Kazuo Nobata

Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy.

Background and aims: The relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease (GORD) is controversial but it is accepted that GORD is associated with increased exposure to gastric acidity. The proinflammatory interleukin (IL)-1B polymorphisms increase the risk of hypochlorhydria and gastric atrophy. We examined the association between proinflammatory cytokine gene polymorphisms, presence of gastric atrophy, and risk of GORD in H pylori positive and negative subjects in Japan. Methods: We studied 320 consecutive dyspeptic patients without peptic ulcers or cancers. GORD symptoms were scored using the Carlsson-Dent questionnaire and erosive oesophagitis was assessed endoscopically. H pylori infection was diagnosed by urea breath test, histological examination, and serology. Gastric atrophy was assessed histologically, and polymorphisms in the IL-1B, IL-10, and tumour necrosis factor α (TNF-A) genes were genotyped. Results: Two hundred and eight patients were H pylori positive and 112 were negative. One hundred and eight (34%) were found to have erosive oesophagitis by endoscopic criteria (grade A: 78; grade B: 23; grade C: 6; grade D: 1). Erosive oesophagitis and GORD symptoms were significantly more common in H pylori negative compared with H pylori positive subjects (p<0.05). H pylori positive subjects were more likely to have corpus gastric atrophy than H pylori negative subjects (p<0.001). Among H pylori positive patients, those without erosive oesophagitis or GORD symptoms were significantly more likely to have corpus atrophy than subjects with erosive oesophagitis or GORD symptoms (p<0.05). Among H pylori positive patients, subjects homozygous for the proinflammatory allele IL-1B−511T had a significantly lower risk of erosive oesophagitis (odds ratio (OR) 0.06 (95% confidence interval (CI) 0.006–0.51); p = 0.01) and GORD symptoms (OR 0.10 (95% CI 0.01–0.85); p = 0.04) compared with those homozygous for the −511C allele, while none of the two other proinflammatory cytokine gene polymorphisms had significant correlations with erosive oesophagitis or GORD symptoms. Conclusions: A proinflammatory IL-1B genotype is associated with increased risk of atrophy and decreased risk of GORD in H pylori infected subjects in Japan. These data indicate that in some genetically predisposed subjects, H pylori infection may protect against GORD through induction of gastric atrophy.

Possible involvement of neutrophil elastase in impaired mucosal repair in patients with ulcerative colitis

Background. Little information is available on the relative contribution of peptide growth factors and leukocyte-derived proteinases to the repair processes in inflammatory bowel disease (IBD). We investigated their possible roles in epithelial cell restitution and proliferation in patients with IBD. Methods. The expression of hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), transforming growth factor-β (TGF-β), and neutrophil elastase (NE) was examined in colonic mucosal tissues. The effects of organ culture supernatants of mucosal tissues on epithelial cell restitution and proliferation were analyzed in vitro using an intestinal cell line, IEC-6 cells. Results. Most organ cultures detected the presence of measurable levels of HGF, with a relative paucity of KGF and TGF-β activity. Greater levels of HGF were obtained in the mucosa involved with IBD, especially in patients with ulcerative colitis (UC). The mucosa involved with UC also showed higher amounts of NE. The supernatants from the mucosa involved with UC possessed a prominent stimulatory effect on the restitution of IEC-6 cells. By contrast, significant suppression beyond baseline levels was observed for the proliferation of IEC-6 cells when they were incubated with recombinant HGF plus the supernatants from the mucosa involved with UC. This suppression was diminished considerably by preincubation of the supernatants with the anti-NE antibody. Conclusions. HGF produced in the intestinal mucosa may be an important stimulator acting on epithelial cell restitution in patients with IBD. However, NE released in situ may impair mucosal repair through inhibiting epithelial cell proliferation in patients with UC.

Abnormalities in the upper gastrointestinal tract in inflammatory bowel disease

Abstract.The predominant histopathologic feature of inflammatory bowel disease is the infiltration of acute and chronic inflammatory cells, including polymorphonuclear neutrophils, macrophages and lymphocytes, in the affected intestine. Helicobacter pylori is recognized as the most common cause of upper gastrointestinal lesions, and Helicobacter pylori-associated gastritis is characterized by increased numbers of acute and chronic inflammatory cells. The pathogenesis of inflammatory bowel disease or Helicobacter pylori-associated gastritis involves immunological abnormalities, including the deficient or excessive expression of cytokines. The chronic inflammatory process in patients with Crohn’s disease may affect any part of the gastrointestinal tract, whereas ulcerative colitis affects mainly the colon and rectum. Here, we discuss abnormalities in the upper gastrointestinal tract in inflammatory bowel disease. Although the prevalence rate of Helicobacter pylori infection is low in Crohn’s disease, these patients often have abnormalities in the upper gastrointestinal tract.

Clarithromycin increases the release of heat shock protein B from Helicobacter pylori

Clarithromycin (CAM) may have certain indirect effects on Helicobacter pylori (H. pylori) other than its inhibitory activity on bacterial growth, as indicated in other infections with Gram‐negative micro‐organisms. In the present study, we examined the effects of lower concentrations of CAM on the release of heat shock protein B (HspB), one of the major antigenic proteins from H. pylori cells, as well as the changes in humoral immune response and histological degree of antral gastritis in patients who received eradication therapy with CAM.

Mucosal expression of matrix metalloproteinases and their tissue inhibitors in ulcerative colitis patients

ruption of the cysteine zinc2 bond associated with conformational change or proteolysis.13 Second, MMP activity is counterbalanced by endogenous inhibitors; a specific tissue inhibitor of MMPs (TIMP) can inhibit active forms of MMPs by 1 : 1 stoichiometric binding where the ratio of active MMPs to TIMPs regulates net enzymatic activity.14 In this issue of the Journal of Gastroenterology, Matsuno and colleagues15 report their investigation of the expression of several MMPs (MMP-1, -2, -3, -7, and -9) and their natural inhibitors (TIMP-1 and -2) in mucosal specimens from patients with UC, using an immunohistochemical method, and confirm the results of earlier studies demonstrating tissue distribution of each MMP and TIMP in colonic mucosa. They also found that the expression of MMPs was increased compared with that of TIMPs in the inflamed mucosa of patients with UC. There was a good correlation between the histological degree of inflammation and the frequency of epithelial expression of MMP-7 at the edge of ulcerative lesions. A similar correlation between MMPs and histological inflammation has been noted previously in the mucosal tissue of patients with UC,7,9 and these results suggest a significant role of the imbalance of MMPs and their natural inhibitors in the pathogenesis of UC. An increase in MMP expression according to the histological degree of inflammation (inflammatory cell density) in the inflamed mucosa of patients with UC probably reflects upregulation of their genes by cytokines and growth factors (e.g., interleukin-1 , tumor necrosis factor-α, transforming growth factor, and epithelial growth factor) produced in situ by inflammatory cells, such as T-lymphocytes, macrophages, endothelial cells, and myofibroblasts.16 In this respect, Salmela and colleagues17 recently reported data showing a functional relationship between MMPs and mucosal injury after T-lymphocyte activation, in their studies using an ex-vivo model with fetal gut explants. Further studies are necessary to dissect the mechanisms Ulcerative colitis (UC) and Crohn’s disease, collectively designated as inflammatory bowel disease (IBD), are chronic intestinal disorders associated with repeated mucosal injury and repair. Chronic intestinal inflammation and subsequent mucosal injury can accompany intensive remodeling of the subepithelial connective tissue, with increased turnover of the extracellular matrix (ECM). Disturbance of the balance between the synthesis and degradation of ECM components is increasingly implicated in the pathological findings of IBD, such as progressive mucosal disintegration and excessive deposition of collagens leading to fibrosis.1,2 Degradation of ECM components is coordinately controlled by the enzymatic activity of several species of metalloproteinase (MMP),3 and current concepts speculate an important role for these enzymes in the process of tissue destruction and remodeling in IBD.4–10 Based on their structure and substrate specificity, the human MMPs can be grouped into five subfamilies; collagenases (MMP-1, -8, and -13), stromelysins (MMP-3, -7, -10, -11, -12, and -26), gelatinases (MMP-2 and -9), membrane-bound MMPs (MMP-14, -15, -16, -17, -24, and -25), and another subfamily (MMP-19, -20, -23, and -28).11 These endopeptidases are released largely from stromal cells, including lymphocytes, polymorphonuclear neutrophils, macrophages, and smooth muscle cells, except for MMP-7 (matrilysin) and MMP-10 (stromelysin-2). The latter two enzymes are produced by epithelial cells and may be involved in epithelial migration through degrading basement membrane components, such as laminin, type IV collagen, casein, proteoglycans, and fibronectin.4,12 The expression of MMPs is strictly controlled under physiological conditions, as expected from their possible harmful nature in vivo. First, they are secreted as latent precursors or zymogens, most of which are activated later by the dis-

Long-term follow-up after eradication of Helicobacter pylori with omeprazole, clarithromycin, and tinidazole (OCT regimen) in a Japanese population

Background.  The long‐term benefit of Helicobacter pylori eradication treatment that includes metronidazole on peptic ulcer disease in Japan is unclear. We investigated the rate of H. pylori re‐infection and ulcer relapse after H. pylori eradication.

DNA typing for Helicobacter pylori isolates from eradication-failed patients: comparison of the isolates before and after therapy

Background : Failure of Helicobacter pylori eradication occurs frequently despite use of multiple microbial agents.

Immunological Status of the Stomach in Inflammatory Bowel Disease – Comparison between Ulcerative Colitis and Crohn’s Disease

Background/Aims: Ulcerative colitis (UC) mainly affects the colon and rectum, whereas the chronic inflammatory process in Crohn’s disease (CD) can affect any part of the gastrointestinal tract. Recently, however, upper gastrointestinal lesions have been reported in UC patients. In this study, we investigated the immunological status of the stomach in UC or CD patients. Methods: 26 patients each with UC, CD or functional dyspepsia (FD) underwent diagnostic upper gastrointestinal endoscopy, and biopsy specimens were obtained from the gastric antrum.The contents of interleukin (IL)-6 and IL-8 in the organ culture supernatants of antral mucosal tissues were measured with enzyme-linked immunosorbent assay. Results: Endoscopically abnormal findings in the stomach were more frequent in CD than in UC or FD patients. Mononuclear cell infiltration and IL-6 production in the gastric antrum did not significantly differ between UC and FD patients, but were higher in those with CD. There was no significant difference in neutrophil infiltration or IL-8 production between UC, CD, and FD patients. Conclusions: UC patients did not show the immunological abnormalities in the stomach seen in CD patients.

Acute Graft‐Versus‐Host Disease of the Large Intestine after Bone Marrow Transplantation

Abstract: A 13‐year old male with acute lymphocytic leukemia was admitted to our hospital for bone marrow transplantation (BMT). Lower abdominal pain and bloody diarrhea developed during the fourth post‐BMT week. Colonoscopy revealed edematous mucosa, erosions and multiple irregular ulcers in the rectum and sigmoid colon. Histologically, multiple apoptotic lesions were recognizable in the crypt basement membrane. Most infiltrating lymphoid cells were mature memory T lymphocytes bearing LFA‐la‐, CD43 and CD45RO antigens. HLA‐DR and ICAM‐1 immunostaining was seen on the vascular endothelium and the epithelium stained positively for HLA‐DR antigens.

3505 GASTROESOPHAGEAL PATHOPHYSIOLOGICAL FACTORS AFFECTING ENDOSCOPIC FINDINGS IN GASTROESOPHAGEAL REFLUX DISEASE (GERD).

Purpose: To investigate (1) the relationships between endoscopic severity of GERD and gastroesophageal pathophysiology, and (2) characteristics of GERD observed after H. pylori eradication. Methods: 1) Fifty two GERD patients (mean age 55.7 yo, 35 males) gave informed consent to entry this study. GERD related symptoms intake (by QUEST), upper gastrointestinal endoscopy, 24 h-long gastroesophageal pH monitoring, and gastric emptying test were done within a week. pH monitoring was performed under hospitalization 72 h after stopping the drugs affecting gastric acidity. Fasting serum gastrin, pepsinogen (PG) I and II levels were measured by radioimmunoassay. Grades of endoscopic esophagitis were classified according to the Los Angeles classification into none (Grade O; 12 cases), mild (Grade A & B; 20 cases), and severe (Grade C & D; 20 cases). 2) Esophagitis happened after H. pylori eradication was examined in 23 patients (mean age 56.0 yo, 17 males) who succeeded in H. pylori eradication among 29 H. pylori -positive gastric ulcer patients. Results; 1) In accordance with grades, prevalence of hiatal hernia was higher (none; 3, mild; 8, severe; 15 cases), and endoscopic atrophy was milder significantly. pH monitoring findings showed higher esophageal pH 3 holding time ratio (none; 28.2%, mild; 23.3%, severe; 16.0%: P H. pylori , nocturnal intragastric pH inversion, gastric emptying, and serum gastrin level. 2) After H. pylori eradication, the mean gastric pH and gastric pH>3 holding time ratio significantly decreased. GER ratio, BAO and BAO/MAO dramatically increased after eradication. Endoscopic esophagitis (Grade A) occurred in 5 patients 4 to 8 weeks after finishing the treatment. Only one patient showed GER ratio at more than 4%, and no differences in investigated factors were observed between in esophagitis and in non-esophagitis patients. Conclusions: These findings suggested that GER, gastric acid secretion capacity, and hiatal hernia of esophagus are responsible for the severity of endoscopic finding in the GERD and that other factors outside of GER may be involved in GERD after H. pylori eradication.