Matrix metalloproteinase (MMP)-9 plays an important role in the pathogenesis of colitis. Recent studies have demonstrated that chymase is involved in the conversion of promatrix metalloproteinase (proMMP)-9 to MMP-9. However, whether chymase contributes to the activation of proMMP-9 in colitis has remained unclear. In this study, we administered 5% dextran sodium sulfate (DSS) solution to mice for 7 days. At 7 days after starting administration, both chymase activity and MMP-9 activity were significantly increased. In extract from colitis in DSS-treated mice, MMP-9 activity was significantly increased after 8 h of incubation, but increased activity was almost completely suppressed in the presence of a chymase inhibitor, 2-(5-formylamino-6-oxo-2-phenyl-1,6-dihydropyrimidine-1-yl)-N-[{3,4-dioxo-1-phenyl-7-(2-pyridyloxy)}-2-heptyl] acetamide (NK3201). At 7 days after starting administration, intestinal length was significantly shorter in DSStreated mice than in normal mice, but these changes were significantly prevented by NK3201 (10 mg/kg per day i.p.). Disease activity index and histological damage score were also significantly reduced by NK3201. The filtrated neutrophil number was significantly decreased by NK3201. Furthermore, NK3201 significantly attenuated not only chymase activity but also MMP-9 activity in DSS-treated mice. These findings suggest that chymase plays an important role in the development of colitis via MMP-9 activation.Ulcerative colitis is an inflammatory bowel disease (IBD) affecting the distal colon; the etiology remains unclear. In chronic tissues of patients with IBD, the synthesis and release of inflammatory cytokines and recruitment of inflammatory cells induce the degradation of extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are important enzymes for degrading ECM proteins, and MMPs are reportedly involved in the pathogenesis of IBD via ECM degradation . MMPs are a family of zinc-and calcium-dependent endopeptidases. Among the MMPs, MMP-2 and MMP-9 are known as gelatinases and are consistently up-regulated during active flares of IBD in patients and animal models of colitis (Baugh et al., 1999;Tarlton et al., 2000). In particular, MMP-9 may play an important role in the degradation of ECM in ulcerative colitis. Oral administration of dextran sodium sulfate (DSS) is used to induce colitis in animal models, and the resulting colonic lesions resemble those observed in patients with ulcerative colitis (Elson et al., 1995). DSS-induced colitis is significantly attenuated in MMP-9-deficient mice but not in MMP-2-deficient mice (Castaneda et al., 2005;Garg et al., 2006). Thus, MMP-9 inhibition might offer a useful strategy for attenuating the development of colitis.Chymase is a chymotrypsin-like serine protease located in the secretory granules of mast cells. Serine proteases, such as MMP-3, and trypsin are known to process promatrix metalloproteinase (proMMP)-9 to MMP-9 in vitro (Sang et al., 1995;Shapiro et al., 1995). Fang et al. (1996Fang et al. ( , 1997 reported tha...

BackgroundProton-pump inhibitors such as omeprazole are a standard treatment to prevent non-steroidal anti-inflammatory drug-induced upper gastrointestinal mucosal injuries. However, it is unclear which drugs may protect against all NSAID-induced digestive-tract injuries. Here, we compare the efficacy of the gastromucoprotective drug irsogladine with omeprazole in preventing NSAID-induced esophagitis, peptic ulcers, and small-intestinal mucosal injury in healthy subjects.MethodsThirty-two healthy volunteers were assigned to an irsogladine group (Group I; n = 16) receiving diclofenac sodium 75 mg and irsogladine 4 mg daily for 14 days, or an omeprazole group (Group O; n = 16) receiving diclofenac sodium 75 mg and omeprazole 10 mg daily for 14 days. Esophagitis and peptic ulcers were evaluated by esophagogastroduodenoscopy and small-intestinal injuries by capsule endoscopy, fecal calprotectin, and fecal occult blood before and after treatment.ResultsThere was no significant difference between Group I and Group O with respect to the change in lesion score in the esophagus, stomach, and duodenum before and after treatment.NSAID treatment significantly increased the number of small intestinal mucosal breaks per subject by capsule endoscopic evaluation, from a basal level of 0.1 ± 0.3 up to 1.9 ± 2.0 lesions in Group O (p = 0.0002). In contrast, there were no significant changes in the mean number of mucosal breaks before and after co-treatment in Group I (0.3 ± 0.8 to 0.5 ± 0.7, p = 0.62), and the between-group difference was significant (p = 0.0040). Fecal calprotectin concentration, when the concentration before treatment was defined as 1, was significantly increased both in Group O (from 1.0 ± 0.0 to 18.1 ± 37.1, p = 0.0002) and Group I (from 1.0 ± 0.0 to 6.0 ± 11.1, p = 0.0280); the degree of increase in Group O was significantly higher compared with that in Group I (p<0.05). In addition, fecal occult blood levels increased significantly in Group O (p = 0.0018), but there was no change in Group I (p = 1.0), and the between-group difference was significant (p = 0.0031).ConclusionIrsogladine protected against NSAID-induced mucosal injuries throughout the gastrointestinal tract, from esophagus to small intestine, significantly better than omeprazole.Trial registrationThis study was registered in the UMIN Clinical Trials Registry (Registry ID number; UMIN000008114)

We compared the prophylactic effects of a mucoprotective drug, GGA, and an H2RA, famotidine, on mucosal injury involving the esophagus to the small intestine related to the two-week oral administration of diclofenac sodium in healthy volunteers. In the upper digestive tract, the prophylactic effects were similar between the two drugs. However, in the small intestine, GGA more markedly inhibited the development of lesions compared to famotidine.

The results suggested that SIMV induces anti-fibrotic activity that is not directly involved in the anti-inflammatory effect from a relatively early stage the healing process of TNBS-induced colitis.

Rapid induction therapy with oral tacrolimus shortened the time to achievement of appropriate trough levels and demonstrated a high remission rate 28 d after treatment initiation. Rapid induction therapy with oral tacrolimus appears to be a useful therapy for the treatment of refractory UC.