Mechanisms underlying the effects of leukocyte apheresis with a fiber filter in a rat model of dextran sulfate sodium-induced colitis.

While several clinical trials have suggested that leukocytapheresis (LCAP) by filtration can benefit patients with active ulcerative colitis, the mechanisms underlying these benefits are largely unknown. The aim of this study was to address the mechanisms that may underlie the therapeutic effects of LCAP using a dextran sulfate sodium-induced colitis model in rats. Treatment with the active column, but not the sham column, improved disease severity by down-regulating pro-inflammatory events, including the cell-proliferative responses and inflammatory cytokine and reactive oxygen production, as well as by up-regulating protective events, including hepatocyte growth factor production, bone marrow-derived endothelial progenitor cell induction, and colonic blood flow levels, which were mediated predominantly by calcitonin gene-related peptide. The improvement was also associated with the increase of Ki-67 labeling in the colonic epithelium. In conclusion, the LCAP procedure was used in a dextran sulfate sodium-induced colitis model in rats under extracorporeal circulation conditions. This approach down-regulated pro-inflammatory events and up-regulated protective events in association with disease improvement. These data suggest that LCAP is feasible in animals and should shed light on the mechanisms of LCAP in clinical settings.

Pro-inflammatory signaling by Jun-N-terminal kinase in inflammatory bowel disease.

Since Jun-N-terminal kinase participates in intracellular signaling cascades resulting in inflammatory responses, inhibiting this pathway may represent a new treatment for inflammatory bowel disease including ulcerative colitis and Crohn's disease. However, the functional significance of the activation of this kinase in inflammatory bowel disease remains unclear. We investigated whether Jun-N-terminal kinase activation is increased in inflammatory bowel disease and analyzed the effects of SP600125, which decreases inflammatory cytokine synthesis by inhibiting the phosphorylation of this kinase. Phosphorylation of the kinase was examined in affected human colon using an enzyme-linked immunosorbent assay and immunohistochemistry. The effect of SP600125 on cytokine production was examined in cultures of patients' leukocytes and colonic tissue. Finally, rats received injection of SP600125 (30 mg/kg, s.c.) or vehicle twice daily 2 h before the induction of colitis with dextran sulfate sodium. SP600125 effects were determined observationally and histologically. Colonic tissue contained increased phosphorylated kinase in patients with inflammatory bowel disease with expression localized to the nucleus of epithelial and lamina propria mononuclear cells in lesions. Culturing mononuclear cells or colonic tissue with SP600125 down-regulated inflammatory cytokine production. Prophylactic treatment with SP600125 significantly reduced clinical and pathological scores in dextran sulfate sodium-treated rats. This first demonstration of the pathogenetic role of Jun-N-terminal kinase in the development of intestinal inflammation suggests that inhibiting its phosphorylation could benefit patients with inflammatory bowel disease.

Increased circulating concentrations of growth-related oncogene (GRO)-alpha in patients with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic inflammatory state associated with increased risk of intestinal cancers. The aim of this study is to examine serum concentrations of growth-related oncogene (GRO)-alpha, a cytokine with inflammatory and growth-regulatory properties, in patients with IBD. We measured serum concentrations of GRO-alpha in 60 patients with ulcerative colitis, 42 patients with Crohn's disease, 16 patients with other colitides, 12 patients with colorectal cancer, and 40 normal subjects using an enzyme-linked immunosorbent assay. We then analyzed how the cytokine was related to clinical and laboratory variables. Serum GRO-alpha concentrations in patients with active IBD were significantly higher than those in patients with quiescent disease, which in turn were higher than those in normal controls. Concentrations in patients with active ulcerative colitis were higher than in patients with active Crohn's disease. Analysis of paired serum samples showed a decrease in GRO-alpha after initiation of therapy. Furthermore, serum GRO-alpha correlated well with laboratory markers of IBD activity. We conclude that GRO-alpha may have an important role in development of IBD, and might itself be used as a marker of activity. Manipulation of GRO-alpha function might prove therapeutically useful.

Bifidogenic growth stimulator for the treatment of active ulcerative colitis: a pilot study.

OBJECTIVES: Experimental studies have shown that luminal antigens are involved in chronic intestinal inflammatory disorders. Bifidogenic growth stimulator (BGS) is a prebiotic preparation produced by Propionibacterium freudenreichii isolated from Swiss cheese. Previously BGS was shown to act in the colon as a growth stimulator of Bifidobacteria. This study investigated the efficacy and safety of BGS in the treatment of ulcerative colitis. METHODS: Twelve patients with mildly to moderately active ulcerative colitis received orally 4.5 g of BGS daily for 4 wk in an open-label treatment protocol while the baseline anti-inflammatory therapy was continued. The response to treatment was evaluated clinically and endoscopically. Concentrations of short-chain fatty acids and the composition of commensal bacteria, including Bifidobacteria, Enterobacteria and Bacteroides species, were studied in stool samples. RESULTS: Patients showed improvement in their clinical activity index scores, with a significant decrease in the score from 7.4 +/- 2.8 to 4.7 +/- 1.5 (mean +/- standard error of the mean, P < 0.01). The endoscopic index score decreased from 4.4 +/- 1.7 to 2.8 +/- 1.8 (P < 0.05) with treatment. Patients showed an increase in stool butyrate concentrations after BGS treatment (P < 0.05). There were no significant changes in stool levels of bacteria as a result of BGS treatment. No side effects related to BGS were observed. CONCLUSIONS: Oral BGS therapy may represent a non-toxic way to treat ulcerative colitis. However, controlled studies are needed to demonstrate its efficacy in the treatment of this disorder.

Interleukin-10 in the pathophysiology of inflammatory bowel disease: increased serum concentrations during the recovery phase.

Using a specific enzyme-linked immunosorbent assay, IL-10 concentrations were measured in serum from 62 patients with ulcerative colitis (UC), 43 with Crohn's disease (CD), 25 with other colitides, and 44 normal control subjects. Serum IL-10 concentrations were increased in patients with active UC but not in those with active CD when compared with normal control subjects. A time course study showed that in patients with UC and CD, serum concentrations of IL-6 and C-reactive protein increased during the acute phase and returned to normal as patients go into remission. Notably, serum IL-10 concentrations increased during the phase of disease resolution and declined thereafter regardless of the treatment modality. Gel filtration analysis indicated that IL-10 circulated predominantly as a dimer. In conclusion, this study shows that serum IL-10 is increased during disease recovery in patients with inflammatory bowel disease, and may be a helpful marker in monitoring disease status.

Treatment of ulcerative colitis patients by long-term administration of germinated barley foodstuff: multi-center open trial.

Germinated barley foodstuff (GBF), which mainly consists of dietary fiber and glutamine-rich protein, is a prebiotic for ulcerative colitis (UC). In our previous study, we carried out a clinical trial of GBF with mildly to moderately active UC patients and showed that GBF treatment was able to attenuate the symptoms of UC in a relatively short-term. The aim of this study was to investigate the efficacy of long-term administration of GBF in the treatment of UC in a multi-center open trial. Twenty-one patients with mildly to moderately active UC received 20-30 g of GBF for 24 weeks in an open-label protocol while baseline treatments (5-amino-salicyrate compounds and/or steroids) were continued. The response to the GBF treatment was evaluated using a clinical scoring and after 24 weeks of observation, the GBF group showed a significant decrease in clinical activity index (especially, the degree of visible blood in stools and the presence of nocturnal diarrhea) compared with the control group (p<0.05). No side effects related to GBF were observed. In conclusion, GBF can reduce the clinical activity of UC over long-term as well as short-term administration. Nutraceutical GBF therapy may have a place in long-term management of UC, but controlled studies are needed to demonstrate its efficacy in the treatment of this disorder.

A patient with hyperlipidemia who had a gallbladder stone caused by administration of fenofibrate.

Fibrates are widely used for treatment of hyperlipidemia. It has been reported that gallbladder stones are formed by administration of clofibrate. It is thought that fenofibrate can cause the formation of gallbladder stone as a side effect. We encountered a patient with hyperlipidemia in whom a gallbladder stone was detected by computed tomographic scanning 3 months after the start of administration of fenofibrate during follow-up observation by blood biochemical examination and computed tomographic scanning. This case report will be of great value and importance.

Efficacy of vascular endothelial growth factor in the treatment of experimental gastric injury.

BACKGROUND/AIMS: Studies indicate that angiogenesis is important in tissue healing. However, the role of vascular endothelial growth factor (VEGF) in tissue healing has not been established. The aim of the study is to determine whether VEGF has a gastroprotective role in experimental gastric injury. METHODS: Acute gastric injury was induced in Sprague-Dawley rats by intragastric administration of 100% ethanol. Expression of gastric VEGF was determined in tissue homogenates by enzyme-linked immunosorbent assay and in paraffin-embedded sections by immunohistochemistry. The effect of systemic administration of anti-VEGF antibodies and recombinant VEGF on injury severity was assessed macroscopically and microscopically. RESULTS: Gastric VEGF concentrations peaked at 6 h and again 3 days after acute injury. The presence of VEGF was demonstrated in epithelial cells and in mononuclear cells. Blocking endogenous VEGF effects with anti-VEGF antibodies exacerbated mucosal injury. Administration of recombinant VEGF after the onset of injury reduced the severity of mucosal injury, irrespective of the timing of initial treatment with VEGF. Immunohistochemical detection of vascular endothelial cells revealed that the VEGF-induced mucosal repair is closely related to the degree of angiogenesis. CONCLUSION: The results provide strong evidence for the role of VEGF in the repair of tissue damage induced by ethanol. The results also show how VEGF may be used in a clinical setting to treat some acute gastric lesions.