Healing Process Of Gastric Ulcer Research Articles

Neuropeptide W facilitates chronic gastric ulcer healing by the regulation of cyclooxygenase and NF-κB signaling pathways

AimsPutative beneficial effects of neuropeptide W (NPW) in the early phase of gastric ulcer healing process and the involvement of cyclooxygenase (COX) enzymes were investigated in an acetic acid-induced gastric ulcer model.Main methodsIn anesthetized male Sprague–Dawley rats, acetic acid was applied surgically on the serosa and then a COX-inhibitor (COX-2-selective NS-398, COX-1-selective ketorolac, or non-selective indomethacin; 2 mg/kg/day, 3 mg/kg/day or 5 mg/kg/day; respectively) or saline was injected intraperitoneally. One h after ulcer induction, omeprazole (20 mg/kg/day), NPW (0.1 μg/kg/day) or saline was intraperitoneally administered. Injections of NPW, COX-inhibitors, omeprazole or saline were continued for the following 2 days until rats were decapitated at the end of the third day.Key findingsNPW treatment depressed gastric prostaglandin (PG) I2 level, but not PGE2 level. Similar to omeprazole, NPW treatment significantly reduced gastric and serum tumor necrosis factor-alpha and interleukin-1 beta levels and depressed the upregulation of nuclear factor kappa B (NF-κB) and COX-2 expressions due to ulcer. In parallel with the histopathological findings, treatment with NPW suppressed ulcer-induced increases in myeloperoxidase activity and malondialdehyde level and replenished glutathione level. However, the inhibitory effect of NPW on myeloperoxidase activity and NPW-induced increase in glutathione were not observed in the presence of COX-1 inhibitor ketorolac or the non-selective COX-inhibitor indomethacin.SignificanceIn conclusion, NPW facilitated the healing of gastric injury in rats via the inhibition of pro-inflammatory cytokine production, oxidative stress and neutrophil infiltration as well as the downregulation of COX-2 protein and NF-κB gene expressions.

The protective effect of small black soybean (Vigna Mungo L.) polysaccharide on acetic acid-induced gastric ulcer in SD rats and its impact on gut microbiota and metabolites

Small black soybean (Vigna Mungo L.) is a kind of medicinal and edible plant with many potential health benefits for the human body. In this study, we investigated the potential anti-gastric ulcer effect of Vigna Mungo L. polysaccharides (VMP) using an acetic acid-induced gastric ulcer model in SD rats. The impact of VMP on the levels of antioxidant factors and growth factors in gastric tissue homogenate, serum metabolites, short-chain fatty acids (SCFAs) and gut microbiota in SD rats were analyzed. The results revealed that VMP exhibited a beneficial role in facilitating the healing process of gastric ulcers, specifically by reducing the area of gastric ulcers, increasing the levels of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), and improving oxidative stress status. Additionally, VMP modulated 20 potential serum biomarkers associated with gastric ulcers, thereby exerting a significant impact on multiple crucial metabolic pathways. Notably, VMP notably increased the levels of SCFAs, including acetic acid, propionic acid, i-butyric acid, n-butyric acid, i-valeric acid, n-valeric acid, in the colonic contents of rats with gastric ulcers. Furthermore, VMP effectively ameliorated gut microbiota dysbiosis in gastric ulcer rats by reducing the relative abundance of Firmicutes, Lachnospiraceae_NK4A136_group, Quinella and Lactobacillus, while increasing the relative abundance of Bacteroidota, Bacteroides, Oscillospiraceae_UCG-005, Muribaculaceae, Parasutterella and Ruminococcus. Correlation analysis showed that the relative abundance of Parasutterella and Lachnospiraceae_NK4A136_group were closely related to the changes of SCFAs and serum metabolites. These findings provide potential groundwork for the development of health products aimed at preventing and treating gastric ulcers.

Evaluation of Therapeutic Efficacy of Stigma and Petal Extracts of Crocus sativus L. on Acetic Acid-Induced Gastric Ulcer in Rats

Saffron (Crocus sativus L.) has long been considered a medicinal plant in Traditional Persian Medicine (TPM) due to its therapeutic properties. Despite this interest, its effects on gastrointestinal disorders have not been completely taken into consideration. Hence, this study aimed to evaluate the pharmacological activity of ethanolic extracts of saffron stigma (SS) and saffron petal (SP) in acetic acid-induced gastric ulcer in rats. The gastric ulcer model was imitated by the serosal application of acetic acid in male Wistar rats. Then, the animals were orally fed with 100 mg/kg and 200 mg/kg of ethanolic extracts of SS or SP, omeprazole (40 mg/kg), or saline for 12 days. The macroscopic and microscopic appearances of gastric ulcers and the levels of malondialdehyde (MDA), vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE2) in gastric tissues were assessed. The highest anti-ulcer activity was observed in the omeprazole-treated animals with the lowest ulcer size (4.29 ± 1.78 mm2). SS could not reduce gastric ulcer size in rats. Compared to the untreated rats, SP treatment significantly decreased ulcer indices in a dose-dependent manner. The gastric levels of PGE2, VEGF, and MDA were significantly elevated in the untreated animals with gastric ulcers compared to rats in the control group. The SS extract suppressed the elevated PGE2 and VEGF levels at both doses, while SP did not have a significant influence. Both SS and SP treatments significantly ameliorated MDA levels in rats with gastric ulcers. Omeprazole treatment enhanced the PGE2 level and suppressed MDA contents, but it did not influence the VEGF level. In conclusion, our findings demonstrated that the saffron stigma has no significant effects on the gastric ulcer healing process, while its petals accelerate the process. This discrepancy can be attributed to the difference in the main secondary metabolites between saffron stigma and petals.

Therapeutic potential of Ferula foetida(Bunge) Regel on gastric ulcer model in rats.

The plant Ferula foetida(Bunge) Regel (FFBR) has a long history in Asian traditional medicine. This study aimed to evaluate the ulcer healing potential of FFBR umbel ethanolic extract on acetic acid-induced chronic gastric ulcer in rats. First, the gastric ulcer model was imitated by serosal application of acetic acid in male Wistar rats. Then, the animals were orally fed by ethanolic extract of FFBR umbel (100 mg/kg, 200 mg/kg, and 300 mg/kg), omeprazole (40 mg/kg), or saline for 12 days. Eventually, on the 13th day, animals were sacrificed, and their stomachs were taken out. The macroscopic and microscopic appearances of gastric ulcers and the levels of malondialdehyde (MDA), vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE2) in gastric tissues were assessed. In addition, the expression of NF-κB p65 was investigated by immunohistochemistry. Compared to the untreated rats with gastric ulcer, FFBR extract significantly decreased ulcer area even superior to omeprazole in a dose-dependent manner. Moreover, histological examination revealed that the extract (300 mg/kg) accelerated the epithelialization and differentiation of proliferative cells to mucosal tissue. The FFBR extract (300 mg/kg) increased tissue levels of VEGF and PGE2, but it did not affect MDA levels in rats with gastric ulcers. FFBR treatment (all doses) could significantly inhibit the expression of NF-κB p65 in gastric tissue. Taken together, experimental findings suggested that FFBR could accelerate the healing process of gastric ulcers in rats through mediating NF-κB and VEGF/PGE2 pathways.

Effectiveness of Opuntia ficus indica L. inermis Seed Oil in the Protection and the Healing of Experimentally Induced Gastric Mucosa Ulcer.

Gastric ulcer is a painful lesion of the gastric mucosa which can be disabling, or even more very serious in the case of a perforation of the stomach and internal hemorrhage. Traditional pharmacopeias have shown the efficacy of various plant extracts in the treatment of this pathology. Some extracts from Opuntia ficus indica (OFI) have been proven to have medicinal therapeutic benefits. The aim of this study was to investigate the preventive and curative effects of OFI seed oil extracted by cold pressing on an ethanol-induced gastric ulcer model in rats. Gastroprotective activities of the oil were assessed as pretreatments prior to ethanol gavage of Wistar rats compared to reference drugs. Two oil dose effects were tested. Ulcer and gastric parameters were measured (ulcerated areas (mm2), % of ulcer inhibition, gastric juice volume and pH, and mucus weight). Macroscopical and microscopical assessments of the stomachs as well as gastric biopsy histological studies were carried out. OFI oil exhibited a high efficiency in the protection of the cytoarchitecture and function of the gastric mucosa against the severe damages provoked by ethanol intake. Ulcerated areas were very significantly reduced and the % of ulcer inhibition was the highest under OFI oil pretreatment. Mucus production was stimulated, gastric juice volume was reduced, and its pH was increased. Histopathological examination of H&E-stained biopsies collected from gastric mucosae from the different experimental groups confirmed the gastroprotective efficacy of OFI oil against ethanol-induced symptoms such as inflammation and damages like bleeding, erosions, lesions, necrosis, and ulcers. Furthermore, OFI oil treatment speeded-up the reduction of the surface of ethanol-induced ulcerated areas in a dose-dependent manner, leading to a time gain in the healing process. The healing rate reached 91% on day 2 and 99% on day 3, and a complete heal was attained at the fourth day under OFI oil treatment, while ulcer areas were still partially unhealed in all the other groups. The therapeutic effects of OFI oil against gastric ulcer could be mediated by its varied bioactive compounds that we have demonstrated in the analytical study. They could act synergistically or in a delayed manner to optimize the healing process through protective antioxidant properties, as well as an antagonism against histamine H2-receptors, a stimulation of the signaling pathways necessary for mucus and bicarbonate production, and reduction of inflammatory processes in the gastric mucosa. Additionally, OFI oil fatty acids (especially unsaturated) and triacylglycerols contribute to the reconstruction and the repair of the cell membrane lipid bilayer during the gastric ulcer healing process.

Roles of Na+/Ca2+ exchanger 1 in digestive system physiology and pathophysiology.

The Na+/Ca2+ exchanger (NCX) protein family is a part of the cation/Ca2+ exchanger superfamily and participates in the regulation of cellular Ca2+ homeostasis. NCX1, the most important subtype in the NCX family, is expressed widely in various organs and tissues in mammals and plays an especially important role in the physiological and pathological processes of nerves and the cardiovascular system. In the past few years, the function of NCX1 in the digestive system has received increasing attention; NCX1 not only participates in the healing process of gastric ulcer and gastric mucosal injury but also mediates the development of digestive cancer, acute pancreatitis, and intestinal absorption. This review aims to explore the roles of NCX1 in digestive system physiology and pathophysiology in order to guide clinical treatments.

Cross-talk between hydrogen sulfide and carbon monoxide in the mechanism of experimental gastric ulcers healing, regulation of gastric blood flow and accompanying inflammation

Hydrogen sulfide (H2S) and carbon monoxide (CO) exert gastroprotection against acute gastric lesions. We determined the cross-talk between H2S and CO in gastric ulcer healing process and regulation of gastric blood flow (GBF) at ulcer margin.Male Wistar rats with acetic acid-induced gastric ulcers were treated i.g. throughout 9 days with vehicle (control), NaHS (0.1–10 mg/kg) +/− zinc protoporphyrin (ZnPP, 10 mg/kg), d,l-propargylglycine (PAG, 30 mg/kg), CO-releasing CORM-2 (2.5 mg/kg) +/− PAG. GBF was assessed by laser flowmetry, ulcer area was determined by planimetry/histology. Gastric mucosal H2S production was analysed spectrophotometrically. Protein and/or mRNA expression at ulcer margin for vascular endothelial growth factor (VEGF)A, epidermal growth factor receptor (EGFr), cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (3-MST), heme oxygenases (HOs), nuclear factor (erythroid-derived 2)-like 2 (Nrf-2), cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS), IL-1β, TNF-α and hypoxia inducible factor (HIF)-1α were determined by real-time PCR or western blot. IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IFN-γ, TNF-α, GM-CSF plasma concentration was assessed using Luminex platform.NaHS dose-dependently decreased ulcer area and increased GBF but ZnPP attenuated these effects. PAG decreased H2S production but failed to affect CORM-2-mediated ulcer healing and vasodilation. NaHS increased Nrf-2, EGFr, VEGFA and decreased pro-inflammatory markers expression and IL-1β, IL-2, IL-13, TNF-α, GM-CSF plasma concentration. CORM-2 decreased IL-1β and GM-CSF plasma levels.We conclude that NaHS accelerates gastric ulcer healing increasing microcirculation and Nrf-2, EGFr, VEGFA expression. H2S-mediated ulcer healing involves endogenous CO activity while CO does not require H2S. NaHS decreases systemic inflammation more effectively than CORM-2.

胃潰瘍の総合医学的治療研究(2) : 精神神経要因の治癒経過への影響について

胃潰瘍の総合医学的治療研究(2) : 精神神経要因の治癒経過への影響について

The Probiotic Effect towards Aspirin-induced Gastric Ulcer Healing Process as Measured by Mucous Thickness, Reepithelization, Gastric Glands Formation, and Angiogenesis in Animal Model

Gastric Ulcer is a common side effect of Non-Steroid Anti Inflammatory Drugs (NSAIDs) use such as Aspirin. Probiotic has many benefits especially for the alimentary system, but the effect on gastric ulcer have yet to be explored. In this research we aimed to find the probiotic effect on histological structure changes during aspirin induced gastric ulcer healing process in animal model. This was simple random sampling animal experimental laboratory, that divided Wistar Rats into two main groups. Both groups were induced with Aspirin (300mg/Kg BW) per oral, once daily for three consecutive days,and subsequently the test group were given probiotic suspension (cfu >108/gr) per oral, once daily, for 14 days. Each subgroups were sacrified serially at day 0, 3, 7, 14. The gaster were collected and processed for histology examination. Better histological structures were shown in the test group at day 14. MANOVA result showed probiotic's effect in enhancing histological structure changes during gastric ulcer healing process. Better histological structure changes were observed in mucus thickness; reepitelization, gastric glands formation, and angiogenesis process of the test group. As a conclusion, probiotic enhanced mucus thickness, reepitelization, glands remodelling, and angiogenesis in Aspirin induced gastric ulcer healing process in animal model. Key words: probiotic, gastric ulcer, histological structure, aspirin, healing process

High-Mobility Group Box 1 Inhibits Gastric Ulcer Healing through Toll-Like Receptor 4 and Receptor for Advanced Glycation End Products

High-mobility group box 1 (HMGB1) was initially discovered as a nuclear protein that interacts with DNA as a chromatin-associated non-histone protein to stabilize nucleosomes and to regulate the transcription of many genes in the nucleus. Once leaked or actively secreted into the extracellular environment, HMGB1 activates inflammatory pathways by stimulating multiple receptors, including Toll-like receptor (TLR) 2, TLR4, and receptor for advanced glycation end products (RAGE), leading to tissue injury. Although HMGB1’s ability to induce inflammation has been well documented, no studies have examined the role of HMGB1 in wound healing in the gastrointestinal field. The aim of this study was to evaluate the role of HMGB1 and its receptors in the healing of gastric ulcers. We also investigated which receptor among TLR2, TLR4, or RAGE mediates HMGB1’s effects on ulcer healing. Gastric ulcers were induced by serosal application of acetic acid in mice, and gastric tissues were processed for further evaluation. The induction of ulcer increased the immunohistochemical staining of cytoplasmic HMGB1 and elevated serum HMGB1 levels. Ulcer size, myeloperoxidase (MPO) activity, and the expression of tumor necrosis factor α (TNFα) mRNA peaked on day 4. Intraperitoneal administration of HMGB1 delayed ulcer healing and elevated MPO activity and TNFα expression. In contrast, administration of anti-HMGB1 antibody promoted ulcer healing and reduced MPO activity and TNFα expression. TLR4 and RAGE deficiency enhanced ulcer healing and reduced the level of TNFα, whereas ulcer healing in TLR2 knockout (KO) mice was similar to that in wild-type mice. In TLR4 KO and RAGE KO mice, exogenous HMGB1 did not affect ulcer healing and TNFα expression. Thus, we showed that HMGB1 is a complicating factor in the gastric ulcer healing process, which acts through TLR4 and RAGE to induce excessive inflammatory responses.

Weak up-regulation of serum response factor in gastric ulcers in patients with co-morbidities is associated with increased risk of recurrent bleeding

BackgroundSerum response factor (SRF) is crucial for gastric ulcer healing process. The study determined if gastric ulcer tissues up-regulate SRF and if such up-regulation correlated with co-morbidities and the risk of recurrent bleeding.MethodsUlcer and non-ulcer tissues were obtained from 142 patients with active gastric ulcers for SRF expression assessed by immunohistochemistry. Based on the degree of SRF expression between these two tissue types, SRF up-regulation was classified as strong, intermediate, and weak patterns. The patients were followed-up to determine if SRF up-regulation correlated to recurrent bleeding.ResultsGastric ulcer tissues had higher SRF expression than non-ulcer tissues (p < 0.05). Patients with strong SRF up-regulation had lower rates of stigmata of recent hemorrhage (SRH) on the ulcer base than the others (p < 0.05). Multivariate logistic regression confirmed that co-morbidities and weak SRF up-regulation were two independent factors of recurrent gastric ulcer bleeding (p < 0.05). Combining both factors, there was an 8.29-fold (95% CI, 1.31~52.62; p = 0.03) higher risk of recurrent gastric ulcer bleeding.ConclusionsSRF expression is higher in gastric ulcer tissues than in non-ulcer tissues. Weak SRF up-regulation, combined with the presence of co-morbidities, increase the risk of the recurrent gastric ulcer bleeding.

Distribution of collagen types I, III, and IV in gastric tissue of marmosets (Callithrix spp., Callitrichidae: Primates)

Extracellular matrix (ECM) components such as fibrillar collagens play a fundamental role in wound repair and have also been studied in association with the gastric ulcer healing process in gastroenterology. Nevertheless, there have been no studies in the literature to date regarding the description and characterization of ECM components, neither in normal nor in injured gastric tissue of primate species. The objective of this study was to investigate the expression of gastric collagen types I, III, and IV in marmosets (Callithrix sp.). Histological specimens from the stomach of 6 Callithrix jacchus, 12 C. kuhli, and 12 C. geoffroyi were evaluated. The specimens were immunostained with anti-types I and III collagen polyclonal antibodies and anti-type IV collagen monoclonal antibody. Collagen types I and III were detected in the submucosa and lamina propria between the mucosal glands while collagen type IV was detected in the muscularis mucosae, muscular layers, blood vessels, and gastric mucosa between the mucosal glands. It is hoped that these findings can contribute to future studies on the gastric extracellular matrix components in primates and to comparative studies in the area of gastroenterology.

The Influence of H pylori Infection on the Healing Process of Gastric Ulcers After Endoscopic Submucosal Dissection

Background & Aim: FEndoscopic submucosal dissection (ESD) is rapidly becoming popular for treatment of mucosal tumors in the GI tract, especially for larger lesions difficult for conventional EMR. We have previously reported that gastric artificial ulcers after ESD would heal within 8 weeks regardless of size and its location, if there is no preoperative fibrosis under the lesion. In this study, we examined the influence of Helicobacter Pylori (HP) infection on the healing process of gastric ulcers after ESD. Method: From 2000 to 2003, 79 patients (male 65, female 14) who underwent ESD for mucosal tumors, and of which infectious state of HP was confirmed either pathologically or serologically, were included. The healing stage, pattern of scar formation was studied at follow up endoscopy performed within 6 to 8 weeks after the treatment. Normal doses of PPI and sucralfate were given for 8 weeks for postoperative medication. In addition, patients whose serum pepsinogen (PG) was evaluated before treatment (66 patients), were divided in 3 groups; PG positive (PG I < 70 and I/II < 3), strongly positive (PG < 30 and I/II < 2) and negative, according to Miki et al, to study the influence of atrophic gastritis on ulcer healing. Result: The average specimen size removed by ESD was 34 mm (range 20 to 90 mm). In 60 cases (76%), the ulcer contracted in the short axis (axial direction) of the stomach, resulting in linear scars along the long axis (sagittal direction). In 19 cases (24%), the ulcer contracted nearly in a concentric form, resulting in an asteroid scar. In 5 patients, a small mucosal defect was still observed at follow up, of which ulcerative findings were present before treatment. Infection of HP was positive in 68 patients, negative in 11 patients (previously eradicated 3, negative with atrophic gastritis 7, negative without atrophic gastritis 1). There were no significant difference in the healing stage or scar formation regarding HP infection state. Patients of PG positive, strongly positive and negative were 36, 15 and 15 patients, respectively. There were no significant difference among the 3 groups. Conclusion: Infection of HP or the degree of atrophic gastritis have no influence on the healing process of gastric ulcers after ESD.

Effect of Jianweiyuyang granule on gastric ulcer recurrence and expression of VEGF mRNA in the healing process of gastric ulcer in rats

To investigate the effect of Jianweiyuyang (JWYY) granule on gastric ulcer recurrence and its mechanism in the treatment of gastric ulcer in rats. Gastric ulcer in rats was induced according to Okeba's method with minor modification and the recurrence model was induced by IL-1beta. The expression of vascular endothelial growth factor mRNA (VEGF mRNA) was examined by reverse transcription polymerase chain reaction in gastric ulcer and microvessel density (MVD) adjacent to the ulcer margin was examined by immunohistochemistry. MVD was higher in the JWYY treatment group (14.0+/-2.62) compared with the normal, model and ranitidine treatment groups (2.2+/-0.84, 8.8+/-0.97, 10.4+/-0.97) in rats (P<0.01). The expression level of VEGF mRNA in gastric tissues during the healing process of JWYY treatment group rats significantly increased compared with other groups (normal group: 0.190+/-0.019, model group: 0.642+/-0.034, ranitidine group: 0.790+/-0.037, P<0.01). JWYY granules can stimulate angiogenesis and enhance the expression of VEGF mRNA in gastric ulcer rats. This might be the mechanism for JWYY accelerating the ulcer healing, and preventing the recurrence of gastric ulcer.

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

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. 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. 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. These findings suggest that Tie-2 and Ang-1 and -2 play an important role in angiogenesis in the early phase of ulcer healing.

Cyclooxygenase-2: its rich diversity of roles and possible application of its selective inhibitors.

In addition to housekeeping cyclooxygenase (COX)-1, which is constitutively expressed in many body cells, an inducible COX-2 has been described and cloned. Induction or presence of COX-2 has been reported not only in isolated cells, but also in cells in various tissues, as well as in both physiological and pathophysiological states, including acute exudative inflammation, proliferative inflammation, animal arthritis, rheumatoid arthritis, angiogenesis, bone absorption, gastric ulcer, colon cancer, hyperalgesia, Alzheimer's disease and certain states of the kidney, brain and female reproductive organs. This review article introduces results from recent works in these fields. COX-1- or COX-2-knockout mice may provide many clues on the roles of COX-2, but may simultaneously cause unnecessary confusion in the recognition of the roles of COX-2, and this is discussed. Recently the roles of COX-2 in exudative inflammation and the anti-inflammatory effects of selective COX-2 inhibitors have been questioned. This is discussed in the text. Prostanoids mediate signals to adjacent cells to provide fine regulation of cellular function. Because of the short duration of the expression of COX-2 gene and protein, COX-2 must play some roles different from those of COX-1 gene and protein in vivo. It is not yet possible to identify all the roles of COX-2, but in some tissues, such as the kidney, the brain and others, COX-2 may be expressed constitutively, whereas the prostaglandin generation by COX-2 may replace that by COX-1 in some states (or vice-versa). Precise analyses of the expression of COX-2 may disclose fine modulation of cellular and organ functions by PGs. Several selective or preferential COX-2 inhibitors have been developed and were shown to be effective in clinical trials. Most were reported to be free of adverse gastrointestinal effects, but it should be noted that in the healing process of gastric ulcers and in sodium-restricted states, adverse effects of selective COX-2 inhibitors could be expected. Soon, with more detailed knowledge of the delicate roles of COX-2 in vivo, effective and safe application of COX-2 inhibitors should be realized.

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.

Midkine gene expression in the healing process of gastric ulcer

Midkine is a newly cloned growth-promoting factor for fibroblastic cells. This study was performed to investigate the possible role of midkine in the stomach. Rats with acute or chronic gastric mucosal lesions were used. Histologically, acute mucosal lesions are not accompanied by the formation of granulation tissue; conversely, chronic mucosal lesions are accompanied by the formation of granulation tissue. The expression of the midkine gene was found in the normal intact gastrointestinal tract, especially the submucosal and muscle layers. Midkine mRNA increased during the healing stage of chronic gastric ulcer accompanied by a fibroblastic reaction. Furthermore, the fibroblast cell line MRC-5 expressed midkine mRNA strongly. Therefore, midkine may have some role in the healing of gastric deep ulcers that is accompanied by fibroblast proliferation.

Effect of rebamipide on the glycosaminoglycan content of the ulcerated rat stomach.

To elucidate the mechanism of the anti-ulcer effect of rebamipide (2-(4-chlorobenzoylamino)-3-[2-(1H)-quinolinon-4-yl] propionic acid), changes in glycosaminoglycan (GAG), uronic acid and hexosamine contents of stomach tissue were examined in rats treated with the ulcer-inducing agents and/or rebamipide. Uronic acid and hexosamine contents in acid hydrolysates of stomach tissue were increased after diethyldithiocarbamate (DDC, 800 mg/kg, s.c.) or histamine (300 mg/kg, i.p.) treatment, and similar changes in the GAG, uronic acid, and hexosamine levels were observed in stomach tissue extracts. Pretreatment with rebamipide (60 mg/kg, i.p.) resulted in an additional increase in the contents of the above components after DDC or histamine treatment. However, rebamipide treatment alone did not increase the gastric contents of GAG and GAG components in normal rats. Gel filtration chromatography of extracted GAGs suggested that DDC, histamine and rebamipide treatments do not cause a change in the aggregated forms of gastric GAGs. These results suggest that rebamipide stimulates the GAG synthesis in the ulcerated stomach and that this effect may contribute to the healing process of gastric ulcer.

Expression of Ets-1 Transcription Factor in Relation to Angiogenesis in the Healing Process of Gastric Ulcer

Ets-1 is a transcription factor known to control the expression of genes involved in extracellular matrix remodeling. The purpose of this study is to evaluate the expression of Ets-1 in the process of healing of ulceration in the rats. The time-dependent changes and distribution of Ets-1 in the margins of ulcer were examined. Ets-1 did not express in the normal gastric mucosa. In the marginal granulation tissue, fibroblasts and endothelial cells of capillaries were immunopositive for Ets-1. Ets-1 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-1. Protein levels and mRNA expression of Ets-1 were confirmed by Western blotting and RT-PCR. These findings suggest that Ets-1 plays an important role in angiogenesis in the early phase of ulcer healing.