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Biomedical subjects

K Kusugami

Publications and source records attributed to K Kusugami.

At least 19 recordsLinked to original sources
PubMed1998

Expression of Bcl-2 and p53 correlates with the morphology of gastric neoplasia.

The growth of a tumour can be determined by an interplay between cell proliferation and loss. The expression of apoptosis-related proteins (Bcl-2 and p53), cell proliferation (Ki-67), and apoptotic cell death were investigated using immunohistochemistry and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling in gastric neoplams, to evaluate whether they correlate with the morphology of the tumour. The materials included ten cases of gastric adenoma and 40 cases of early gastric carcinoma consisting of differentiated adenocarcinomas (n = 20) and undifferentiated carcinomas (n = 20). All cases of adenoma and eight cases of differentiated adenocarcinoma were of the elevated type, while 12 differentiated adenocarcinomas and all of the undifferentiated carcinomas were of the depressed type. The diffuse expression of Bcl-2 was observed in all cases of adenoma and seven out of eight (88 per cent) of elevated-type differentiated adenocarcinoma. In contrast, Bcl-2 expression was absent or focal in the depressed type of carcinoma. Overexpression of p53 was found exclusively in the depressed type of carcinoma. Thus, Bcl-2 and p53 expression was associated with tumour morphology. It seemed unlikely that Bcl-2 and p53 expression was involved in the morphogenesis of the gastric tumours through inhibiting apoptotic cell death, since the degree of apoptosis in Bcl-2-positive gastric tumours was rather higher than that in Bcl-2-negative ones and it did not differ significantly between p53-positive and p53-negative tumours. Instead, the diffuse distribution of Bcl-2 correlated with the superficial distribution of Ki-67-positive proliferating cells, and the overexpression of p53 had a tendency to correlate with the diffuse distribution of proliferating cells. These results suggest that diffuse Bcl-2 expression and a superficial distribution of proliferating cells may contribute to the elevated configuration, and that overexpression of p53 and a diffuse distribution of proliferating cells may result in the depressed configuration in the relatively early stages of gastric tumourigenesis.

Adenocarcinoma↗
PubMed1998

Effect of intragastric administration of beta-endorphin on thyrotropin-releasing hormone and somatostatin release into gastric lumen of rats.

The neuropeptides beta-endorphin (BE), thyrotropin-releasing hormone (TRH), and somatostatin (SOM) in the gastric mucosa have the capacity to regulate gastric function. To clarify the possible role of BE in the interactions of neuropeptides and gastric acid secretion we investigated the effect of the intragastric administration of BE on TRH and SOM release into the gastric lumen. BE (100ng/kg) induced an immediate decrease in TRH release and a reciprocal increase in SOM release into the gastric lumen, followed by the suppression of gastric acid secretion. When various doses of BE (0-500ng/kg) were administered, changes in TRH and SOM occurred in a dose-dependent manner. Pretreatment with naloxone dihydrochloride (5 mg/kg, intraperitoneally) completely inhibited the BE-induced changes in the release of these peptides. These findings suggest that BE has a paracrine effect on TRH and SOM release into the gastric lumen through opioid receptors, and that these interactions may be involved in the regulation of gastric acid secretion.

Animals↗
PubMed1998

Inhibitory effect of somatostatin on Helicobacter pylori proliferation in vitro.

BACKGROUND & AIMS: Somatostatin regulates gastric function and cell proliferation. We investigated whether exogenous somatostatin modulates Helicobacter pylori proliferation in vitro. METHODS: Bacteria were cultured in 5 mL Brucella broth. Bacterial numbers of H. pylori (ATCC 43504) and Escherichia coli were calculated 48 and 5 hours after incubation, respectively, by counting the colonies on the blood agar. Chemicals were dissolved in absolute methanol and added to the broth at a final methanol concentration of 1%. Intrabacterial guanosine 3',5'-cyclic monophosphate (cGMP) and adenosine 3',5'-cyclic monophosphate (cAMP) levels were measured by radioimmunoassay. RESULTS: Somatostatin significantly suppressed H. pylori proliferation at levels at or above 10(-11) mol/L. A similar antiproliferative effect was observed with 8-bromo-cGMP. At concentrations at or above 10(-8) mol/L, dibutyryl cAMP slightly but significantly stimulated bacterial proliferation. Gastrin had no effect. Somatostatin antibody immunoglobulin G fraction blocked the antiproliferative effect of somatostatin on ATCC 43504. Scatchard plot showed that ATCC 43504 has one class of binding site with relatively high affinity (Kd, 0.31 nmol/L). Somatostatin at 10(-11) mol/L increased cGMP and cAMP in H. pylori 11-fold and 6-fold, respectively. In contrast, somatostatin neither bound E. coli nor affected its proliferation. CONCLUSIONS: Somatostatin, at a similar level in human gastric juice (approximately 10(-11) mol/L), suppresses H. pylori proliferation mediated in part by a cGMP-dependent pathway in vitro, indicating a possible inhibitory effect of somatostatin in the gastric lumen on H. pylori proliferation in humans.

Antibodies↗
PubMed1998

Interleukin 15 activity in the rectal mucosa of inflammatory bowel disease.

BACKGROUND & AIMS: Interleukin (IL)-15 has been found to share many immunoregulatory activities in lymphocytes with IL-2. The aim of this study was to investigate IL-15 activity in organ cultures, localization of IL-15 messenger RNA (mRNA), and proliferation of lamina propria mononuclear cells (LPMCs) in response to recombinant IL-15 using the mucosal tissues obtained from patients with inflammatory bowel disease (IBD). METHODS: The contents of IL-15, tumor necrosis factor alpha, and IL-2 in the culture supernatant of the rectal mucosal tissues were determined by an enzyme-linked immunosorbent assay. Expression of IL-15 mRNA was analyzed by in situ hybridization, and proliferative response of LPMCs to recombinant IL-15 was determined by [3H]thymidine incorporation into DNA. RESULTS: Significantly greater IL-15 activity was detected in active IBD, and this elevation was also observed in inactive ulcerative colitis. In contrast, greater tumor necrosis factor alpha activity was observed only in active IBD, and IL-2 was not detected in organ cultures. In situ hybridization showed IL-15 mRNA in macrophages and epithelial cells in active IBD specimens, and recombinant IL-15 induced a dose-dependent proliferative response in LPMCs. CONCLUSIONS: Mucosal IL-15 may be involved in the pathogenesis of IBD as one of the important mediators in activation of mucosal immune cells.

Adolescent↗
PubMed1998

Differential normalization of mucosal interleukin-8 and interleukin-6 activity after Helicobacter pylori eradication.

There is differential resolution of mucosal infiltration with neutrophils and mononuclear cells following successful Helicobacter pylori eradication. We investigated the effects of H. pylori eradication on mucosal interleukin-8 (IL-8) and IL-6 activity in relation to the resolution of H. pylori-associated gastritis. Eighty-one duodenal ulcer patients with H. pylori infection received dual- or triple-treatment eradication therapy, and mucosal biopsy specimens obtained at the initial and follow-up endoscopic examinations were cultured in vitro for 24 h. The levels of IL-8 and IL-6 were measured by enzyme-linked immunosorbent assays. In the 42 patients in whom H. pylori eradication failed, there was little change in the numbers of neutrophils and mononuclear cells infiltrating the mucosa and in IL-8 and IL-6 activity. In the 39 patients in whom H. pylori was eradicated, there was normalization both in the numbers of infiltrating neutrophils and in mucosal IL-8 activity, which was evident within 1 month following therapy. In contrast, there was a gradual resolution of mononuclear cell infiltration over a 6-month period, accompanied by a gradual normalization in IL-6 levels. Addition of H. pylori to cultures of mucosal tissues induced a significant increase in IL-8 activity in both uninfected control subjects and patients from whom H. pylori was eradicated. However, this introduction yielded a significant increase in IL-6 activity only in the latter group. This study indicates a dichotomy in the changes of mucosal IL-8 and IL-6 activity after H. pylori eradication. The rapid normalization of IL-8 after H. pylori eradication and the ability of H. pylori cells to stimulate IL-8 in control tissues indicate that IL-8 induction is a part of the innate (nonimmune) responses to this organism. In contrast, the results of experiments analyzing IL-6 activity in cultured mucosal tissues suggest that the gradual resolution of mucosal IL-6 activity and mononuclear infiltration after successful eradication observed in vivo may reflect gradually diminishing residual immune responses against H. pylori.

Adult↗
PubMed1998

Central action of adrenomedullin to prevent ethanol-induced gastric injury through vagal pathways in rats.

Adrenomedullin (AM), belongs to the calcitonin gene-related peptide (CGRP) family and interacts with AM and CGRP1 receptors. Specific AM receptors and immunoreactivity are present in the rat brain. The effect of intracisternal injection of rat AM on ethanol-induced gastric lesions was studied in conscious Wistar rats. The peptide was injected intracisternally or intravenously under short anesthesia 20 min before intragastric injection of 70% ethanol. Corpus lesions were determined 1 h after ethanol. Intracisternal AM (75, 150, and 300 pmol) dose-dependently inhibited ethanol-induced gastric lesions by 40-72% and rat alpha-CGRP (150 pmol ic) by 76%. Intravenous AM (300 pmol) had no effect. The CGRP1 receptor antagonist CGRP-(8-37) (9.6-19.2 nmol ic) dose-dependently inhibited the protective effect of intracisternal alpha-CGRP but not that of AM. Subdiaphragmatic vagotomy and peripheral injection of atropine, indomethacin, or NG-nitro-L-arginine methyl ester (L-NAME) prevented AM protective action. L-Arginine but not D-arginine blocked L-NAME action. These data suggest that both AM and CGRP act in the brain to prevent ethanol-induced gastric lesions through interaction with their specific receptors. AM action may involve vagal cholinergic-dependent modulation of prostaglandins and nitric oxide protective mechanisms.

Adrenomedullin↗
PubMed1997

Fas-mediated cytotoxicity by intestinal intraepithelial lymphocytes during acute graft-versus-host disease in mice.

BACKGROUND & AIMS: Host-derived intestinal intraepithelial lymphocytes (IELs) increase in number during acute graft-versus-host disease (GVHD) in mice. In the present study, we examined Fas-mediated cytotoxicity by host-derived IELs against Fas-expressing target cells to see whether Fas/Fas ligand (Fas-L) interaction is involved in the pathogenesis of enteropathy during acute GVHD. METHODS: Acute GVHD was induced by injection of parental spleen cells into nonirradiated F1 mice. The expression of Fas antigen on the intestinal epithelial cells (IECs) was examined by flow cytometry, and the expression of messenger RNA (mRNA) for Fas-L, interleukin 2, and interferon gamma in host-derived IELs was assessed by reverse-transcription polymerase chain reaction. Fas-mediated cytotoxicity by host-derived IELs was assessed using Fas-transfected cells, IECs, and Fas immunoglobulin Fc fusion protein (Fas Fc). RESULTS: Fas antigen was constitutively expressed on the cell surface of IECs before and after GVHD induction. Although Fas-L mRNA was not detected or detected scarcely in either alphabeta or gammadelta IELs before GVHD induction, both IELs expressed high levels of mRNA for Fas-L and interferon gamma after GVHD induction. Host-derived IELs during acute GVHD showed cytotoxicity against Fas-transfected target cells and IECs, which was partly blocked by addition of Fas Fc. CONCLUSIONS: Fas/Fas-L-mediated cytotoxicity by host-derived IELs may be partly responsible for the enteropathy during acute GVHD.

Animals↗
PubMed1997

Mucosal chemokine activity in Helicobacter pylori infection.

We examined secretion, mRNA expression, and histologic localization of interleukin-8 (IL-*) and growth-related gene product-alpha (GRO alpha) in the Helicobacter pylori-infected gastric antral mucosa. Antral biopsies were obtained from an area of endoscopically intact mucosa. Significantly higher levels of IL-8 and GRO alpha were secreted in organ cultures from patients with H. pylori infection, and their elevation was prominent in patients with duodenal ulcer. There was a significant association between these alpha-chemokine levels and histologic grades of activity, inflammation, and H. pylori density. In fresh antral biopsies, IL-8 and GRO alpha mRNA expression was detected more frequently in H. pylori-infected patients compared with those without infection. Immunofluorescence microscopy showed localization of IL-8 and GRO alpha proteins in gastric epithelial cells and infiltrating CD68+ macrophages. In the chemotaxis assay, a significant positive correlation was found between neutrophil migration induced by the organ culture supernatants and their contents of IL-8 and GRO alpha. After H. pylori eradication, a significant decrease was observed in IL-8 and GRO alpha levels detected in organ cultures. In conclusion, mucosal alpha-chemokine activity correlates well with histologic severity of H. pylori-associated antral gastritis and can be used to predict the effects of H. pylori eradication therapy.

Adult↗
PubMed1997

Mucosal interleukin-8 is involved in neutrophil migration and binding to extracellular matrix in inflammatory bowel disease.

OBJECTIVES: In this study, our purpose was to determine whether locally generated interleukin-8 (IL-8) is involved in neutrophil migration and binding to extracellular matrix, using the colonic mucosal specimens obtained from patients with inflammatory bowel disease (IBD). METHODS: Levels of IL-8 secreted in the organ cultures were measured by enzyme-linked immunosorbent assay. Chemotactic activity and binding capacity of neutrophils were induced by the organ culture supernatants. RESULTS: Significantly higher levels of IL-8 were secreted in patients with IBD, and its elevation was more prominent in patients with active ulcerative colitis. The organ culture supernatants induced higher chemotactic activity and binding capacity of neutrophils in patients with IBD, especially in those with active ulcerative colitis, compared with controls. These effects were inhibited significantly when the supernatants were submitted to preincubation with neutralizing anti-IL-8 antibody. CONCLUSIONS: Increased mucosal generation of IL-8 may attract neutrophils from the circulation into the inflammatory site and induce binding of neutrophils in the interstitial tissue, contributing to accumulation and activation of neutrophils in the affected mucosa with IBD.

Adolescent↗
PubMed1996

Expression of adhesion molecules in primary B-cell gastric lymphoma and lymphoid follicles.

To determine whether primary B-cell gastric lymphoma (GL) is one entity, we examined the expression of three adhesion molecules in the microvasculature of lymphomas. Stromal cells, including vascular endothelial cells, within lymphoid follicies of the gastric mucosa were also investigated. Twenty-two surgical specimens of GL were classified into low-grade malignant lymphoma arising from mucosa-associated lymphoid tissue (low-grade lymphoma, n = 9), and high-grade malignant lymphoma with (secondary high-grade lymphoma, n = 6) or without (primary high-grade lymphoma, n = 7) a low-grade component. The proportion of venules positive for ELAM-1 or VCAM-1 was significantly higher (P < 0.001) in primary high-grade lymphoma than in low-grade and secondary high-grade lymphomas. In gastric lymphoid follicles, the stromal cells of the germinal centre (GC) were positive for ICAM-1, ELAM-1, and VCAM-1, but the stromal cells of the marginal zone (MZ) were positive only for ICAM-1. We found two patterns of adhesion molecule expression in gastric lymphoid follicles, the MZ pattern and the GC pattern. Low-grade and secondary high-grade lymphomas, which had the MZ pattern, might be of MZ-cell lineage, but most primary high-grade lymphomas, which had the GC pattern, might be of follicular centre cell lineage.

Cell Adhesion Molecules↗
PubMed1996

Abnormal neuropeptide concentration in rectal mucosa of patients with inflammatory bowel disease.

Regulatory neuropeptides are widely distributed in the gastrointestinal tract, where they play an important role in motility, secretion, and immune and inflammatory responses. In this study, the rectal mucosal content of somatostatin (SOM), substance P (SP), beta-endorphin (BE), and thyrotropin-releasing hormone (TRH) was measured by radioimmunoassay in 56 patients with ulcerative colitis (UC), 15 patients with Crohn's disease (CD), 15 patients with acute infectious colitis (AIC), and 11 controls, who showed no inflammation of the rectal mucosa, nor abnormal bowel movements. The content of immunoreactive (ir)-SOM was decreased in UC patients, especially in those with persistent disease activity, while the levels of ir-SP, BE, and TRH were increased in such patients. Some changes of ir-peptide levels were also observed in CD and AIC patients. The changes in neuropeptide levels were analyzed in relation to histological grades of inflammation in UC patients, grades 4-5 showing the most significant changes. The levels of ir-SOM, SP, BE, and TRH showed no significant change in chronic persistent UC when measured 6-12 months after the initial examination. In contrast, in patients with remitting intermittent UC, the levels of SP and BE decreased during remission. Abnormal intestinal neuropeptide content may be implicated in the continued mucosal immune and inflammatory responses that are manifested in patients with inflammatory bowel disease.

Adult↗
PubMed1996

Lamina propria mononuclear cells express and respond to interleukin-2 differently in Crohn's disease and ulcerative colitis.

Lymphokine-activated killer (LAK) cell activity and messenger RNA (mRNA) expression for interleukin-2 (IL-2) were analyzed using lamina propria mononuclear cells (LPMC) in inflammatory bowel disease patients. Compared with control LPMC, Crohn's disease (CD) LPMC exhibited significantly higher levels of LAK cell activity, whereas ulcerative colitis (UC) cells showed significantly lower levels of cytolytic activity with a difference in the frequency of CD3+, CD56+ and CD3+, CD56+ LAK precursor cells. After incubation with IL-2, the proportion of CD3+, CD56+ lymphocytes continued to be higher in CD cultures and substantially lower in UC cultures. Freshly isolated CD LPMC exhibited significantly higher levels of IL-2 mRNA than controls. However, no significant difference was observed between UC and control cells. The level of IL-2 expression or responsiveness to IL-2 may be responsible for different mucosal immune reactivity between CD and UC patients.

Adolescent↗
PubMed1996

Neoadjuvant chemotherapy in scirrhous cancer of the stomach using uracil and tegafur and cisplatin.

We administered a mixture of uracil and tegafur (UFT)/cisplatin (CDDP) chemotherapy in 28 patients with scirrhous gastric cancer. In the regimen, UFT was orally administered at a dose of 200 mg/m2 twice a day. The CDDP was administered at a dose of 90 mg/m2 by 24-hour continuous infusion every 4 weeks. As a result, antitumor effects for primary gastric foci were achieved in 14 of the 28 patients (50%). Ascites from peritoneal dissemination disappeared completely in eight of 13 patients (62%). Total gastrectomy was performed in ten patients after 2 to 3 courses of chemotherapy. Histological response grades assessed on the resected specimen were Grade 2 in four, Grade 1b in three, Grade 1a in one and Grade 0 in two patients. Neoadjuvant chemotherapy is feasible against scirrhous gastric cancer and a subsequent prospective randomized trial should be prepared to clarify the survival benefit of the treatment.

Adenocarcinoma, Scirrhous↗
PubMed1996

Interleukin-8 activity correlates with histological severity in Helicobacter pylori-associated antral gastritis.

OBJECTIVES: To examine the background histology, interleukin-8 (IL-8) secretion, and expression of IL-8 mRNA and protein, using the gastric antral mucosa infected with Helicobacter pylori. METHODS: The antral biopsies were obtained from an area of endoscopically intact mucosa in 147 patients whose endoscopic diagnoses were normal (n = 41), duodenal ulcer (n = 58), gastric ulcer (n = 21), or gastritis (n = 27). Levels of IL-8 secreted in the organ cultures of mucosal biopsies were measured by an ELISA assay, and the expression of IL-8 mRNA and protein was analyzed in fresh biopsy tissues with RT-PCR and immunofluorescent microscopy, respectively. RESULTS: Significantly greater levels of IL-8 were secreted in patients with H. pylori infection, and its elevation was more prominent in duodenal ulcer patients than in those with gastric ulcer or endoscopically defined gastritis. There was an association among H. pylori density, IL-8 activity, and histological severity of activity and inflammation of gastritis in the Sydney system. Consistent with enhanced IL-8 activity in the organ cultures, IL-8 mRNA was detected in 16 of 23 fresh biopsy tissues studied in H. pylori-positive patients. In contrast, IL-8 transcript was detected in only one of 12 H. pylori-negative cases. Immunofluorescent microscopy showed localization of IL-8 protein in the gastric epithelial cells and lamina propria cells, primarily CD68+ macrophages in specimens with H. pylori infection. CONCLUSIONS: This study indicates that a strong correlation exists between mucosal IL-8 activity and histological severity in H. pylori-associated antral gastritis. Further studies will be necessary to determine the mechanisms involved in elevated mucosal IL-8 activity in H. pylori infection.

Adult↗
PubMed1995

Phenotypic and functional characterization of T-cell lines generated from colonoscopic biopsy specimens in patients with ulcerative colitis.

Intestinal T-cell lines were generated from lamina propria mononuclear cells isolated from colonoscopic biopsies in ulcerative colitis patients and controls. In both ulcerative colitis and controls, expanded cells were constituted largely by T-cell receptor alpha beta+, CD4+, CD45RA- (helper), and CD8+, CD11b- (cytotoxic) phenotypes. T-cell receptor V beta gene usage was not significantly changed after cell expansion and no difference was observed between ulcerative colitis and controls. Ulcerative colitis cells, especially those derived from the patients with long-standing disease, showed significantly higher levels of cytotoxicity against the target cells, including those of colonic epithelial origin, and enhanced production of tumor necrosis factor-alpha and interferon-gamma after short incubation with anti-CD3 antibody. Generation of T-cell lines from colonoscopic biopsy specimens may be useful for detailed functional characterization of locally infiltrating T cells in ulcerative colitis patients.

Adolescent↗