A case of spontaneous colonic perforation in collagenous colitis.

BACKGROUND: Collagenous colitis (CC) is a clinicopathologic syndrome characterized by chronic watery diarrhea and distinctive histopathologic features. Spontaneous perforation of CC is extremely rare, because CC is usually managed medically, and the need for surgical intervention is rare. We report a surgical case of spontaneous colonic perforation of CC with acute abdomen disease. CASE PRESENTATION: A 77-year-old man was admitted to our hospital for abdominal pain and watery diarrhea. Computed tomography (CT) showed a thickened bowel wall with edema involving free air around the splenic flexure of the colon. Therefore, we performed emergency surgery with a diagnosis of colonic perforation. Intraoperative findings revealed colonic necrosis at the splenic flexure, so we performed a left hemicolectomy. Histopathological examination revealed typical findings of CC, a thick subepithelial collagenous band and deep ulcers with perforation. The postoperative course was uneventful, and the patient was discharged on the 28th postoperative day. After changing the proton pump inhibitor (PPI) from lansoprazole (LPZ) to rabeprazole (RPZ), he has not complained of diarrhea symptoms. CONCLUSIONS: Although spontaneous perforation is a rare complication of CC, it is possible to be diagnosed by symptom of acute abdomen disease. This is the seventh case of spontaneous colonic perforation of CC worldwide.

Magnified single-balloon enteroscopy in the diagnosis of intestinal follicular lymphoma: a case series.

The objective of this study was to evaluate the magnified endoscopic findings in the diagnosis of follicular lymphoma in the small intestine in comparison with those of intestinal follicular lymphoma and lymphangiectasia. Four patients with follicular lymphoma and 3 with lymphangiectasia in the small intestine were retrospectively analyzed. A prototype magnifying singleballoon enteroscope was used. The findings of the intestinal follicular lymphoma and lymphangiectasia were retrospectively analyzed to determine the magnified endoscopic findings of follicular lymphoma in the small intestine. Opaque white granules were observed in 3 of the 4 patients with follicular lymphoma. Magnified narrow-band imaging (NBI) of the opaque white granules showed stretched microvessels, which had a diminutive tree-like appearance. The remaining patient had no opaque white granules and only displayed whitish villi. Magnified NBI observation of the whitish villi revealed the absence of marginal villus epithelium, which was confirmed by histology. The magnified NBI enteroscopy revealed the diminutive tree-like appearance on the opaque white granules and the absence of marginal villus epithelium of the whitish villi in intestinal follicular lymphoma. These findings may be useful in diagnosing follicular lymphoma.

Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease.

BACKGROUND: Interleukin (IL)-36 (IL-36α, IL-36ß, and IL-36γ) is a recently reported member of the IL-1 cytokine family. In this study, we investigated IL-36 expression in the inflamed mucosa of patients with inflammatory bowel disease and characterized the proinflammatory actions of IL-36 cytokines in human colonic epithelial cells. METHODS: IL-36 mRNA expression was evaluated using real-time PCR. IL-36 protein expression was analyzed using immunoblotting and immunohistochemical technique. Intracellular signaling pathways were evaluated by immunoblotting and by specific siRNA-transfected cells. RESULTS: The mRNA expression of IL-36α and IL-36γ, but not of IL-36ß, was enhanced in the inflamed mucosa of patients with inflammatory bowel disease, in particular, in ulcerative colitis. Immunohistochemical analysis showed that T cells, monocytes, and plasma cells are the source of IL-36α and IL-36γ in colonic mucosa. DNA microarray analysis indicated that IL-36α induces the mRNA expression of CXC chemokines and acute phase proteins in intestinal epithelial cell line, HT-29 cells. IL-36α and IL-36γ dose-dependently and time-dependently induced the mRNA and protein expression of CXC chemokines (CXCL1, CXCL2, CXCL3 etc.) in HT-29 and Widr cells. Stimulation with IL-36α and IL-36γ assembled MyD88 adaptor proteins (MyD88, TRAF6, IRAK1, and TAK1) into a complex and induced the activation of NF-κB and AP-1 and also the phosphorylation of MAPKs. MAPK inhibitors and siRNAs specific for NF-κB and c-Jun AP-1 significantly reduced IL-36-induced CXC chemokine expression. CONCLUSIONS: IL-36α and IL-36γ may play a proinflammatory role in the pathophysiology of inflammatory bowel disease through induction of CXC chemokines and acute phase proteins.

Interleukin (IL)-1ß Is a Strong Inducer of IL-36γ Expression in Human Colonic Myofibroblasts.

BACKGROUNDS AND AIMS: Interleukin (IL)-36 cytokines are members of the IL-1 cytokine family. In this study, we investigated the expression of IL-36γ in human colonic myofibroblasts to explore the molecular mechanisms underlying IL-36γ induction. MATERIALS AND METHODS: IL-36 mRNA was analyzed by real-time PCR method. Secretion of IL-36γ protein was evaluated by Western blot and ELISA analyses. Molecular mechanism of IL-36γ induction was evaluated by siRNA analyses and immunofluorescence experiments. RESULTS: IL-36γ mRNA expression was scarcely detected in the cells without stimulation. IL-1ß induced a marked increase of IL-36γ mRNA expression. TNF-α markedly enhanced IL-1ß-induced IL-36γ mRNA expression. These responses were confirmed at the protein levels. The inhibitors for ERK1/2 (PD98059 and U0216) and a p38 MAPK (SB203580) significantly reduced the IL-1ß-induced IL-36γ mRNA expression. In addition, the siRNAs specific for NF-κB p65 and AP-1 (c-Jun) significantly reduced the expression of IL-1ß-induced IL-36γ mRNA. CONCLUSIONS: Colonic myofibroblasts are cellular source of IL-36γ in the intestine. IL-36γ expression was induced by the combination of IL-1ß and TNF-α via activation of MAPKs and transcription factors, NF-κB and AP-1.

A case of Crohn's disease that developed anti-infliximab and anti-adalimumab antibodies.

There are few reports about the rapid appearance of anti-adalimumab antibodies in patients with Crohn's disease positive for anti-infliximab antibodies. We report the case of a 29-year-old female patient with a diagnosis of Crohn's disease who revealed a loss of response to infliximab due to high levels of antibodies to infliximab, and did not respond to the subsequent therapy by adalimumab, with a rapid appearance of antibodies to adalimumab. As one of the possible mechanisms of non-response to adalimumab, immunologic reactivity of infliximab to adalimumab was suspected, since the patient's IgG that was obtained just before the induction of adalimumab reacted with infliximab and adalimumab. We should pay attention to the easy appearance of anti-adalimumab antibodies in association with reactivity of anti-infliximab antibodies to adalimumab in patients with high levels of anti-infliximab antibodies.

Agranulocytosis immediately after oral administration of cibenzoline and dabigatran in a patient with paroxysmal atrial fibrillation.

This case report describes agranulocytosis immediately after oral administration of cibenzoline and dabigatran in a 70-year-old woman with paroxysmal atrial fibrillation (AF). No blasts were found in peripheral blood and bone marrow, and the white blood cell count increased abruptly by intravenous administration of granulocyte colony-stimulation factor, suggesting an allergic response caused by cibenzoline or dabigatran, or both. Though antiarrhythmic drugs with anticoagulation therapy are commonly used to treat paroxysmal AF, caution has to be paid to drug-induced agranulocytosis.

[An elderly woman with duodenal perforation difficulty diagnose].

An 86-year-old woman was referred with acute epigastric pain. She had tenderness, but no muscular guarding of the epigastric lesion. Abdominal ultrasound showed a gallstone with a normal gallbladder wall and no ascites. The white blood cell count was 11,600/mm(3), but she was negative for C-reactive protein (CRP). An upper gastrointestinal tract endoscopic examination revealed only edema of the duodenal mucosa. Although H2-receptor antagonists were given, she had to be admitted due to chills and high fever. While the abdominal symptoms did not change, the CRP concentration became 14.79mg/dl. While plain abdominal X-ray did not show an abnormal gas pattern, subsequent abdominal CT examination showed air and fluid collection around the second portion of the duodenum. We diagnosed duodenal perforation and prepared for emergency operation. However, her general condition had markedly deteriorated during the hours. Laparotomy revealed a free purulent fluid around second portion of the duodenum caused by perforation of a duodenal diverticulum. The patient gradually recovered and was discharged after 58 days. Since a duodenal perforation in an elderly patient is difficult to diagnose early in spite of serious illness, abdominal CT should be encouraged.

Increased aggregation response of platelets in patients with inflammatory bowel disease.

BACKGROUND: Platelets play an important role in hemostatic and inflammatory responses. To evaluate any potential enhancement of platelet activity in patients with inflammatory bowel disease (IBD), we measured the platelet aggregation responses to various stimuli. METHODS: Twenty-two healthy controls, 24 patients with ulcerative colitis (UC) and 25 patients with Crohn's Disease (CD) were studied. The aggregation responses induced by three agonists (epinephrine, collagen, and ADP) were measured by an 8-channel aggregometer. The platelet-derived microparticles (PDMP) levels were measured by an enzyme-linked immunosorbent assay. RESULTS: Twenty-one out of the 22 healthy controls did not respond to epinephrine (0.1 microg/ml), collagen (0.2 microg/ml), or ADP (1.0 microM). Eight out of the 12 active UC patients were sensitive to all agonists, and 4 patients showed increased sensitivity to epinephrine/collagen or epinephrine/ADP. Three out of the 12 inactive UC patients were normal, but 9 of these patients showed increased sensitivity, mainly to epinephrine. Ten out of the 12 active CD patients were sensitive to all agonists, and 2 active CD patients were sensitive to epinephrine/collagen or epinephrine/ADP. Eight out of the 13 inactive CD patients were sensitive to two or all agonists. Even after remission, almost all of the UC and CD patients showed some increased sensitivity to the agonists. The platelet number and the plasma PDMP levels were significantly higher in the active IBD patients than in the control group. CONCLUSIONS: Platelet aggregation responses are enhanced in IBD, even in inactive-phase patients. This increased sensitivity of the platelets may play an important role in the pathophysiology of IBD.

[Characteristic of elderly patients with ulcerative colitis and therapeutic issue].

AIM: Ulcerative colitis (UC) primarily affects young adults, but the proportion of elderly patients with UC seems to be increasing. It is important that the clinical characteristics of elderly patients be analyzed. METHODS: In the older group consisted of 32 outpatients (23 aged 50-64 years old, 9 aged 65 or over) in our hospital, we evaluated disease duration, severity, therapeutic efficacy and other clinical problems. RESULTS: The age distributions of the disease onset showed a peak at early age and decreased with aging. The degree of severity was mainly mild, and left-sided or pancolitis were more frequent than expected in the older group. Most elderly patients suffered other diseases, and care was required in the administration of steroids. CONCLUSION: The clinical features of elderly patients with UC were similar to those of younger patients. However, It should be considered that elderly patients often have complications requiring care in the use of steroids.

Elevated circulating platelet-derived microparticles in patients with active inflammatory bowel disease.

OBJECTIVES: Platelet-derived microparticles (PDMPs) are active molecules involved in the hemostatic and inflammatory responses. To evaluate the changes in the platelet function in patients with inflammatory bowel disease (IBD), we measured circulating PDMP levels. METHODS: Twenty-five healthy controls, 44 patients with ulcerative colitis (UC), and 43 patients with Crohn's Disease (CD) were studied. The PDMP and soluble P-selectin (sP-selectin) levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the healthy controls, the PDMP levels were 17.2 +/- 6.2 U/mL. Significant differences were not observed between the healthy controls and inactive UC patients (20.8 +/- 9.5 U/mL, n = 25) or between the healthy controls and inactive CD patients (17.6 +/- 7.8 U/mL, n = 24). In contrast, the PDMP levels were significantly higher in both active UC (49.2 +/- 33.6 U/mL, n = 19) and active CD (48.6 +/- 42.8 U/mL, n = 19) patients than in the healthy controls. A significant correlation was found between the PDMP levels and the clinical activity indexes (CAI) of UC patients (r = 0.65, p < 0.01, n = 44), and between the PDMP levels and Crohn's disease activity indexes (CDAI) (r = 0.72, p < 0.01, n = 43). Elevated PDMP levels in active patients were significantly reduced after remission. A significant correlation was observed between the PDMP levels and the sP-selectin levels (r = 0.60, p < 0.01, n = 122). CONCLUSION: Elevated circulating PDMPs in active IBD patients suggest a role for platelets in the pathogenesis of IBD.

Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts.

BACKGROUND & AIMS: Interleukin (IL)-22, a member of the IL-10 subfamily, is a recently identified T-cell-derived cytokine. We investigated IL-22 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and analyzed its biologic activities in human colonic subepithelial myofibroblasts (SEMFs). METHODS: Mucosal IL-22 expression was evaluated by immunohistochemical procedures. The effects of IL-22 on colonic SEMFs were investigated by cDNA microarrays, Northern blots, enzyme-linked immunosorbent assay, and electrophoretic gel mobility shift assays (EMSAs). RESULTS: IL-22 was not detectable in normal colonic mucosa. In IBD mucosa, IL-22 expression was detectable in CD4-positive T cells. IL-22-positive cells were increased in ulcerative colitis and even more so in Crohn's disease. IL-22 receptor expression colocalized with a marker of SEMFs. IL-22 did not modulate SEMF proliferation and collagen synthesis. cDNA microarray analyses demonstrated that, in colonic SEMFs, IL-22 increased the messenger RNA (mRNA) expression of inflammatory cytokines (IL-6, IL-8, IL-11, and leukemia inhibitory factor [LIF]), chemokines, and matrix metalloproteinases. IL-22 induced an activation of nuclear factor (NF)-kappaB and activating protein (AP)-1 within 1 hour, and a blockade of NF-kappaB and AP-1 activation markedly reduced IL-22 induction of IL-6, IL-8, IL-11, and LIF mRNA. MAP-kinase inhibitors (PD98059, U0216, and SB202190) significantly reduced IL-22 induction of cytokine secretion. The combination of either IL-17 plus IL-22 or IL-19 plus IL-22 additively up-regulated cytokine secretion. CONCLUSIONS: IL-22 derived from activated T cells acts on SEMFs to elicit expression of proinflammatory cytokines and matrix-degrading molecules indicating proinflammatory/remodeling roles in IBD.

Interleukin-17 augments tumor necrosis factor-alpha-induced granulocyte and granulocyte/macrophage colony-stimulating factor release from human colonic myofibroblasts.

BACKGROUND: Interleukin (IL)-17 is a newly identified T-cell-specific cytokine. In this study, we investigated the effects of IL-17 on colony-stimulating factor (CSF) release in human colonic subepithelial myofibroblasts (SEMFs). METHODS: CSF release and mRNA expression were determined by enzyme-linked immunosorbent assay (ELISA) and Northern blotting, respectively. Nuclear factor (NF)-kappaB- and activating protein (AP-1)-DNA binding activities were evaluated by electrophoretic gel mobility shift assays (EMSAs). RESULTS: Unstimulated cells secreted a small amount of granulocyte G- and granulocyte/macrophage (GM)-CSF, and a considerable amount of M-CSF. IL-17 weakly enhanced G-CSF release, but did not affect GM- and M-CSF release. IL-17 selectively enhanced tumor necrosis factor (TNF)-alpha-induced G- and GM-CSF release. The combination of IL-17 plus TNF-alpha induced a marked increase in NF-kappaB- and AP-1-DNA binding activities. The adenovirus-mediated transfer of a stable form of IkappaBalpha and/or a dominant negative mutant of c-Jun markedly inhibited the IL-17 plus TNF-alpha-induced G- and GM-CSF mRNA expression. Furthermore, a stability study showed that IL-17 plus TNF-alpha markedly enhanced the stability of G- and GM-CSF mRNA. CONCLUSIONS: IL-17 augments TNF-alpha-induced G- and GM-CSF release via transcriptional and posttranscriptional mechanisms.

Development of dextran sulfate sodium-induced colitis is aggravated in mice genetically deficient for complement C5.

The complement system is a potent effector of innate immunity. To elucidate the pathophysiological role of the complement system in inflammatory bowel disease (IBD), we evaluated the development of dextran sulfate sodium (DSS)-induced colitis in genetically complement C5-deficient mice. We used DBA2/J mice, which are genetically deficient in complement C5. DBA1/J mice have a normal complement system, and were used as controls. Experimental colitis was induced by the oral administration of 3.5% (w/v) DSS in their drinking water for 10 days. On day 10, all mice were sacrificed and their colons were collected. The development of colitis was assessed by the histological score, disease activity index, myeloperoxidase (MPO) activity, and macroscopic changes of the colon. Body weight loss was more apparent in the DBA2/J mice than in control DBA1/J mice. The colon length was shorter in the DBA2/J mice than in DBA1/J mice. The disease activity index, histological colitis score, and MPO activity were all significantly higher in the DBA2/J mice than in DBA1/J mice. Microscopically, mucosal edema, cellular infiltration and disruption of the epithelium were much more severe in the DBA2/J mice than in DBA1/J mice. The development of DSS colitis was aggravated in genetically C5-deficient DBA2/J mice. These findings suggest that the complement system might play a protective role in the development of DSS-induced experimental colitis.

Suppression of inflammatory cytokine secretion by granulocyte/monocyte adsorptive apheresis in active ulcerative colitis.

To elucidate the molecular mechanisms involved in the therapeutic effects of granulocyte/monocyte adsorption apheresis, changes were investigated in the cytokine responses of peripheral blood mononuclear cells (PBMC) before and after granulocyte/monocyte adsorptive apheresis in ulcerative colitis (UC) patients. Four patients with active UC were enrolled. All patients responded to granulocyte/monocyte adsorptive apheresis. A total of 20 sessions of four patients were analyzed. Peripheral blood mononuclear cells were isolated from peripheral venous blood within 5 min before and after each session of granulocyte/monocyte adsorptive apheresis. The cells were stimulated with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha for 24 h, and the secreted IL-8 and IL-6 levels were determined by enzyme-linked immunosorbent assay (ELISA). IL-1beta-induced IL-8 and IL-6 secretion was significantly decreased after granulocyte/monocyte adsorptive apheresis. TNF-alpha-induced IL-8 secretion was also significantly decreased after apheresis, but there was no significant difference in TNF-alpha-induced IL-6 secretion (P = 0.052). In conclusion, granulocyte/monocyte adsorptive apheresis down-regulates the IL-1beta- and TNF-alpha-induced inflammatory responses in PBMC. The induction of hyporesponsiveness to pro-inflammatory cytokines may be an important factor mediating the clinical effects of granulocyte/macrophage adsorptive apheresis in UC patients.

Interleukin-1beta and tumor necrosis factor-alpha upregulate interleukin-23 subunit p19 gene expression in human colonic subepithelial myofibroblasts.

The recently identified cytokine interleukin-23 (IL-23) consists of p19 and p40 subunits. The major cellular source of IL-23 is dendritic cells and/or macrophages. We investigated the expression of IL-23 p19 mRNA in human colonic subepithelial myofibroblasts (SEMFs). p19 mRNA was not expressed in unstimulated SEMFs, but IL-1beta and TNF-alpha strongly induced p19 mRNA expression in these cells. The effects of IL-1beta were much stronger than those of TNF-alpha. These responses were observed in both a dose- and time-dependent manner. Furthermore, these cytokines acted synergistically when used in combination. A blockade of NF-kappaB activation by the overexpression of a stable form of IkappaBalpha completely blocked these responses, indicating that the induction of p19 mRNA expression by IL-1beta and TNF-alpha was mediated by the NF-kappaB activation pathway. In conclusion, this is the first report demonstrating that IL-23 p19 mRNA is inducible in colonic myofibroblasts by IL-1beta and TNF-alpha. The p19 expression in these cells might play a role in mucosal immune responses.