Koji Maruta

Magnetic resonance enterocolonography in detecting erosion and redness in intestinal mucosa of patients with Crohn's disease

In Crohns disease (CD), assessment of disease activity and extension is important for clinical management. Endoscopy is the most reliable tool for evaluating disease activity in these patients and it distinguishes between lesions based on ulcer, erosion, and redness. Magnetic resonance imaging (MRI) is less invasive than endoscopy; however, the sensitivity of MRI in detecting lesions is believed to be lower, and whether MRI can detect milder lesions has not been studied. The aim of this study was to compare the detection ability of magnetic resonance enterocolonography (MREC) with ileocolonic endoscopy in patients with CD.

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.

Phlebosclerotic colitis that was difficult to distinguish from collagenous colitis

Phlebosclerotic colitis is a rare and recently known disease entity and its etiology is still to be elucidated. Some phlebosclerotic colitis cases are difficult to distinguish from collagenous colitis because of the similarity of pathological findings. In all Japanese case reports of phlebosclerotic colitis in which an association with the use of Chinese herbal medicine is suspected, sansisi (gardenia fruit) was included, suggesting pathogenesis of this disease. We report a case of phlebosclerotic colitis that wasdifficult to be distinguished from collagenous colitis, and an association with the use of Chinese herbal medicine was suspected as the cause of the disease.

Beneficial effect of an omega-6 PUFA-rich diet in non-steroidal anti-inflammatory drug-induced mucosal damage in the murine small intestine

AIM To investigate the effect of a fat rich diet on non-steroidal anti-inflammatory drug (NSAID)-induced mucosal damage in the murine small intestine. METHODS C57BL6 mice were fed 4 types of diets with or without indomethacin. One group was fed standard laboratory chow. The other groups were fed a fat diet consisting of 8% w/w fat, beef tallow (rich in SFA), fish oil, (rich in omega-3 PUFA), or safflower oil (rich in omega-6 PUFA). Indomethacin (3 mg/kg) was injected intraperitoneally from day 8 to day 10. On day 11, intestines and adhesions to submucosal microvessels were examined. RESULTS In the indomethacin-treated groups, mucosal damage was exacerbated by diets containing beef tallow and fish oil, and was accompanied by leukocyte infiltration (P < 0.05). The mucosal damage induced by indomethacin was significantly lower in mice fed the safflower oil diet than in mice fed the beef tallow or fish oil diet (P < 0.05). Indomethacin increased monocyte and platelet migration to the intestinal mucosa, whereas safflower oil significantly decreased monocyte and platelet recruitment (P < 0.05). CONCLUSION A diet rich in SFA and omega-3 PUFA exacerbated NSAID-induced small intestinal damage via increased leukocyte infiltration. Importantly, a diet rich in omega-6-PUFA did not aggravate inflammation as monocyte migration was blocked.

Pregnant woman with non‐comatose autoimmune acute liver failure in the second trimester rescued using medical therapy: A case report

We present the case of a 25‐year‐old woman at 16 weeks of gestation who presented with non‐comatose autoimmune acute liver failure and was at high risk of developing fulminant hepatitis. Predictive formulas indicated a high probability of developing fulminant hepatitis. Unenhanced computed tomography showed marked hepatic atrophy and broadly heterogeneous hypoattenuating areas. The course of her illness was subacute, and the etiology of liver injury was unclear. Considering all of the above, we predicted a poor prognosis. Plasma exchange (PE) and continuous hemodiafiltration (CHDF) therapy were initiated just after admission. A few days after admission, a high titer (×80) of antinuclear antibody was noted. Because autoimmune hepatitis (AIH) was considered a cause of liver failure, treatment with moderate prednisolone (30 mg/day) doses was administrated, with careful consideration of her pregnancy. Thereafter, her laboratory findings and clinical course gradually improved without the need for liver transplantation. A liver biopsy at 18 days after admission indicated a diagnosis of AIH. She continued the pregnancy and delivered a healthy baby without any complications. Eventually, prednisolone doses were decreased to 10 mg, after which her liver function worsened. The second liver biopsy also indicated a diagnosis of AIH. Accordingly, low‐dose prednisolone and azathioprine doses (50 mg/day) were administrated to recover her liver function, after which her liver function regained normalcy. This case illustrates that a pregnant woman with non‐comatose autoimmune acute liver failure in the first or second trimester of pregnancy and her fetus can be rescued by PE/CHDF therapy and safe moderate doses of prednisolone.

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.

Mo1725 Possible Protective Role of Lymphangiogenesis in the Inflamed Colonic Mucosa of Inflammatory Bowel Diseases

Background: Lymphocyte infiltration into the intestinal mucosa is an important pathogenic feature of inflammatory bowel diseases (IBD). In case of dermatitis, lymphatics play a role as drainage route of lymphocytes from skin and an inhibition of lymphangiogenesis keeps lymphocytes remaining in the local area leading to exacerbate inflammation. However, the role of lymphatics in enterocolitis is not well understood. In this study, we examined changes in lymphatic densities and expression of lymphangiogenic factors in patients with IBD and in animal model of colitis, and investigated a role of lymphangiogenic using inhibitor of VEGF (vascular endothelial growth factor)-R3. Method: Colonic biopsies were obtained from 40 patients with ulcerative colitis (UC), 17 patients with Crohns disease (CD), and controls. Messenger RNA expressions of lymphangiogenic factors, VEGFC & D, VEGFR3, podoplanin, Prox-1, and LYVE1 were determined using real time RT-PCR. Expression of CD34 and LYVE1 was studied immunohistochemically. In dextran sulfate sodium (DSS)-induced mice colitis, a VEGF-R3 kinase inhibitor (10mg/kg) was administered every day and the effects of lymphangiogenetic inhibition on activity of colitis and lymphatic density were determined in the colonic mucosa. Result: In the colonic mucosa of patients with UC and CD, the expressions of VEGFC, VEGFR3, podoplanin, and LYVE1 were significantly increased than the mucosa of control patients. The expression levels of podoplanin and LYVE1 were well correlated to endoscopic Matts score in UC patients. By immunohistochemistry, the lymphatic densities in the colonic mucosa of IBD patients also increased compared to control patients. However, interestingly those densities were not significantly increased in the severely inflamed mucosa of IBD patients compared with those in the quiescent mucosa, suggesting that lymphangiogenesis and lymphatic drainage are not well organized in the severely inflamed mucosa. In murine colitis model, VEGF-R3 inhibition group showed significant aggravation of colitis such as shortening of colonic length and increase in the lymphocyte infiltration in the submucosa compared with DSS-treatment alone. Lymphatic densities decreased in the submucosa of VEGF-R3 inhibition group. Conclusions: The results of our study revealed that lymphangiogenic factors and lymphatic density are increased in both UC and CD patients. However, the density of lymphatic did not increase as inflammation advanced. Aggravation of colitis by lymphangiogenic receptor inhibition suggests that lymphatic networks may play some protective roles as exit of immune cells from intestinal mucosa, and that some mechanisms which block lympangiogenesis play aggravating role in severe IBD patients. In the severely inflamed conditions lymphatic drainage through lymphangiogenesis is not well functioning in IBD.

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.