Mutsumi Matsuu

Mechanism of the antiulcerogenic effect of IL-11 on acetic acid-induced gastric ulcer in rats

The purpose of this study was to evaluate the healing effect of interleukin-11 (IL-11) on acetic acid-induced gastric ulcer in rats. Gastric ulcers were induced in male Wistar rats by applying acetic acid to the fundus of the stomach. Recombinant human interleukin-11 (rhIL-11 100 microg/kg/twice daily, subcutaneously) was administered starting on the 2nd day before ulcer induction up through the 7th day after ulcer induction. Control rats were injected with bovine serum albumin. At 12 hours and 7 days after ulcer induction, the animals were sacrificed, and the ulcer index, proliferating cell nuclear antigen (PCNA) expression, and IL-11alpha receptor expression in the gastric tissues were studied. The ulcer index of the rhIL-11-treated rats was significantly lower than that of the control rats at the 7th day. The expression of PCNA as evaluated by Western blotting and immunohistochemistry, was enhanced in both the mucosal proliferative zone and proper muscle layer of the rhIL-11-treated rats in comparison with that in the control rats. IL-11alpha receptor expression was observed in the mucosal neck cells of the rhIL-11-treated rats and control rats. These findings suggest that IL-11 accelerates ulcer healing by inducing the proliferation of mucosal and muscular cells.

Altered Expression of β-Catenin during Radiation-induced Colonic Carcinogenesis

Summary Radiotherapy for malignant pelvic disease is commonly accompanied by treatment-induced proctitis, and rarely by colorectal cancer. Translocation of the b-catenin protein, which is a key downstream effector of the Wnt signal transduction pathway, is frequently found in colorectal cancer. Nuclear β-catenin enhances transcriptional activity of the cyclin D1 gene in cancer cells. Here, we evaluate the involvement of the Wnt pathway in radiation-induced colon carcinogenesis with rats (n = 36). β-catenin, APC, and cyclin D1 expression profiles were analyzed by immunohistochemistry in radiation-induced chronic colon injury including cancers and ulcerative lesions in rats (n = 12 in treated group, n = 12 in control group). In total, 3 cases of invasive adenocarcinomas were developed in the irradiated portion 50 weeks after a single dose of 36 Gy irradiation.Nuclear translocation of β-catenin was observed in all radiation-induced colon cancers, whereas this protein was also found in the cytoplasm and/or nucleus of 9 cases of non-neoplastic irradiated colonocytes. Nuclear translocation of β-catenin correlated with loss of APC and gain of cyclin D1 expression, suggesting activation of the Wnt pathway during radiation-induced colorectal carcinogenesis. A single dose of 10 Gy was also given for acute injury (n = 12: 3 each in days 0, 3, 5, and 7, respectively). β-catenin expression was distributed in the cytoplasm of degenerating glands at day 3 and 5, and was observed in the cell membrane of those glands with histological normalization at day 7 after irradiation. Because translocation of β-catenin was found in irradiated-colonic mucosa as well as colon cancer, disruption of β-catenin expression might be one of the early events in radiation-induced colonic carcinogenesis.

Expression of Tie-2 and angiopoietin-1 and -2 in early phase of ulcer healing

Background. Angiogenesis is an important process in tissue development and wound healing. The Tie-2 receptor tyrosine kinases and ligands, angiopoietin (Ang)-1 and -2 have been postulated to play key roles in vascular development. The purpose of this study was to evaluate the expression of Tie-2 and Ang-1 and -2 in an acetic acid-induced gastric ulcer healing process in rats. Methods. Gastric specimens were obtained at 0 (control), 1, 3, 5, 7, and 14 days after ulcer induction for reverse transcription polymerase chain reaction (RT-PCR), Western blot analysis, and immunohistochemical analysis. Results. Expression of Tie-2 and Ang-1 and -2 mRNAs was detected in normal gastric tissue and ulcerative tissues by RT-PCR. Western blot analysis revealed that Tie-2 expression reached a maximum on the third to fifth days. Expression of Ang-1 and -2 peaked on the first day. Ang-1 expression gradually became weaker in 2 weeks, whereas Ang-2 expression returned to normal in a few days. Immunohistochemically, Tie-2 was expressed constitutively in the endothelial cells of pre-existing vessels of the gastric wall, and Tie-2 expression was increased in the new capillaries of the ulcer base. Conclusions. These findings suggest that Tie-2 and Ang-1 and -2 play an important role in angiogenesis in the early phase of ulcer healing.

Sympathetic hyperfunction causes increased sensitivity of the autonomic nervous system to whole-body X irradiation

Abstract Matsuu, M., Shichijo, K., Ikeda, Y., Ito, M., Naito, S., Okaichi, K., Nakashima, M., Nakayama, T. and Sekine, I. Sympathetic Hyperfunction Causes Increased Sensitivity of the Autonomic Nervous System to Whole-Body X Irradiation. Radiat. Res. 163, 137–143 (2005). Although the etiology of radiation sickness is still unknown, disturbance of the autonomic nervous system is suggested to be a factor. This study was designed to compare the radiosensitivity of spontaneously hypertensive rats possessing sympathetic hyperfunction and control Wistar-Kyoto rats, and to analyze the effects of radiation on the autonomic nervous system in both strains. After a 7.5-Gy dose of whole-body X irradiation, the blood pressure decreased significantly at 8 h and 2 days in the spontaneously hypertensive rats, but not in the Wistar-Kyoto rats. Epinephrine levels in the adrenal gland of spontaneously hypertensive rats decreased at 4, 8 and 24 h, unlike the Wistar-Kyoto rats. Radiation evoked a stronger increase in norepinephrine in the jejunum and colon of spontaneously hypertensive rats than in Wistar-Kyoto rats. Acethylcholine levels in the jejunum of spontaneously hypertensive rats decreased, in contrast to the increase in Wistar-Kyoto rats within 24 h after irradiation. The survival rate of spontaneously hypertensive rats was lower than that of Wistar-Kyoto rats and weight loss, appetite loss and morphological changes in the jejunum were greater in spontaneously hypertensive rats than in Wistar-Kyoto rats after irradiation. These results indicated that X irradiation caused greater activities in autonomic nervous function and severe radiation injury in spontaneously hypertensive rats. Sympathetic hyperfunction may be associated with a higher sensitivity to radiation, including radiation injury and radiation sickness.

Regulation of mesenchymal and epithelial remodeling by ETS-1 transcription factor in ulcer healing

BackgroundControlledproteolysisis needed for cell migration,angiogenesis, and matrix remodeling during normal wound repair. Coordination among these processes has not been well studied. Ets-l is a transcription factor known to control gene expression of matrix metalloproteases (MMPs) such as MMP-l, MMP-3, MMP-9, and MMP-lO. MMP-I and MMP-3 are deeply involved in angiogenesis and matrix remodeling. MMP-9 and MMP-1O playa pivotal role of epithelial cell migration. The purposeof this study is to evaluateexpressionof Ets-I and its target genes of MMPs in the healing process of gastric ulcer. Materials and Methods Acetic acid ulcers were produced in male Wistar rats. Gastric tissues were sampled rats on days I, 3, 5, 7, 14, and 28 after the days of induction. Time-dependent changes of Ets-I and MMPs in ulcer margin were examined by Western blotting and RT-PCR. Distribution of Ets-l , MMP-I, MMP-9, and MMP-lO were evaluated by immunohistochemistry and in situ hybridization (ISH). Effects of antisense Ets-I oligonucleotide (50 JLM) on the expressionof Ets-I and MMPs in ulcer healingwere evaluated. ResultsEts-I did not express in the normal gastric mucosa. In the marginal granulationtissues, the nuclei of mesenchymalcells (fibroblast, endothelial cell) and epithelial cells (regenerative cell, damaged mucosal cell) were immunopositive for Ets-I. Ets-I expression was significantly increased at the early phase, and returned to normal levels at the scarred phase. Serial sectioning revealed that fibroblasts and endothelial cells also expressed MMP-l. Expressionsof MMP-9 and MMP-1O were detected in regenerative and damaged epithelium by immunohistochemistry and ISH. Timedependent changes of MMPs were similar to Ets-I. Antisenseoligonucleotide retarded ulcer healing and suppressed the expressions of Ets-I and MMPs. Conclusion These findings suggest that Ets-I plays a key role of angiogenesis and re-epithelization by regulation of MMPs in the early phase of ulcer healing.