Expression of functional neurokinin-1 receptors in regenerative glands during gastric wound healing in rodents

BACKGROUND & AIMS: Although functions of the neurokinin-1 receptor have been well explored in neurogenic inflammation and immunoinflammatory responses, little is known about neurokinin-1 receptors during gastric wound healing. The aim of this study was to assess whether neurokinin-1 receptors play a role in gastric wound healing. METHODS: In vitro neurokinin-1 receptor autoradiography and immunohistochemistry were performed to identify, locate, and quantify neurokinin-1 receptors during wound healing in rodents with cryoulcers in the gastric corpus and antrum. Moreover, to assess the functionality of these receptors, the effect of the neurokinin-1 receptor antagonist NKP608 on gastric wound healing was quantified in vivo in wild-type and cyclooxygenase-2(-/-) mice. RESULTS: Regenerative glands of the mucosal ulcer margin of rat cryoulcers of the gastric corpus showed strong expression of neurokinin-1 receptors in binding studies between days 3 and 22, with little expression on days 29-84. In addition, strong immunoreactivity for neurokinin-1 receptors was detected on the cell membrane of these regenerative glands. Expression of neurokinin-1 receptors in regenerative glands was confirmed in the rat antrum and the mouse gastric corpus. Moreover, in vivo functional tests during gastric ulcer healing showed that cell proliferation in the regenerative epithelia of the ulcer margin was significantly decreased by NKP608 compared with placebo; furthermore, gastric ulcer healing was significantly delayed by NKP608 both in wild-type and cyclooxygenase-2(-/-) mice. CONCLUSIONS: This report shows the time-limited overexpression of neurokinin-1 receptors in the mucosal repair tissue of the corpus and antrum. Our in vitro and in vivo data suggest that neurokinin-1 receptors are involved in gastric wound healing.     

Effect of local application of growth factors on gastric ulcer healing and mucosal expression of cyclooxygenase-1 and -2

BACKGROUND/AIMS: Ulcer healing involves expression of various growth factors such as epidermal growth factor (EGF), hepatocyte growth factor (HGF) and basic fibroblast growth factor (bFGF) at the ulcer margin, but the influence of EGF, HGF and bFGF applied locally with or without neutralizing anti-EGF, HGF and bFGF antibodies or cyclooxygenase (COX)-1 and COX-2 inhibitors on ulcer healing and the expression of COX-1 and COX-2 during ulcer healing have only been studied a little. METHODS: Rats with gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2 received a submucosal injection of either (1) vehicle (saline), (2) EGF, (3) HGF, and (4) bFGF with or without antibodies against EGF, HGF and bFGF or indomethacin (2 mg/kg/day i.p.), a nonspecific inhibitor of COX, or NS-398 (10 mg/kg/day i.g.) and Vioxx (5 mg/kg/day i.g.), both highly specific COX-2 inhibitors. A separate group of animals with chronic gastric fistulas was also used to assess gastric secretion during ulcer healing with and without growth factors. Each growth factor and specific antibody against EGF, HGF and bFGF (100 ng/100 microl each) were injected just around the ulcer immediately after ulcer induction and this local injection was repeated on day 2 following anesthesia and laparotomy. On days 13 and 21, the ulcer area was determined by planimetry, gastric blood flow (GBF) at the ulcer margin was examined by the H2-gas clearance technique, and mucosal generation of PGE2 and the gene expression of COX-1 and COX-2 in the non-ulcerated and ulcerated gastric mucosa were assessed. Gastric ulcers healed progressively within 21 days after induction and this effect was accompanied by a significant increase in GBF at the ulcer margin and in the expression of COX-2 in the ulcer area. Local treatment with EGF, HGF and bFGF produced a significant decrease in gastric acid secretion and significantly accelerated the rate of ulcer healing and raised GBF at the ulcer margin causing further significant upregulation of COX-2 but not COX-1 expression in the ulcerated mucosa. The acceleration of ulcer healing and hyperemia at the ulcer margin exhibited by locally applied EGF, HGF and bFGF were similar to those obtained with systemic administration of these growth factors. HGF applied submucosally, upregulated COX-2 expression and this was significantly attenuated by concurrent treatment with antibody against this peptide. Anti-EGF and anti-bFGF antibodies completely abolished the acceleration of the ulcer healing and hyperemia at the ulcer margin induced by these growth factors. Indomethacin and both COX-2 inhibitors significantly prolonged ulcer healing, while suppressing the generation of PGE2 in non-ulcerated and ulcerated gastric mucosa and GBF at the ulcer margin. The acceleration of ulcer healing by EGF, HGF and bFGF and the accompanying rise in GBF at the ulcer margin were significantly attenuated by the concurrent treatment with indomethacin or NS-398 and Vioxx. CONCLUSIONS: (1) Growth factors accelerate ulcer healing due to enhancement in the microcirculation around the ulcer and these effects are specific because they can be abolished by neutralization with antibodies; (2) COX-2-derived prostaglandins and suppression of gastric secretion may play an important role in the acceleration of ulcer healing by various growth factors, and (3) the local effects of EGF, HGF and bFGF on ulcer healing can be reproduced by their systemic application indicating the high efficacy of growth factors to accelerate this healing.     

Insulin-Like Growth Factor I Accelerates Gastric Ulcer Healing by Stimulating Cell Proliferation and by Inhibiting Gastric Acid Secretion

Background: Given the importance of Insulin-Like Growth Factor I (IGF-I) to intestinal maintenance and the presence of IGF-I in salivary glands, we hypothesized that IGF-I participates in the healing of gastric ulcers. The aim of the study was to determine: 1) whether IGF-I applied locally would support gastric ulcer healing by increasing cell proliferation and 2) the effect of IGF-I on gastric acid secretion. Methods: Gastric ulcers were induced with a cryoprobe. Immediately thereafter, IGF-I (0.4, 4.0 and 40 µg) or vehicle was infiltrated perifocally. In another group, animals received a daily dose of 40 µmol omeprazole subcutaneously. Ulcer healing was evaluated by ulcer size and histological examination at 7 days. Pentagastrin-stimulated gastric acid secretion was evaluated in conscious rats with gastric fistula, after IGF-I (400 µg) had been injected intravenously. Results: IGF-I significantly reduced ulcer size, but only at low doses (0.4 µg/kg body weight (BW), P = 0.008; 4 µg/kg BW, P     

Effects of Aloe vera and sucralfate on gastric microcirculatory changes, cytokine levels and gastric ulcer healing in rats

AIM: To compare the effects of Aloe vera and sucralfate on gastric microcirculatory changes, cytokine levels and gastric ulcer healing. METHODS: Male Spraque-Dawley rats (n=48) were divided into four groups. Groupl served as control group, group 2 as gastric ulcer group without treatment, groups 3 and 4 as gastric ulcer treatment groups with sucralfate and Aloe vera. The rats from each group were divided into 2 subgroups for study of leukocyte adherence, TNF-αand IL-10 levels and gastric ulcer healing on days 1 and 8 after induction of gastric ulcer by 20% acetic acid. RESULTS: On day 1 after induction of gastric ulcer, the leukocyte adherence in postcapillary venule was significantly (P<0.05) increased in the ulcer groups when compared to the control group. The level of TNF-αwas elevated and the level of IL-10 was reduced. In the ulcer groups treated with sucralfate and Aloe vera, leukocyte adherence was reduced in postcapillary venule. The level of IL-10 was elevated, but the level of TNF-αhad no significant difference. On day 8, the leukocyte adherence in postcapillary venule and the level of TNF-αwere still increased and the level of IL-10 was reduced in the ulcer group without treatment. The ulcer treated with sucralfate and Aloe vera had lower leukocyte adherence in postcapillary venule and TNF-αlevel. The level of IL-10 was still elevated compared to the ulcer group without treatment. Furthermore, histopathological examination of stomach on days 1 and 8 after induction of gastric ulcer showed that gastric tissue was damaged with inflammation. In the ulcer groups treated with sucralfate and Aloe vera on days 1 and 8, gastric inflammation was reduced, epithelial cell proliferation was enhanced and gastric glands became elongated. The ulcer sizes were also reduced compared to the ulcer group without treatment. CONCLUSION: Administration of 20% acetic acid can induce gastric inflammation, increase leukocyte adherence in postcapillary venule and TNF-αlevel and reduce IL-10 level. Aloe vera treatment can reduce leukocyte adherence and TNF-αlevel, elevate IL-10 level and promote gastric ulcer healing.     

Gastric Mucosal EGF and PDGF Receptor Expression with Ulcer Healing by Ebrotidine

Objectives: Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) play important roles in the process of mucosal repair and restitution, and their biological effects are mediated by receptors located on the target cell surfaces. The purpose of this study was to assess the effect of the antiulcer agent, ebrotidine, on the expression of EGF and PDGF receptors with chronic ulcer healing. Methods: Chronic gastric ulcers were developed in the rat by acetic acid technique. The animal were divided into two groups and were treated twice daily for 14 consecutive days, either with ebrotidine at 100 mg/kg, or placebo. At different stages of treatment, the animals were sacrificed and used for the isolation and quantification of gastric mucosal EGF and PDGF receptors. Results: The binding assays revealed that ulcer healing was accompanied by an increase in mucosal expression of both types of receptors. A 1.7–1.8-fold increase in PDGF and EGF receptors occurred by the 4th day after the development of ulcer and reached a maximum of 3-fold increase by the 14th day, when the ulcer was essentially healed. Treatment with ebrotidine caused accelerated ulcer healing (7 days) which was accompanied by a significant enhancement in receptor expression. Compared to the controls, a 1.5-fold increase in EGF and 1.7-fold increase in PDGF receptor expression occurred by the 7th day of ebrotidine treatment, and a 1.4- to 1.5-fold increase was still observed at the 14th day of treatment. Conclusions: The results suggest that ebrotidine is capable of enhancement of gastric mucosal proliferative activities associated with ulcer healing through the stimulation of EGF and PDGF receptor expression.     

Expression of a Specific Mucin Type Recognized by Monoclonal Antibodies in the Rat Gastric Mucosa Regenerating from Acetic Acid-induced Ulcer

Background: Detailed research on the healing process of gastric mucosa from injury due to various necrotizing agents is important for regenerating medicine as well as for estimating the quality of ulcer healing. To elucidate this issue, we prepared monoclonal antibodies reacting with mucin molecules present in the specific region and layer of the gastrointestinal mucosa. Methods: Acetic acid-induced gastric ulcers were prepared in 8-week-old male Wistar rats. Following 24-h fasting, the animals were killed at 20, 30 and 50 days after acid insult and their stomachs were removed immediately. Serial paraffin sections of the ulcer area were made and immunostained with three distinct monoclonal antibodies. RGM21 and HIK1083 react with mucins derived from the surface mucous cells of the corpus and the gland mucous cells of corpus and antrum, respectively. HCM31 stains sialomucin present in the small intestine and colonic mucosa of rat, but does not react with the intact gastric mucosa, except in the very narrow cardiac gland area. Results: On the 20th day after ulcer preparation, the cells stained with RGM21 and HIK1083 were restricted only to the surface layer and the bottom layer of regenerating epithelia, respectively. HCM31 staining covered most of the regenerating epithelia. On the 30th day, the staining of HCM31 was enhanced in the regenerating area. Staining of RGM21 did not change, but the HIK1083 stained area increased in the lower part of the regenerating epithelia. On the 50th day, the staining with HCM31 weakened markedly in the lower part, and this area was occupied with HIK1083 positive cells. Conclusion: A notable but temporary expression of a kind of sialomucin specifically stained with HCM31 was observed in the regenerating epithelia during the healing stage of acetic acidinduced gastric damage.     

Delayed gastric ulcer healing after extirpation of submandibular glands is sex-dependent

This study examines the effect of excision of the submandibular salivary glands, the main source of epidermal growth factor (EGF), and the role of gender on the healing of acetic acid-induced gastric ulcers in rats. In male rats excision of the submandibular glands delayed ulcer healing. At 15 and 25 days the unhealed ulcer areas were significantly larger in the sialoadenectomy group than in control animals, and fewer completely healed ulcers were seen in this group at 25 days. Ulcer healing in female rats was slower. At day 25 ulcers were healed in 12% of female rats with intact salivary glands, compared with 68% in males. Female rats also showed larger unhealed ulcer areas after sialoadenectomy than controls. We conclude that removal of the main source of EGF in the gastrointestinal tract is associated with a delay in healing of gastric ulcers. The significant difference in healing observed between female and male rats may be influenced by the known androgenic regulation of EGF production in the salivary glands.     

Recombinant Human Interleukin-6 Induces Hepatocyte Growth Factor Production in Cancer Patients

Background: Experiments in animals demonstrate an important role for interleukin-6 (IL-6) in liver regeneration. It is suggested that IL-6 initiates hepatocyte growth factor (HGF) synthesis. Methods: The aim of the study was to examine the effect of exogenously administered recombinant human IL-6 (rhIL6), in doses of 0.5, 1.0, 2.5, 5, 10 and 20 µg/kg/day, on HGF serum levels in humans. Serum HGF levels were measured on days 1, 2, 3, 8 and 15 and were correlated with serum amyloid A (SAA) and C-reactive protein (CRP). Results: Median HGF levels increased to 124% at day 3 (P &lt; 0.05) and 157% (P &lt; 0.05) at day 8 as compared to 100% levels at day 1. An IL-6 dose-dependent increase in HGF was found at day 8 (R = 0.53, P &lt; 0.02). The percentual change in serum HGF level at day 8 correlated with IL-6 serum levels at day 1 R = 0.59, P &lt; 0.01). HGF levels did not correlate with CRP and SAA. Conclusion: In humans, rhIL-6 administration resulted in an increase in serum HGF levels.     

Limited Effect of Rebamipide in Addition to Proton Pump Inhibitor (PPI) in the Treatment of Post-Endoscopic Submucosal Dissection Gastric Ulcers: A Randomized Controlled Trial Comparing PPI Plus Rebamipide Combination Therapy with PPI Monotherapy

Background/AimsThe ability of endoscopic submucosal dissection (ESD) to resect large early gastric cancers (EGCs) results in the need to treat large artificial gastric ulcers. This study assessed whether the combination therapy of rebamipide plus a proton pump inhibitor (PPI) offered benefits over PPI monotherapy.MethodsIn this prospective, randomized, multicenter, open-label, and comparative study, patients who had undergone ESD for EGC or gastric adenoma were randomized into groups receiving either rabeprazole monotherapy (10 mg/day, n=64) or a combination of rabeprazole plus rebamipide (300 mg/day, n=66). The Scar stage (S stage) ratio after treatment was compared, and factors independently associated with ulcer healing were identified by using multivariate analyses.ResultsThe S stage rates at 4 and 8 weeks were similar in the two groups, even in the subgroups of patients with large amounts of tissue resected and regardless of CYP2C19 genotype. Independent factors for ulcer healing were circumferential location of the tumor and resected tissue size; the type of treatment did not affect ulcer healing.ConclusionsCombination therapy with rebamipide and PPI had limited benefits compared with PPI monotherapy in the treatment of post-ESD gastric ulcer (UMIN Clinical Trials Registry, UMIN000007435).     

Rebamipide prevents delay of acetic acid-induced gastric ulcer healing caused by Helicobacter pylori infection in Mongolian gerbils

In this study, we examined the effect of rebamipide, a mucoprotective drug, on gastric ulcer healing in Mongolian gerbils infected with H. pylori. Male Mongolian gerbils were inoculated with H. pylori or vehicle alone 12 hr after the production of an acetic acid-induced gastric ulcer. On day 5, the gerbils inoculated with H. pylori were divided into three groups and fed rebamipide-containing diet (0.038%, 60 mg/kg, or 0.0038%, 6 mg/kg), or standard laboratory chow. The gerbils inoculated with the vehicle were fed standard laboratory chow throughout the experiment. The gerbils were killed on day 5, 15, or 30 after ulcer production, and removed stomachs were subjected to calculation of ulcer size, culture for H. pylori, and measurement of myeloperoxidase activity, a marker for neutrophil infiltration, in ulcerated tissue. Apoptotic and proliferating cells of gastric epithelium in ulcer margins were detected by the in situ DNA nick end-labeling method and immunohistochemical staining for 5-bromo-2'-deoxyuridine (BrdU), respectively. Rebamipide did not affect colonization levels of H. pylori. Infection with H. pylori did not affect ulcer size by day 5 but significantly delayed ulcer healing by days 15 and 30, accompanied by an increase in the number of apoptotic cells, a decrease in the number of BrdU-positive cells, and an increase in myeloperoxydase activity. Rebamipide prevented delay of ulcer healing and abolished these effects of H. pylori on cell kinetics and neutrophil infiltration. In conclusion, rebamipide may prevent the delay of acetic acid-induced gastric ulcer healing caused by H. pylori through modulating cell kinetics and inhibiting neutrophil infiltration.     

Increased expression of epidermal growth factor receptor during gastric ulcer healing in rats.

Expression of epidermal growth factor receptor (EGFR) was studied immunohistochemically in rat gastric mucosa during healing of acetic acid-induced ulcers. In normal control gastric oxyntic mucosa, EGFR was expressed in proliferative zone cells and in some parietal cells. In mucosa of the ulcer margin, at 3, 7, and 16 days after ulcer induction, there was a 75-fold increase (over controls) in the number of cells expressing EGFR. Seventy percent of ulcers healed by the 16th day, and all were healed by the 25th day. The mucosal scar that replaced the ulcer was composed of dilated glands lined with poorly or aberrantly differentiated cells showing persistence of increased EGFR expression. An increased EGFR expression indicates an important role of EGF in ulcer healing and scar formation.     

The immunohistochemical study on the recurrent mechanism of acetic acid induced gastric ulcer in rats--extracellular matrix and cellular kinetics]

The localization of fibronectin (FN) and laminin (LM) and cellular kinetics of epithelium in acetic acid induced gastric ulcers were examined by immunohistochemistry, comparing fundic glands ulcer with fundic-pyloric border ulcer. Ulcers on fundic glands had become scars in 30 days and didn't relapse after that. More than half of ulcer on fundic-pyloric border changed into scar in 30 days, however, they started to recur at about 45 days. The localization of LM was observed on basement membrane (BM) beneath epithelia, blood vessel walls and musculature. The percentage change in intra-blood-vessel area compared to total area was analyzed by immunohistochemical distribution of LM. As for ulcer on fundic glands, the percentage of intra-blood-vessel returned to normal numbers after healing to scars (30 days). On the other hand, the percentage of intra-blood-vessel of ulcer on fundic-pyloric border after changing into scar (30 days) and recurring (45 days) significantly increased compared with initial healing (10 days, 20 days). The stratum of spindly cells with FN-positive surface appeared under regenerative epithelia of ulcers on fundic-pyloric border from 10 days to 20 days. This part was proven to be spare in blood vessels by distribution of LM. Though this stratum was not observed at every stages after recurrence, the collagen fibers of ulcer on fundic-pyloric border had got mature thickly. These results may lead the following theory; the phenomenon that the distribution of blood supply in stomach seems to be more dominant in submucosal fibrous layer than in mucosa may cause the recurrence of fundic-pyloric border ulcers. The cell number of S-phase was significantly more numerously observed in relapsed ulcer on fundic-pyloric border than in pre-relapsed one (10 day). The cell number of S-phase on fundic gland ulcer tended to decrease after healing to scar stage. The immediate restoration of connective tissue under the mucosa is considered to promote epithelial cellular kinetics in recovering and maturing.     

Antacid provides better restoration of glandular structures within the gastric ulcer scar than omeprazole.

Mucosa of healed gastric ulcers displays histological abnormalities that are possibly the basis of ulcer recurrence. The influence of antacid and omeprazole treatment was studied on the quality of ulcer healing. Sixty four rats with gastric cryoulcers were treated daily either with placebo, antacid, omeprazole, or antacid plus omeprazole. Ulcer size was measured three times per week with a novel video endoscopic method. Prostaglandin generation (day 6), cell proliferation (day 8 and 15), height and cell composition of ulcer margin (day 8), and mucosal scar (day 15) were quantitatively assessed. Antacid, omeprazole, and antacid plus omeprazole significantly accelerated ulcer healing predominantly during days 3-8. Compared with placebo, the height of ulcer margin and mucosal ulcer scar was significantly increased in antacid (+7 and +9% respectively) and significantly decreased in omeprazole (-33 and -22% respectively) and antacid plus omeprazole (-26 and -18% respectively) treated rats. The number of bromodeoxyuridine labelled cells (+42%, day 8), epithelial cell mass (+42%, day 15), and the ratios of epithelial cells/connective tissue (+73%, day 15) and epithelial cells/gland lumen (+100%, day 15) were significantly increased in antacid treated rats. In conclusion, both antacid and omeprazole accelerate ulcer healing but antacid provides a better quality of healing. This advantage is lost by cotreatment with omeprazole.     

Influence of gastric colonization with Candida albicans on ulcer healing in rats: Effect of ranitidine,aspirin and probiotic therapy

Objective. Candida albicans frequently inhabits the gastrointestinal tract of humans leading to gastrointestinal candidiasis, especially following suppression of gastric acidity, but studies on the relation between this fungal infection and gastric pathology are limited due to lack of convenient animal models resembling Candida infection in humans. Material and methods. We compared the effects of C. albicans and vehicle inoculation on gastric secretion and healing of gastric ulcers induced by acetic acid in rats treated with 1) ranitidine (30 mg kg^?1 day^?1 s.c.) and 2) aspirin (ASA) (60 mg kg^?1 day^?1 i.g.) with or without probiotic bacteria Lactobacillus acidophillus. At day 0 and at 4, 15 and 25 days after ulcer induction, the ulcer area, the gastric blood flow (GBF), the quantitative gastric cultures of Candida and the expression of mRNAs for pro-inflammatory cytokines IL-1β and TNF-α and growth factors EGF and TGFα were assessed in the gastric mucosa. Results. Gastric acid output was reduced by over 40% soon after Candida inoculation and this effect persisted during all time intervals tested. The area of ulcers in control rats significantly decreased at day 15 and the ulcers disappeared almost completely after 25 days of their induction. In contrast, the ulcers were present until day 25 in Candida-inoculated rats followed by a fall in GBF and a rise in plasma gastrin levels, these effects being significantly attenuated by the co-treatment with Lactobacillus. Candidiasis was accompanied by up-regulation of mRNA for IL-1β, TNF-α, EGF and TGFα and a significant increment in plasma IL-1β and TNF-α levels. Conclusions. 1) Persistent colonization with Candida could be achieved in rats treated with antisecretory agents or non-steroidal anti-inflammatory drugs (NSAIDs) such as ASA; 2) candidiasis reduces gastric acid secretion, while delaying ulcer healing possibly due to the impairment in GBF in the ulcer area and enhanced expression and release of IL-1β and TNFα and 3) probiotic therapy could be useful in the treatment against the deleterious action of fungal infection on the healing of pre-existing gastric ulcers.     

Influence of gastric colonization with Candida albicans on ulcer healing in rats: effect of ranitidine, aspirin and probiotic therapy

OBJECTIVE: Candida albicans frequently inhabits the gastrointestinal tract of humans leading to gastrointestinal candidiasis, especially following suppression of gastric acidity, but studies on the relation between this fungal infection and gastric pathology are limited due to lack of convenient animal models resembling Candida infection in humans. MATERIAL AND METHODS. We compared the effects of C. albicans and vehicle inoculation on gastric secretion and healing of gastric ulcers induced by acetic acid in rats treated with 1) ranitidine (30 mg kg(-1) day(-1) s.c.) and 2) aspirin (ASA) (60 mg kg(-1) day(-1) i.g.) with or without probiotic bacteria Lactobacillus acidophillus. At day 0 and at 4, 15 and 25 days after ulcer induction, the ulcer area, the gastric blood flow (GBF), the quantitative gastric cultures of Candida and the expression of mRNAs for pro-inflammatory cytokines IL-1beta and TNF-alpha and growth factors EGF and TGFalpha were assessed in the gastric mucosa. RESULTS: Gastric acid output was reduced by over 40% soon after Candida inoculation and this effect persisted during all time intervals tested. The area of ulcers in control rats significantly decreased at day 15 and the ulcers disappeared almost completely after 25 days of their induction. In contrast, the ulcers were present until day 25 in Candida-inoculated rats followed by a fall in GBF and a rise in plasma gastrin levels, these effects being significantly attenuated by the co-treatment with Lactobacillus. Candidiasis was accompanied by up-regulation of mRNA for IL-1beta, TNF-alpha, EGF and TGFalpha and a significant increment in plasma IL-1beta and TNF-alpha levels. CONCLUSIONS: 1) Persistent colonization with Candida could be achieved in rats treated with antisecretory agents or non-steroidal anti-inflammatory drugs (NSAIDs) such as ASA; 2) candidiasis reduces gastric acid secretion, while delaying ulcer healing possibly due to the impairment in GBF in the ulcer area and enhanced expression and release of IL-1beta and TNFalpha and 3) probiotic therapy could be useful in the treatment against the deleterious action of fungal infection on the healing of pre-existing gastric ulcers.