Activation of Myofibroblast TRPA1 by Steroids and Pirfenidone Ameliorates Fibrosis in Experimental Crohn's Disease.

BACKGROUND & AIMS: The transient receptor potential ankyrin 1 (TRPA1) channel is highly expressed in the intestinal lamina propria, but its contribution to gut physiology/pathophysiology is unclear. Here, we evaluated the function of myofibroblast TRPA1 channels in intestinal remodeling. METHODS: An intestinal myofibroblast cell line (InMyoFibs) was stimulated by transforming growth factor-ß1 to induce in vitro fibrosis. Trpa1 knockout mice were generated using the Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. A murine chronic colitis model was established by weekly intrarectal trinitrobenzene sulfonic acid (TNBS) administration. Samples from the intestines of Crohn's disease (CD) patients were used for pathologic staining and quantitative analyses. RESULTS: In InMyoFibs, TRPA1 showed the highest expression among TRP family members. In TNBS chronic colitis model mice, the extents of inflammation and fibrotic changes were more prominent in TRPA1-/- knockout than in wild-type mice. One-week enema administration of prednisolone suppressed fibrotic lesions in wild-type mice, but not in TRPA1 knockout mice. Steroids and pirfenidone induced Ca2+ influx in InMyoFibs, which was antagonized by the selective TRPA1 channel blocker HC-030031. Steroids and pirfenidone counteracted transforming growth factor-ß1-induced expression of heat shock protein 47, type 1 collagen, and α-smooth muscle actin, and reduced Smad-2 phosphorylation and myocardin expression in InMyoFibs. In stenotic intestinal regions of CD patients, TRPA1 expression was increased significantly. TRPA1/heat shock protein 47 double-positive cells accumulated in the stenotic intestinal regions of both CD patients and TNBS-treated mice. CONCLUSIONS: TRPA1, in addition to its anti-inflammatory actions, may protect against intestinal fibrosis, thus being a novel therapeutic target for highly incurable inflammatory/fibrotic disorders.

Significant contribution of TRPC6 channel-mediated Ca2+ influx to the pathogenesis of Crohn's disease fibrotic stenosis.

Intestinal fibrosis is an intractable complication of Crohn's disease (CD), and, when occurring excessively, causes severe intestinal obstruction that often necessitates surgical resection. The fibrosis is characterized by an imbalance in the turnover of extracellular matrix (ECM) components, where intestinal fibroblasts/myofibroblasts play active roles in ECM production, fibrogenesis and tissue remodeling, which eventually leads to the formation of stenotic lesions. There is however a great paucity of knowledge about how intestinal fibrosis initiates and progresses, which hampers the development of effective pharmacotherapies against CD. Recently, we explored the potential implications of transient receptor potential (TRP) channels in the pathogenesis of intestinal fibrosis, since they are known to act as cellular stress sensors/transducers affecting intracellular Ca2+ homeostasis/dynamics, and are involved in a broad spectrum of cell pathophysiology including inflammation and tissue remodeling. In this review, we will place a particular emphasis on the intestinal fibroblast/myofibroblast TRPC6 channel to discuss its modulatory effects on fibrotic responses and therapeutic potential for anti-fibrotic treatment against CD-related stenosis.

Multiple lesions of gastrointestinal tract invasion by monomorphic epitheliotropic intestinal T-cell lymphoma, accompanied by duodenal and intestinal enteropathy-like lesions and microscopic lymphocytic proctocolitis: a case series.

BACKGROUND: In East Asia, monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), previously known as type II enteropathy-associated T-cell lymphoma (EATL), occurs more frequently than type I EATL, and coeliac disease is rare. CASE PRESENTATION: Here we present four cases of MEITL in Japanese patients, including the endoscopic and pathological findings of their duodenal and colorectal lesions. Tumor specimens obtained from duodenal, intestinal, and colorectal biopsies in all four patients showed a diffuse intramucosal infiltration of small to/or medium-sized lymphoma cells and numerous atypical intraepithelial lymphocytes (IELs). These cells were immunohistologically positive for CD103, CD3, CD7, CD8, CD56, and T-cell intracellular antigen-1. Upper and lower gastrointestinal and antegrade double-balloon endoscopy revealed foci of edematous mucosa, with or without villous atrophy, in the non-neoplastic mucosa. Histological studies demonstrated duodenal and intestinal enteropathy-like lesions as well as microscopic (lymphocytic) proctocolitis with increased CD3- and CD8-positive and CD56-negative T-IELs in all four patients. The clinicopathological findings of the non-neoplastic lesions were similar to those characteristic of coeliac disease, suggesting that variants of coeliac disease may be present in the prodromal lesions of MEITL. CONCLUSIONS: Our study supports the need for random gastrointestinal biopsies to determine tumor spread, the features of MEITL in the particular patients, and the presence of prodromal non-neoplastic lesions.

Retrospective Analysis of Growth Speed of 54 Lesions of Colitis-associated Colorectal Neoplasia.

AIM: This study used a multicenter questionnaire survey to evaluate the morphology and progression of the initial lesion in cases of colitis-associated colorectal neoplasia (CRN). PATIENTS AND METHODS: Endoscopic images of lesions that had been definitively diagnosed as CRN by pathological examination were retrospectively reviewed. RESULTS: This resulted in the identification of 54 initial lesions in 49 patients. The 54 initial lesions fell into the following categories: 22 endoscopically visible localized lesions consisting of 18 elevated lesions and 4 depressed lesions, as well as 32 lesions that were not endoscopically visible as localized and consisted of 20 active-phase mucosal lesions and 12 remission-phase mucosal lesions. Nineteen of the lesions eventually became advanced cancers, while 35 lesions eventually became early-stage cancers. The final lesions were 40 elevated lesions, 5 flat or depressed lesions and 9 stenotic lesions. The form of growth of the advanced cancers was progressive stenosis or increased elevation. For approximately 69% of the early-stage cancers, the growth form was increasing elevation or development of elevation. For 73.6% of the advanced cancers, the initial lesion underwent rapid growth and became advanced cancer within 3 years; they accounted for 25.9% of the total cancers. Approximately 40% of the initial lesions of CRN were endoscopically visible as localized lesions, while approximately 60% were judged to be inflammatory mucosal lesions. CONCLUSION: It will be necessary to proactively take biopsy inflammatory mucosal lesions in order to discover tumors early and periodic surveillance should be performed with the knowledge that tumors may grow very quickly.

High Expression of Intestinal Homing Receptor CD103 in Adult T-Cell Leukemia/Lymphoma, Similar to 2 Other CD8+ T-Cell Lymphomas.

We investigated the expression of the αEß7 integrin (CD103)-intestinal homing receptor of T-intraepithelial lymphocytes (IELs) in 130 cases of adult T-cell leukemia/lymphoma (ATLL). We detected CD103 lymphoma cells in 55% (31/56) of mainly gastrointestinal (GI)-involved ATLL cases. Among them, lymphoma cells of 18 cases located in other involved organs had similar CD103 expression patterns. Histologically, we found (a) increased reactive IELs in non-neoplastic mucosal layers in 28% (5/18) of surgical and mucosal resection cases, (b) preserved epithelial glands, and (c) numerous small intraepithelial ATLL nests in involved lesions in 36 (69%) and 21 (40%), respectively, of the 52 examined cases. These 3 patterns were common in intestinal type II enteropathy-associated T-cell lymphoma but were rare in intestinal EBV nasal-type/like T/natural killer (NK)-cell lymphoma. We detected CD103 tumor cells in 41% (16/39) of lymph node-involved ATLL, in 31% (11/35) of skin-involved ATLL, in 68% (21/31) of type II CD4 enteropathy-associated T-cell lymphoma cases, in 36% (8/22) of primary gastric T/NK-cell lymphomas, and in 77% (7/9) of CD8 epidermotropic mycosis fungoides. CD103 ATLL prefers involving the GI tract over the skin (P<0.05). CD103 expression in GI-involved and/or total ATLL cases was significantly higher than in other 9 T/NK-cell lymphoma groups (P<0.05 or 0.01). Only ATLL cases were commonly CD103 in CD4 T/NK-cell lymphoma groups (P<0.05 or 0.01). Human T-lymphotropic virus-1-infected CD103 T-IELs and mucosal T cells may be important sources of ATLL.

Endoscopic ultrasonography of duodenal aberrant pancreas: comparison with histology after endoscopic resection.

We present the case of a 45-year-old man with an aberrant pancreas in the duodenum. He was referred to our hospital for gastric cancer screening. On upper gastrointestinal endoscopy, a submucosal tumor was noted in the second portion of the duodenum; it was 10 mm in diameter, with a smooth surface and bridging fold. Endoscopic ultrasonography (EUS) showed a hypoechoic lesion with small anechoic areas located in the third sonographic layer of the duodenum wall. To confirm the exact diagnosis, endoscopic resection was performed. The histological diagnosis was aberrant pancreas, Heinrich type II. The hypoechoic lesion and anechoic areas on EUS findings clearly corresponded with pancreatic acinus cells and duct dilation on histological findings, respectively. EUS findings are useful to diagnosis a duodenal aberrant pancreas that has ductal structures.

A Hereditary Enteropathy Caused by Mutations in the SLCO2A1 Gene, Encoding a Prostaglandin Transporter.

Previously, we proposed a rare autosomal recessive inherited enteropathy characterized by persistent blood and protein loss from the small intestine as chronic nonspecific multiple ulcers of the small intestine (CNSU). By whole-exome sequencing in five Japanese patients with CNSU and one unaffected individual, we found four candidate mutations in the SLCO2A1 gene, encoding a prostaglandin transporter. The pathogenicity of the mutations was supported by segregation analysis and genotyping data in controls. By Sanger sequencing of the coding regions, 11 of 12 other CNSU patients and 2 of 603 patients with a diagnosis of Crohn's disease were found to have homozygous or compound heterozygous SLCO2A1 mutations. In total, we identified recessive SLCO2A1 mutations located at seven sites. Using RT-PCR, we demonstrated that the identified splice-site mutations altered the RNA splicing, and introduced a premature stop codon. Tracer prostaglandin E2 uptake analysis showed that the mutant SLCO2A1 protein for each mutation exhibited impaired prostaglandin transport. Immunohistochemistry and immunofluorescence analyses revealed that SLCO2A1 protein was expressed on the cellular membrane of vascular endothelial cells in the small intestinal mucosa in control subjects, but was not detected in affected individuals. These findings indicate that loss-of-function mutations in the SLCO2A1 gene encoding a prostaglandin transporter cause the hereditary enteropathy CNSU. We suggest a more appropriate nomenclature of "chronic enteropathy associated with SLCO2A1 gene" (CEAS).

Endoscopic removal of a tablespoon lodged within the duodenum.

Here we report the case of a 34-year-old man who underwent endoscopic removal of a tablespoon from the stomach that was lodged within the duodenum. Removal required the use of a two-channel upper endoscope and polypectomy snares. Using the double-snare technique, the spoon was grasped at the proximal and distal parts of the handle. The double-snare was first pulled unsuccessfully and then pulled with simultaneous manual abdominal compression of the bulbus from the body surface. Compression was gently applied towards the stomach. As a result, the head of the spoon prolapsed from the bulbus, and was easily retracted from the stomach without any complications. In cases of foreign body lodging within the duodenum, the manual abdominal compression technique may help clinicians pull out the object and avoid surgery. The usefulness of manual compression is dependent on the foreign body's sharpness and the location.

Intestinal myofibroblast TRPC6 channel may contribute to stenotic fibrosis in Crohn's disease.

BACKGROUND: Intestinal fibrosis is a frequent complication of Crohn's disease (CD) and often leads to detrimental stricture formation. Myofibroblasts play active roles in mediating fibrotic changes in various tissues. We investigated whether transient receptor potential channels in intestinal myofibroblasts are involved in CD-associated intestinal fibrosis. METHODS: An intestinal myofibroblast cell line (InMyoFibs) was stimulated with transforming growth factor-ß1 (TGF-ß1) to model excessive fibrosis. Biopsy samples from nonstenotic or stenotic intestinal regions from patients with CD were used for quantitative comparisons of transient receptor potential channel and fibrosis-associated factor expression levels. RESULTS: TGF-ß1 treatment transformed spindle-shaped InMyoFibs into filament-shaped cells with enhanced α-actin stress fiber formation, transient receptor potential canonical (TRPC) 4 and TRPC6 messenger RNA and protein expression, and basal- and agonist-induced Ca influxes. TGF-ß1 also enhanced the formation of TRPC6/smooth muscle α-actin, TRPC6/N-cadherin, and TRPC4/N-cadherin coimmunoprecipitates. Inhibition of TRPC6 in InMyoFibs by RNA interference or dominant-negative mutations suppressed TGF-ß1-induced Ca influxes, stress fiber formation, and smooth muscle α-actin expression, but increased COL1A1, interleukin (IL)-10, and IL-11 expression, as well as Smad-2, ERK, and p38-MAPK phosphorylation. Similar increases in phosphorylation levels were observed with TRPC and calcineurin inhibitors. In stenotic areas in patients with CD, TRPC6, ACTA2 (smooth muscle α-actin), CDH2 (N-cadherin), COL1A1, IL-10, and IL-11 were significantly increased. CONCLUSIONS: These results suggest that augmented Ca influxes due to TRPC6 upregulation facilitate stress fiber formation and strengthen cell-cell interactions by negatively regulating the synthesis of antifibrotic factors in TGF-ß1-treated myofibroblasts. Similar changes observed in stenotic areas of patients with CD suggest the therapeutic significance of targeting TRPC6.

Effectiveness of concomitant enteral nutrition therapy and infliximab for maintenance treatment of Crohn's disease in adults.

BACKGROUND: One of the problems associated with infliximab (IFX) treatment for Crohn's disease (CD) is loss of response during maintenance therapy. AIMS: The aim of this multicenter, retrospective, cohort study was to determine whether enteral nutrition (EN) added to the IFX therapy regimen is effective for maintaining remission in adult CD patients. METHODS: Patients with CD who had started IFX therapy between April 2003 and March 2008 at any one of the seven participating medical centers and who met the following inclusion criteria were enrolled in the study: remission after triple infusions of IFX followed by IFX maintenance therapy every 8 weeks, and follow-up data available for ≥ 1 year. Remission was defined as a C-reactive protein (CRP) level of <0.3 mg/dL, and recurrence was defined as an increase in CRP to ≥ 1.5 mg/dL or shortening of the IFX interval. Patients were classified by EN dosage into two groups (EN group and non-EN group). The cumulative remission period and related factors were analyzed. RESULTS: Of the 102 adult CD patients who met the inclusion criteria, 45 were in the EN group and 57 were in the non-EN group. The cumulative remission rate was significantly higher in the EN group than in the non-EN group (P = 0.009). Multivariate analysis revealed that EN was the only suppressive factor for disease recurrence (P = 0.01). CONCLUSIONS: The results demonstrate that among this CD patient cohort, EN combined with IFX maintenance treatment was clinically useful for maintaining remission.

Elevated paraneoplastic hypercholesterolemia in a case of hepatoid adenocarcinoma of the stomach with liver metastasis.

A 67-year-old man was admitted to our hospital because of a large liver tumor revealed by ultrasonography. Laboratory data showed increased serum levels of alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), which are tumor markers for hepatocellular carcinoma. In addition, the serum cholesterol level was extremely high. Endoscopic examination revealed advanced gastric cancer. Histological findings of the stomach and liver tumor showed they were both hepatoid adenocarcinomas and were both positive for antibodies against AFP as well as DCP, suggesting that the tumors were gastric cancer with liver metastasis. Moreover, 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a key enzyme for regulation of cholesterol synthesis, was upregulated in the tumor tissues. Accordingly, we diagnosed this patient with AFP- and DCP-producing gastric cancer accompanied by paraneoplastic hypercholesterolemia. Paraneoplastic hypercholesterolemia is sometimes seen in hepatocellular carcinoma, but never in gastric cancer. This case is interesting because of the feature of hepatoid adenocarcinoma.

Eosinophilic gastroenteritis in a patient with chronic hepatitis C who received treatment with pegylated interferon.

A 54-year-old male was treated for chronic hepatitis C with pegylated interferon (PEG-IFN) α-2a administered for 24 weeks. HCV-RNA was negative at 24 weeks after treatment, showing sustained virological response (SVR). Abdominal distention and diarrhea were observed 28 weeks after commencing the treatment, i.e., 4 weeks after completing treatment. The elevation of eosinophil count was observed in blood tests and ascites, and because eosinophilic infiltration was also observed on gastrointestinal histopathology, the patient was diagnosed with eosinophilic enteritis. As the eosinophil count spontaneously improved and abdominal symptoms disappeared, the patient was not treated with steroids. The onset of eosinophilic enteritis during interferon therapy is comparatively rare. In this case, PEG-IFN was considered to be the causative factor. Furthermore, we suggested that subserosal eosinophilic enteritis may have characteristic symptoms in patients having hepatic diseases treated with interferon.

Diagnostic value of endoscopic and endoscopic ultrasound characteristics of duodenal submucosal tumour-like heterotopic gastric mucosa.

OBJECTIVE: Recent studies have reported that duodenal heterotopic gastric mucosa (HGM) has been observed in 8.9% of patients who undergo esophagogastroduodenoscopy. However, there are few reports concerning the endoscopic and endoscopic ultrasound characteristics of submucosal tumour-like HGM in the duodenum. METHODS: Endoscopic, endoscopic ultrasound (EUS) and histological findings were analyzed in six patients with submucosal tumour-like HGM, which were confirmed by pathological examination of biopsy or endoscopic polypectomy specimens. RESULTS: Endoscopically, the lesions appeared as a solitary, sessile submucosal tumour-like mass with a depression at the top. In four of six patients, small granular structures were found in the depressed area of the mass. On EUS, all masses demonstrated a heterogeneous pattern, among which four patients presented anechoic areas while two patients showed no anechoic areas. All lesions were localized within the mucosa and submucosa on EUS. Histologically, they consisted of gastric glands and some dilated glands, and were covered with normal duodenal epithelium. In four of six lesions, the tumours were composed of gastric-type foveolar epithelium showing papillary growth, fundic glands and pyloric glands, while the others consisted of gastric-type foveolar epithelium and pyloric glands. CONCLUSION: A heterogeneous pattern on EUS and small granular structures on esophagogastroduodenoscopy represent valuable diagnostic features of submucosal tumour-like HGM.

[A case of ulcerative colitis following smoking cessation].

A 59-year-old man was admitted to our hospital because of watery diarrhea and bloody stool lasting for a month. The patient had been a habitual smoker, smoking 25 cigarettes/day for 35 years. However, he had recently stopped smoking since a giant bulla in the left lung had been found. One month after discontinuing smoking, the patient's symptoms appeared. Colonoscopic examination demonstrated granulated mucosa, edema, and diminished vascular pattern were over the entire colon. Endoscopic and histological findings were compatible with the diagnosis of ulcerative colitis. We reported a case of ulcerative colitis that developed after smoking cessation and discussed the relationship between smoking and ulcerative colitis. Smoking may be associated with ulcerative colitis developed in middle aged person.

Clinical advantages of combined seton placement and infliximab maintenance therapy for perianal fistulizing Crohn's disease: when and how were the seton drains removed?

BACKGROUND/AIMS: Perianal fistulas are often found in patients with Crohn's Disease (CD), however, the complete management of such fistulas tends to be difficult. The aim of this study is to critically evaluate the clinical advantages of combined seton placement and infliximab maintenance therapy for perianal fistulizing CD. METHODOLOGY: Fourteen patients (9 males, 5 females) were evaluated for perianal fistulizing CD with the seton and infliximab therapy. Almost all patients were examined for the presence of either an abscess or fistulas by computed tomography (CT) and/or Magnetic Resonance Imaging (MRI) in addition to their physical findings. Seton placement was performed under general anesthesia, following the administration of inflixmab at a dose of 5 mg/kg for weeks 0, 2 and 6, and then about every 8 weeks as a maintenance therapy. RESULTS: For all patients average number of inserted drains was 4.5 and the average number of infliximab infusions was 9.4 times. The mean follow-up period was 12.1 months. A redness and/or swelling in perianal lesion were seen in 12 patients, moreover, pus discharge was seen in 7 patients, and serous exudate was seen in 7 patients. After the administration of these treatments, a reversal of the redness and/or swelling was seen in the exudate and a wet-to-dry wound change was found in all patients. Furthermore, the seton drains were completely removed in 11 patients. In most patients, seton drains were completely removed after 5 rounds of infliximab infusion. Following the removal of the seton drains from all the patients, they reported their post-treatment health and well-being to be good while also reporting a good quality of life (QOL). In addition, no serious adverse events were observed. CONCLUSIONS: The combined seton placement and infliximab maintenance therapy for perianal fistulizing CD was therefore found to be effective in terms of fistula closure and the removal of seton drains. This treatment modality is therefore considered to be a safe clinical procedure which improves the QOL in patients with CD.

Validity of activity indices in ulcerative colitis: comparison of clinical and endoscopic indices.

AIM: Various different clinical indices (CI) and endoscopic indices (El) have been used to evaluate the clinical disease activity of ulcerative colitis (UC). However, no standardized CI or El of UC has been established. The aim of the present study was to determine whether or not any of the CI and/or EI for assessing the disease activity of UC could be established as a standard. METHODS: The most frequently used CI and EI were identified from 100 published clinical trials dealing with UC, and representative CI and El were selected. Seventy-four patients were enrolled in this study and their CI and El were assessed prior to treatment and at 2, 4 and 8 weeks after treatment. Furthermore, changes over time and relationships among the indices were analyzed. In this study, the clinical activity index (CAI), the disease activity index (DAI), the Lichtiger index (LI) and the Seo index were selected as the representative CI, and the Baron score and the Rachmilewitz endoscopic index (REI) were selected as the representative EI. RESULTS: A significant decrease in all the CI and El was observed after treatment, as compared with the baseline values. Moreover, there were positive relationships among the CI and between the CI and El. CONCLUSION: Our results demonstrated that all the CI and El examined were almost equally useful for evaluating disease activity in UC patients. Further studies may help to determine which of the indices is the most suitable for use in UC clinical trials.

Clinicopathological characteristics of primary gastric T-cell lymphoma.

AIMS: To investigate the clinicopathological characteristics of 20 primary gastric T-cell lymphoma (GTCL) cases without human T-lymphotropic virus type I infection in Japan, a non-endemic area for coeliac disease. METHODS AND RESULTS: Fifteen cases had no history of persistent diarrhoea or severe hypoproteinaemia. Histologically, 13 cases (65%) consisted of large cell lymphoma and seven (35%) were of medium-sized cells. Intraepithelial lymphoma cell invasion was found in three cases (15%). Two of 10 surgical cases (20%) showed intramucosal tumour cell spreading with enteropathy-like features. Helicobacter pylori CagA gene was detected in three of 10 cases (30%). The lymphoma cells of all 20 cases were positive for CD3 and/or TCRbetaF1 and negative for CD56. CD4- and CD8- lymphoma was found in 11 cases (55%), CD4+ lymphoma in seven (35%) and CD8+ lymphoma in two (10%). CD30+, CD5+ and CD25+ lymphomas were detected in nine (45%), 10 (50%) and 11 (55%) cases, respectively. Five-year survival of the 16 available cases was 54%. Early clinical stage and medium-sized cell lymphoma were significantly (P < 0.05) better prognostic factors. CONCLUSIONS: Patients with GTCL exhibit distinct clinicopathological findings and prognoses from those with enteropathy-associated T-cell lymphomas. GTCL may be mainly derived from lamina propria and parafollicular T cells.

Oral administration of mesalazine protects against mucosal injury and permeation in dextran sulfate sodium-induced colitis in rats.

OBJECTIVE. Mesalazine, from which 5-aminosalicylic acid is released, is a therapeutic drug for inflammatory bowel disease. There has been no study concerning the effect of orally administered mesalazine on dextran sodium sulfate (DSS)-induced colitis in the rat model of ulcerative colitis. MATERIAL AND METHODS. Colitis was evaluated by means of the length of the colon, white blood cell count (WBC), tissue myeloperoxidase (MPO) activity, and histological inflammation scores. Colonic mucosal permeation was evaluated using Evans blue. The localization of a tight junction protein, occludin, was evaluated immunohistochemically and examined using confocal laser scanning microscopy. RESULTS. Mesalazine significantly improved changes in the length of the colon, tissue MPO activity, WBC, and the histological inflammation score as compared with DSS-induced colitis. Furthermore, the drug completely inhibited the increased permeation in DSS-induced colitis in rats. The immunofluorescence signals of occludin were disrupted and irregularly distributed in DSS-induced colitis, while the signals appeared as a typical reticular pattern but with reduced intensity by the administration of mesalazine, without any reduction in the protein content. In addition, the oral administration of mesalazine significantly improved mucosal permeation, thereby protecting the intestinal mucosa against injury in DSS-induced colitis in rats. CONCLUSIONS. These findings suggest that the recovery of mucosal impairment due to treatment with mesalazine may be associated with the protection of the tight junction protein occludin in DSS-induced colitis.