Hiroto Hiraga

Cyclosporine regulates intestinal epithelial apoptosis via TGF-β-related signaling

Cyclosporine is a potent immunomodulator and has a beneficial effect in the treatment of ulcerative colitis (UC). We analyzed the mechanism of the effects of cyclosporine on the regulation of epithelial apoptosis via TGF-beta-related signaling, because the balance between the apoptosis and regeneration of epithelial cells seems to be a key factor to maintain the intestinal homeostasis. For this purpose, colitis was induced by treatment of 4% dextran sulfate sodium (DSS), and the effect of treatment with cyclosporine and anti-TGF-beta antibody was assessed. Treatment with cyclosporine ameliorated body weight loss, mucosal destruction, and epithelial apoptosis in DSS-induced colitis. Cyclosporine was shown to upregulate the expression of TGF-beta in the colonic tissue, enhance the expression of p-Smad2 and cFLIP in epithelial cells, and inhibit caspase-8 activity but not caspase-1 or -9. Upregulation of cFLIP in the colonic epithelial cells, amelioration of body weight loss, and mucosal destruction by cyclosporine were attenuated by anti-TGF-beta antibody treatment. These results indicated that cyclosporine could have a protective role against epithelial apoptosis associated with upregulation of TGF-beta-related signaling.

Estimation of perioperative invasiveness of colorectal endoscopic submucosal dissection evaluated by energy metabolism

The aim of this study was to assess the perioperative invasiveness of endoscopic submucosal dissection for colorectal cancer quantitatively by using energy metabolism. In fifty-three patients who underwent endoscopic submucosal dissection for colorectal cancer, resting energy expenditure using an indirect calorimeter, body weight and basal energy expenditure using the Harris–Benedict equation before and after endoscopic submucosal dissection. Resting energy expenditure/body weight and resting energy expenditure/basal energy expenditure were 19.7 ± 2.5 kcal/kg/day and 0.96 ± 0.12 on the day of endoscopic submucosal dissection, whereas one day after the endoscopic submucosal dissection they increased to 21.0 ± 2.9 kcal/kg/day and 1.00 ± 0.13 (p<0.001 and p<0.05, respectively). The stress factor on the postoperative day 1 was computed as 1.06. The increase was lower comparing with that experienced for surgery, suggesting that the perioperative invasiveness of colorectal endoscopic submucosal dissection is lower in comparison to that during surgery. Furthermore, in spite of technical difficulty, stress factor of colorectal endoscopic submucosal dissection was approximately equal to that of gastric endoscopic submucosal dissection. (The study of the resting energy metabolism and stress factor using an indirect calorimeter in the perioperative period of endoscopic operation: UMIN000027135)

Successful adalimumab treatment and usefulness of capsule endoscopy for gut inflammation concomitant with ankylosing spondylitis

Abstract Here we describe a 20-year-old man with ankylosing spondylitis and gut inflammation, who was successfully treated with adalimumab. Capsule endoscopy and ileocolonoscopy showed multiple erosions and aphthoid ulcers in the ileum and the ileocecal valve. Immunohistochemical analysis of the terminal ileum demonstrated that the number of IL-23p19 expressing macrophages was increased. Adalimumab was administered, and his back pain and abdominal symptoms improved. Adalimumab might be an effective treatment for gut inflammation related to ankylosing spondylitis.

P-299 Protective Effect of Tacrolimus on DSS-induced Colitis via Direct Activation of TGF-β–Smad Signaling Pathway in Intestinal Epitherial Cells

Background: Dysfunctions of intestinal barriers are reported to play important roles in the pathogenesis of Ulcerative colitis (UC). Cellular component of intestinal barriers is intestinal epitherial cells (IECs). Thus, homeostasis of IECs would be an object to prevent inflammatory bowel disease. Transforming growth factor (TGF)-&bgr; plays an important role in maintaining homeostasis of IECs. Calcineurin inhibitors are reported to upregulate TGF-&bgr; signaling pathway in renal tissue. Tacrolimus (Tac) is highly effective for steroid-resistant UC. The immunosuppressive function of Tac was reported to inhibit T cell proliferation and induce apoptosis of activated T cells. In addition, it is reported that Tac also suppressed the activity of macrophage and induced apoptosis. However, the effects on IECs have not clarified yet. The aim of this study was to investigate the effects of Tac on TGF-&bgr; signal in IECs and to examine its protective effect in an experimental colitis model. Methods: Colitis was induced by feeding of 4% dextran sodium sulfate (DSS) in C57/BL6 mice. We investigated protective effects of Tac with or without anti-TGF-&bgr; antibody by measuring body weight, histological assessment of mucosal damages and TdT-mediated dUTP nick end labeling (TUNEL) analysis for apoptosis of IECs. Next, we assessed phosphorylation of Smad2/3 in purified IECs by western blotting (WB) and muptiplex bead assay (MBA). Expression of TGF-&bgr; and TGF-&bgr; receptors in colonic epithelial cells were assessed by MBA and WB. We also examined whether Tac has direct effects on intestinal epitherial cells (IECs) or not using the intestinal epithelial cell line Caco2. The expression of TGF-&bgr; receptor type II (TGF-&bgr;RII) mRNA was evaluated by quantitative polymerase chain reaction (qPCR). Results: Treatment with Tac ameliorated mucosal destruction and prevented from weight loss through the reduction of epithelial apoptosis. The protective effect of Tac was partially maintained under anti-TGF-&bgr; antibody treatment. The expressions of TGF-&bgr;RI and II in purified IECs from Tac-treated mice were upregulated compared with that in vehicle-treated mice. Phospho-Smad2/3 expression at 6 hours after Tac injection was upregulated and the effect was observed despite of anti-TGF-&bgr; treatment. The expressions of active TGF-&bgr;1, 2, 3 in IECs or lamina propria in Tac-treated mice were not upregulated compared with that in vehicle-treated mice. In Caco2 cells, the expressions of TGF-&bgr;RI and II were upregulated in the treatment with Tac. Conclusions: These results indicate that Tac has an protective effect from apoptosis-mediated epithelial injury via activating TGF-&bgr;R-Smad pathway.

Capsule Endoscopy for Differentiating Early Crohn's Disease from Behçet'sDisease

Objective: Crohns disease (CD) and Behcets disease (BD) are two major causes of inflammatory lesions in the small bowel. For detecting such lesions, the most sensitive exam is small-bowel capsule endoscopy (CE), an imaging modality suitable for evaluating lesions of the small intestine, with a relatively low rate of capsule retention. However, few reports have employed CE to compare the small-bowel inflammation in early CD with that in early BD. Thus, the aim of our study was to obtain a systematic characterization of small-bowel lesions in early CD and BD by using CE. Methods: This retrospective single-center study included 22 patients with early CD and 16 patients with early BD. The patients underwent small-bowel CE for detection and characterization of small-bowel lesions. After reviewing the CE findings in each patient, we assessed the small-bowel mucosal inflammation using the Lewis score, an inflammatory biomarker (C-reactive protein), and the disease activity index. The CE findings (number, distribution, and shape of lesions), Lewis score, disease activity index, and C-reactive protein levels were compared between the groups of CD and BD patients. Results: Small-bowel lesions were observed in 90.9% of CD patients, and in 68.7% of BD patients. Regarding distribution, CD patients exhibited multiple concentrated ulcers, which were more severe distally, while BD patients mostly exhibited solitary ulcers. Regarding shape, linear and longitudinal ulcers were observed, respectively, in 68.2% and 50% of CD patients; however, no such ulcers were observed in BD patients. C-reactive protein levels and disease activity indices were poorly correlated with Lewis score for both diseases. Capsule retention during CE did not occur in any patient included in this study. Conclusion: CE is a valuable tool to assess the mucosal inflammation of the small bowel in early CD and BD. Greater mucosal inflammation in the distal small bowel, and presence of linear and longitudinal ulcers may be the key findings for the differential diagnosis of small-bowel inflammation between early CD and BD