Takako Ae

Role of microsomal prostaglandin E synthase-1 in the facilitation of angiogenesis and the healing of gastric ulcers

The importance of prostaglandin E(2) in various pathophysiological events emphasizes the necessity of understanding the role of PGE synthases (PGESs) in vivo. However, there has been no report on the functional relevance of microsomal PGES-1 (mPGES-1) to the physiological healing processes of gastric ulcers, or to angiogenesis, which is indispensable to the healing processes. In this report, we tested whether mPGES-1 plays a role in the healing of gastric ulcers and in the enhancement of angiogenesis using mPGES-1 knockout mice (mPGES-1 KO mice) and their wild-type (WT) counterparts. Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. mPGES-1 together with cyclooxygenase-2 were induced in the granulation tissues compared with normal stomach tissues. The healing of acetic acid-induced ulcers was significantly delayed in mPGES-1 KO mice compared with WT. This was accompanied with reduced angiogenesis in ulcer granulation tissues, as estimated by CD31 mRNA levels determined by real-time PCR and the microvessel density in granulation tissues. The mRNA levels of proangiogenic growth factors, such as transforming growth factor-β, basic fibroblast growth factor, and connective tissue growth factor in ulcer granulation tissues determined were reduced in mPGES-1 KO mice compared with WT. The present results suggest that mPGES-1 enhances the ulcer-healing processes and the angiogenesis indispensable to ulcer healing, and that a selective mPGES-1 inhibitor should be used with care in patients with gastric ulcers.

Clinical outcomes of endoscopic oblique aspiration mucosectomy for superficial esophageal cancer.

BACKGROUND EMR is now a widely accepted option for the treatment for superficial esophageal cancer (SEC). However, studies of medium-term to long-term outcomes are scarce. OBJECTIVE To evaluate outcomes in patients with SEC who are undergoing medium-term to long-term follow-up after endoscopic oblique aspiration mucosectomy (EOAM). DESIGN A single-center retrospective study. SETTING Kitasato University East Hospital, Sagamihara, Kanagawa, Japan. PATIENTS AND INTERVENTIONS From November 1999 to October 2005, 85 patients with SEC underwent EOAM. All tumors were macroscopically classified as the superficial type on the basis of preoperative endoscopic and EUS findings. Patients were followed-up, with an endoscopy every 6 months. MAIN OUTCOME MEASUREMENTS Therapeutic efficacy, complications, and follow-up results. RESULTS The rate of complete resection was 82.5% (70/85). In patients who underwent an incomplete resection, argon plasma coagulation and heat probe coagulation were, in addition, performed. The median longest diameter of the resected specimens was 25 mm. The median time required for a resection was 27 minutes. There was no perforation. Bleeding after an EOAM occurred in 1 patient (1.2%). Esophageal stenosis developed in 8 patients (9.4%). All strictures were managed by endoscopic balloon dilation, and symptoms improved. The median follow-up period after EMR was 36 months (range 6-72 months). Local recurrence occurred in 5 patients (5.9%); the nonrecurrence rate was 96.4% at 1 year, 95.0% at 2 years, and 93.4% at 3 years. As additional treatment, argon plasma coagulation was performed in 4 patients, and endoscopic mucosal dissection was conducted in 1 patient. CONCLUSIONS EOAM is a safe, easy, and effective procedure for the treatment of SEC that can be completed within a short time. The rate of local recurrence is low on medium-term to long-term follow-up.

Thromboxane A(2) receptor signaling promotes liver tissue repair after toxic injury through the enhancement of macrophage recruitment.

It is thought that thromboxane A(2) (TxA(2)) contributes to the progression of inflammation during acute hepatic injury; however, it is still unknown whether TxA(2) is involved in liver repair. The objective of the present study was to examine the role of TxA(2) receptor (TP) signaling in liver injury and repair in response to toxic injury. Carbon tetrachloride (CCl(4)) was used to induce liver injury in TP knockout (TP(-/-)) mice and wild-type (WT) mice. In WT mice, serum levels of alanine aminotransferase (ALT) and the size of the necrotic area peaked at 24 and 48h, respectively, and then declined. In TP(-/-) mice, the changes in ALT levels were similar to WT mice, but liver regeneration was impaired as evidenced by remained elevated levels of hepatic necrosis and by delayed hepatocyte proliferation, which was associated with the reduced expression of growth factors including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), and hepatocyte growth factor (HGF). In TP(-/-) mice, the accumulation of hepatic CD11b(+)/F4/80(+) macrophages in injured livers was attenuated, and the hepatic expression of monocyte chemoattractant protein-1 (MCP-1/CCL2) and its receptor, the C-C chemokine receptor (CCR2), was reduced compared to WT. Additionally, the application of the TP receptor agonist, U-46619, enhanced the expression of MCP-1/CCL2 and CCR2 in peritoneal macrophages, which was associated with increased levels of IL-6, TNFα and HGF. These results suggested that TP receptor signaling facilitates liver recovery following CCl(4)-induced hepatotoxicity by affecting the expression of hepatotrophic growth factors, and through the recruitment of macrophages mediated by MCP-1/CCL2-CCR2 expression.

Roles of prostaglandin E2-EP1 receptor signaling in regulation of gastric motor activity and emptying

It is widely accepted that the inhibition of gastric motor activity as well as the maintenance of gastric mucosal blood flow and mucous secretion are important for the homeostasis of the gastric mucosa. The present study was performed to ascertain whether or not endogenous PGs, which can protect the stomach from noxious stimuli, affect gastric motor activity and emptying. The myoelectrical activity of rat gastric smooth muscle was increased at intragastric pressures of over 2 cmH(2)O. Replacement of intragastric physiological saline with 1 M NaCl solution significantly increased PGI(2) and PGE(2) in stomach and suppressed the myoelectrical activity under a pressure of 2 cmH(2)O by 70%. Indomethacin inhibited the suppression of myoelectrical activity by 1 M NaCl. The myoelectrical activity under a pressure of 2 cmH(2)O was suppressed by continuous infusion of a selective EP1 agonist (ONO-DI-004, 3-100 nmol·kg(-1)·min(-1)) into the gastric artery in a dose-dependent manner, but not by that of the PGI receptor agonist beraprost sodium (100 nmol·kg(-1)·min(-1)). Suppression of myoelectrical activity with 1 M NaCl was inhibited by continuous infusion of a selective EP1 antagonist (ONO-8711, 100 nmol·kg(-1)·min(-1)) into the gastric artery. Furthermore, gastric emptying was tested in EP1 knockout mice and their wild-type counterparts. Gastric emptying was strongly suppressed with intragastric 1 M NaCl in wild-type mice, but this 1 M NaCl-induced suppression was not seen in EP1 knockout mice. These results suggest that PGE(2)-EP1 signaling has crucial roles in suppression of myoelectrical activity of gastric smooth muscles and inhibition of gastric emptying and that EP1 is an obvious target for drugs that control gastric emptying.

A rare case of histologically mixed-type intramucosal gastric cancer accompanied by nodal recurrence and liver metastasis after endoscopic submucosal dissection

biopsy of the spleen: high clinical efficacy and low risk in a multicenter Italian study. Am J Hematol 2001;67:93-9. 9. Fritscher-Ravens A, Mylonaki M, Pantes A, et al. Endoscopic ultrasound-guided biopsy for the diagnosis of focal lesions of the spleen. Am J Gastroenterol 2003;98:1022-7. 10. Saftoiu A, Vilmann P, Guldhammer Skov B, et al. Endoscopic ultrasound (EUS)-guided trucut biopsy adds significant information to EUS-guided fine-needle aspiration in selected patients: a prospective study. Scand J Gastroenterol 2007;42:117-25. 11. Wittmann J, Kocjan G, Sgouros SN, et al. Endoscopic ultrasoundguided tissue sampling by combined fine needle aspiration and trucut needle biopsy: a prospective study. Cytopathology 2006;17: 27-33. Department of Medicine (I.I.E.H., A.K., K.M.M., K.E.F.), Department of Pathology (K.E.S.), Department of Surgery (K.M.A.-E.), University of Pittsburgh Medical Center, Division of Gastroenterology, Hepatology, and Nutrition (A.K.), VA Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA.

NSAID, aspirin delays gastric ulcer healing with reduced accumulation of CXCR4(+)VEGFR1(+) cells to the ulcer granulation tissues.

BACKGROUND Ulcer healing is a complex process, which involves cell migration, proliferation, angiogenesis and re-epithelialization. Several growth factors have been implicated in this process but the precise mechanism is not well understood. This study examined the involvement of VEGFR1 signaling in the gastric ulcer healing. METHODS Gastric ulcers were induced by the serosal application of 100% acetic acid, and the areas of the ulcers were measured thereafter. RESULTS The healing of acetic acid induced ulcers and the progenitor cells expressing CXCR4(+)VEGFR1(+) cell were significantly delayed in NSAID treated mice. The areas of the ulcer was significantly suppressed in tyrosine kinase-deficient VEGFR1 mice (VEGFR1TKKO) compared with wild type (WT) mice. The plasma level of SDF-1 and stem cell factor (SCF) and bone marrow level of pro-matrix metallopeptidase 9 (pro-MMP-9) were significantly reduced in VEGFR1TKKO mice. In VEGFR1 TKKOmice, the progenitor cells expressing CXCR4(+)VEGFR1(+) cell from bone marrow and the recruitment of these cells in healing ulcer were suppressed. Furthermore, VEGFR1 TKKO mice treated with NSAID did not suppress gastric ulcer healing compared to vehicle mice. These results suggested that NSAID suppressed VEGFR1 TK signaling plays a critical role in ulcer healing through mobilization of CXCR4(+)VEGFR1(+) cells. CONCLUSION VEGFR1 signaling is required for healing of NSAID induced gastric ulcer and angiogenesis with increased recruitment of CXCR4(+)VEGFR1(+) cells to the ulcerative lesion.

Quadruple therapy with ecabet sodium, omeprazole, amoxicillin and metronidazole is effective for eradication of Helicobacter pylori after failure of first-line therapy (KDOG0201 Study).

Background and object:  An antiulcer agent, ecabet sodium, is active against Helicobacter pylori. The aim of the present study was to clinically examine whether eradication therapy, which includes ecabet sodium, is effective in eradication of H. pylori after failure of first‐line therapy.