of inflammatory bowel disease (IBD). Recent studies show that interaction between platelets and podoplanin on lymphatic endothelial cells (LECs) suppresses lymphangiogenesis. We aimed to investigate the role of platelets in the inflammatory process of colitis, which is likely to be through modulation of lymphangiogenesis. Lymphangiogenesis in colonic mucosal specimens from patients with IBD was investigated by studying mRNA expression of lymphangiogenic factors and histologically by examining lymphatic vessel (LV) densities. Involvement of lymphangiogenesis in intestinal inflammation was studied by administering VEGF-receptor 3 (VEGF-R3) inhibitors to the mouse model of colitis using dextran sulfate sodium and evaluating platelet migration to LVs. The inhibitory effect of platelets on lymphangiogenesis was investigated in vivo by administering antiplatelet antibody to the colitis mouse model and in vitro by coculturing platelets with lymphatic endothelial cells. Although mRNA expressions of lymphangiogenic factors such as VEGF-R3 and podoplanin were significantly increased in the inflamed mucosa of patients with IBD compared with those with quiescent mucosa, there was no difference in LV density between them. In the colitis model, VEGF-R3 inhibition resulted in aggravated colitis, decreased lymphatic density, and increased platelet migration to LVs. Administration of an antiplatelet antibody increased LV densities and significantly ameliorated colitis. Coculture with platelets inhibited proliferation of LECs in vitro. Our data suggest that despite elevated lymphangiogenic factors during colonic inflammation, platelet migration to LVs resulted in suppressed lymphangiogenesis, leading to aggravation of colitis by blocking the clearance of inflammatory cells. Modulating the interaction between platelets and LVs could be a new therapeutic means for treating IBD.

Atypical Clinical Presentation of Crohn's Disease with Superior Mesenteric Vein Obstruction and Protein-losing Enteropathy

We herein report a 44-year-old man suffering from systemic edema due to protein-losing enteropathy (PLE) with superior mesenteric vein (SMV) obstruction and development of collateral veins, which subsequently proved to be a chronic result of thrombosis and a complication of Crohns disease (CD). PLE was supposedly induced by both intestinal erosion and thrombosis-related lymphangiectasia, which was histologically proven in his surgically-resected ileal stenosis. Elemental diet and anti-TNFα agent improved his hypoalbuminemia after surgery. The rarity of the simultaneous coexistence of SMV obstruction and PLE and the precedence of these complications over typical abdominal symptoms of CD made the clinical course complex.

Nicotine treatment ameliorates DSS‐induced colitis by suppressing MAdCAM‐1 expression and leukocyte recruitment

The enhanced recruitment of leukocytes to the inflamed colon is a key feature of ulcerative colitis (UC). The gut‐specific adhesion molecules involved in leukocyte recruitment have emerged as recent therapeutic targets. Nicotine absorbed from smoking has been reported to work protectively in UC patients. Our hypothesis is that nicotine may suppress the aberrant leukocyte recruitment and colonic inflammation via the suppression of the overexpressed gut‐specific adhesion molecules in the inflamed colon. To test this hypothesis, the severity of colitis and the degree of leukocyte recruitment induced by gut‐specific adhesion molecules were assessed in dextran sulfate sodium (DSS) colitis mice (C57BL/6J mice treated with 3% DSS) with or without nicotine treatment. We also studied the in vitro changes in the expression of adhesion molecules by using a vascular endothelial cell line. DSS‐induced colitis was accompanied by increases in disease activity index (DAI), histological score, recruitment of leukocytes, and the expression of adhesion molecules, mucosal vascular addressin cell adhesion molecule‐1 (MAdCAM‐1) and VCAM‐1. Nicotine treatment significantly attenuated MAdCAM‐1 expression, leukocyte recruitment, DAI, and histological score. The expression of β7‐integrin, the ligand for MAdCAM‐1, on leukocytes was not affected by nicotine treatment. In vitro study, the TNF‐α‐enhanced mRNA expression of MAdCAM‐1 was reduced by the coadministration of nicotine in a dose‐dependent manner, possibly via nicotinic receptor activation. These results supported our hypothesis that nicotine treatment ameliorated colitis through the suppression of MAdCAM‐1 expression on the microvessels in the inflamed colon. Further investigation is warranted on the role of nicotine in the treatment of UC.

Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine-1-phosphate lyase inhibitor: SPL inhibitor ameliorates murine colitis

Sphingosine‐1‐phosphate (S1P) receptor 1, a therapeutic target of the S1P1 agonist FTY720, plays a crucial role in lymphocyte migration and is expressed in several cells including naïve T lymphocytes and endothelial cells. 2‐Acetyl‐4‐tetrahydroxybutyl imidazole (THI), an inhibitor of S1P lyase, exhibits immunomodulatory activity through increasing the S1P concentration in the secondary lymphoid organs, but its effects on colitis remain unclear. This study aimed to clarify how THI affects colitis and migration of naïve T lymphocytes in Peyers patches (PPs).

Evaluation by MR Enterocolonography of Lansoprazole-induced Collagenous Colitis Accompanied with Protein-losing Enteropathy - A Case Report

We herein describe a 69-year-old man suffering from chronic diarrhea caused by lansoprazole (LPZ)-induced collagenous colitis (CC) accompanied with protein-losing enteropathy (PLE), diagnosed by increased fecal alpha-1 antitrypsin clearance and the findings of leakage from the descending colon to the sigmoid colon on scintigraphy. MR enterocolonography (MREC) was also performed for differentiating digestive diseases, and inflamed findings were observed around the same portion as those on scintigraphy, suggesting that this region was responsible for protein loss in this case. The MREC findings improved after the cessation of LPZ, and hypoalbuminemia also improved simultaneously. This case suggests that MREC may be a new and useful diagnostic tool for CC with PLE.

Vitamin A-coupled liposome system targeting free cholesterol accumulation in hepatic stellate cells offers a beneficial therapeutic strategy for liver fibrosis: Targeting free cholesterol in liver fibrosis

Liver fibrosis is a life‐threatening disorder for which no approved therapy is available. Recently, we reported that mouse hepatic stellate cell (HSC) activation increased free cholesterol (FC) accumulation, partly by enhancing signaling through sterol regulatory element‐binding protein 2 (SREBP2) and microRNA‐33a (miR‐33a), which resulted in HSC sensitization to transforming growth factor‐β (TGFβ)‐induced activation in a “vicious cycle” of liver fibrosis.

Human intestinal spirochetosis mimicking ulcerative colitis

Human intestinal spirochetosis (HIS) is a colorectal infection caused by the Brachyspira species of intestinal spirochetes, whose pathogenicity in humans remains unclear owing to the lack of or mild symptoms. We monitored the 5-year clinical course of a woman diagnosed with HIS in whom ulcerative colitis (UC) had been suspected. Following a positive fecal occult blood test, she underwent a colonoscopic examination at a local clinic where she was diagnosed with “right-sided” UC concomitant with incidentally detected HIS, and was referred to our hospital. Colonoscopic, histopathological, and cytological examination revealed localized erosive colitis in the ascending and the right transverse colon concomitant with HIS resembling skip lesions of UC. Initially, we chose the wait-and-watch approach; however, she gradually developed bloody diarrhea. Metronidazole improved her abdominal symptoms, as well as her colonoscopic and histopathological findings, suggesting that HIS was responsible for her colorectal inflammation. This case reveals (1) a possible pro-inflammatory role of HIS, (2) difficulties in diagnosing HIS in chronic proctocolitis, and (3) a possible inclusion of some HIS cases in “UC”. HIS could mimic UC and might be included in differential diagnoses for UC. Antibiotic administration is necessary following the detection of HIS, particularly in patients demonstrating an atypical presentation of UC.

Uric acid ameliorates indomethacin‐induced enteropathy in mice through its antioxidant activity

Uric acid is excreted from blood into the intestinal lumen, yet the roles of uric acid in intestinal diseases remain to be elucidated. The study aimed to determine whether uric acid could reduce end points associated with nonsteroidal anti‐inflammatory drug (NSAID)‐induced enteropathy.

Mo1689 Nicotine Significantly Affects the Expression of Vascular Endothelial Adhesion Molecules and Ameliorates DSS Induced Colitis

Introduction Anti-adhesion molecule therapy is useful for inflammatory bowel diseases. Smoking has been reported to have a harmful effect on Crohns disease, but it is still controversial in ulcerative colitis. Although effect of nicotine on adhesion molecules of cardiovascular system has been well recognized, it has not been studied in the intestine. We investigated effect of nicotine on murine colitis induced by dextran sodium sulfate (DSS) and compared expression of adhesion molecules in vitro in several conditions including preconditioning exposure. Involvement of nicotinic acetylcholine receptor (nAChR) was also examined. Method In in vivo study C57BL/6J mice were treated with 3% DSS and 0.1mg/ ml nicotine in drinking water for 7 days. Disease activity of colitis was assessed by DAI score. mRNA expressions of ICAM-1, VCAM-1 and MAdCAM-1 in colonic tissues were measured by qPCR. Microvascular endothelial cell line, bEnd3, was used for in vitro study. The cultured cells (2x105/ml) were treated with 5ng/ml TNF-α and 200μg/ml nicotine for 12 hours. mRNA expressions of ICAM-1, VCAM-1 and MAdCAM-1 in cells were measured by qPCR. Various concentrations of nicotine (0.01-1000μM) were tested. In pre-treatment protocol, cells were treated with nicotine for 3 days, and after 12 hours interval without nicotine, exposed to TNF-α and nicotine for 12 hours as treatment. In some experiments cells were cultured with TNF-α and nicotine under the presence of 0.01μM mecamylamine (Meca, nonselective nAChR antagonist) or 0.01μM methyllycaconitine (MLA, selective α7nAChR antagonist). Result In in vivo study, nicotine treatment decreased DAI score induced by DSS. Although nicotine alone did not affect expression of ICAM-1, VCAM-1 and MAdCAM-1 in control mice, addition of nicotine to DSS mice significantly attenuated the increased expression of VCAM-1 and MAdCAM-1 induced by DSS, and tended to inhibit ICAM-1. In in vitro study, expression of ICAM-1, VCAM-1 and MAdCAM-1 was increased by TNF-α. Increased expression of MAdCAM-1 was significantly attenuated by simultaneous administration of nicotine. In dose-response study, degree of ICAM-1 inhibition by nicotine was only observed at high doses, whereas that of MAdCAM-1 was observed in a low dose already. Interestingly pretreatment with nicotine before TNF-α decreased inhibitory effect of nicotine. These inhibitory effects tended to be attenuated by Meca or MLA, but not