Mucosal Defensive Factors Research Articles

S1673 HMGB1 Contributes to the Development of Acute Murine Colitis

loss of colonic crypts with inflammatory mononuclear cell infiltration. In contrast, WT colons had well preserved colonic architecture with inflammatory cell infiltration. Conclusions: We have shown that IAP-KO mice were unable to recover from DSS-induced chronic colitis compared with wild-type. The lack of weight-loss may be due to the enhanced absorption of dietary fat known to occur in the IAP-KO mice. Our results suggest that the gut mucosal defense factor, IAP, may play an important role in protecting the host against effects of intestinal injury/inflammation.

S1675 Crosstalk Between Notch and Toll Signaling in Murine Colitis

loss of colonic crypts with inflammatory mononuclear cell infiltration. In contrast, WT colons had well preserved colonic architecture with inflammatory cell infiltration. Conclusions: We have shown that IAP-KO mice were unable to recover from DSS-induced chronic colitis compared with wild-type. The lack of weight-loss may be due to the enhanced absorption of dietary fat known to occur in the IAP-KO mice. Our results suggest that the gut mucosal defense factor, IAP, may play an important role in protecting the host against effects of intestinal injury/inflammation.

S1674 Dietary Iron Potentiates On Intestinal Inflammation in IL-10 Deficient Mice By Selectively Altering Enteric Microbiota

loss of colonic crypts with inflammatory mononuclear cell infiltration. In contrast, WT colons had well preserved colonic architecture with inflammatory cell infiltration. Conclusions: We have shown that IAP-KO mice were unable to recover from DSS-induced chronic colitis compared with wild-type. The lack of weight-loss may be due to the enhanced absorption of dietary fat known to occur in the IAP-KO mice. Our results suggest that the gut mucosal defense factor, IAP, may play an important role in protecting the host against effects of intestinal injury/inflammation.

S1672 A Novel Protective Moiety of Milk Fat Globule-EGF Factor 8 in the Murine Inflammatory Bowel Disease Model

loss of colonic crypts with inflammatory mononuclear cell infiltration. In contrast, WT colons had well preserved colonic architecture with inflammatory cell infiltration. Conclusions: We have shown that IAP-KO mice were unable to recover from DSS-induced chronic colitis compared with wild-type. The lack of weight-loss may be due to the enhanced absorption of dietary fat known to occur in the IAP-KO mice. Our results suggest that the gut mucosal defense factor, IAP, may play an important role in protecting the host against effects of intestinal injury/inflammation.

Natural Products as Gastroprotective and Antiulcer Agents: Recent Developments

Peptic ulcer, one of the most common gastrointestinal diseases, is a chronic inflammatory disease characterized by ulceration in the regions of the upper gastrointestinal tract where parietal cells are found and where they secrete hydrochloric acid and pepsin. The anatomical sites where ulcer occurs commonly are stomach and duodenum, causing gastric and duodenal ulcer, respectively. Physiopathology of ulcer is due to an imbalance between aggressive factors, such as acid, pepsin, Helicobacter pylori and non-steroidal anti-inflammatory agents, and local mucosal defensive factors, such as mucus bicarbonate, blood flow and prostaglandins. Several drugs are widely used to prevent or treat gastro-duodenal ulcers. These include H2-receptor antagonists, proton pump inhibitors and cytoprotectives. Due to problems associated with recurrence after treatment, there is therefore the need to seek alternative drug sources against ulcers. In recent years, a widespread search has been launched to identify new gastroprotective drugs from natural sources. The aim of the present review is to highlight the recent advances in current knowledge on natural products as gastroprotective and antiulcer agents and consider the future perspectives for the use of these compounds.

Intestinal alkaline phosphatase is a gut mucosal defense factor maintained by enteral nutrition

Under conditions of starvation and disease, the gut barrier becomes impaired, and trophic feeding to prevent gut mucosal atrophy has become a standard treatment of critically ill patients. However, the mechanisms responsible for the beneficial effects of enteral nutrition have remained a mystery. Using in vitro and in vivo models, we demonstrate that the brush-border enzyme, intestinal alkaline phosphatase (IAP), has the ability to detoxify lipopolysaccharide and prevent bacterial invasion across the gut mucosal barrier. IAP expression and function are lost with starvation and maintained by enteral feeding. It is likely that the IAP silencing that occurs during starvation is a key component of the gut mucosal barrier dysfunction seen in critically ill patients.

Status of Mucosal Offensive and Defensive Factors in Pylorus Ligated-Induced Gastric Ulceration in NIDDM Rats vis-a-vis Plantain Banana

Objective: The aim of the present study was to evaluate the status of gastric mucosal defense in pylorus-ligated (PL)-induced gastric ulceration (GU) and secretion in normal and non-insulin dependent diabetes mellitus (NIDDM) rats and to study the effect of methanolic extract of dried powder of unripe plantain banana pulp ( Musa sapientum var. paradisiaca , MSE) shown to have both ulcer protective action and hypoglycemic principle in normal and NIDDM rats with concurrent gastroduodenal ulceration. Methods: NIDDM was induced in 5 days old rat pups by administering 70 mg/kg of streptozotocin intraperitoneally and blood glucose estimation was done after 12 weeks (blood glucose level >140 mg/dL and stable). Gastric ulcers were induced both in normal (NR) and NIDDM rats by 4 h PL. MSE was used in a dose of 100 mg/kg, orally (po), once daily (od) for 6 days. Standard ulcer protective drug sucralfate (SFT) and standard oral hypoglycemic agent glibenclamide (GLC) were used in a dose of 500mg/kg and 0.6 mg/kg respectively, po, od for 6 days. Results: MSE but not SFT tended to decrease blood glucose level at the ulcer protective dose used, while GLC significantly reduced it both in normal as well as in NIDDM rats. There was an increased propensity to gastric ulceration in NIDDM-PL rats compared to the normal PL rats. NIDDM rats showed a tendency to increase in acid-pepsin secretion and decrease in mucin secretion and life span of mucosal cells. Both SFT and MSE showed significant antiulcer activity against PL-GU in NR and NIDDM rats, where as GLC showed a significant effect only against PL-GU in NIDDM rats. Both MSE (having little or no effect on offensive acid-pepsin secretion) and SFT (caused decrease in pepsin secretion) significantly increased the defensive factors like mucin secretion and life span of mucosal cells both in NR-PL and NIDDM-PL rats while, GLC reversed the above parameters only in NIDDM-PL rats near to the normal control level. Conclusion: The study thus indicated that diabetes do affect both the offensive and defensive gastric mucosal factors and correction of either blood sugar level or promotion of defensive mucosal factors do overcome the damage induced by diabetes vis a vis gastric ulceration. Plantain banana by virtue of its having both ulcer protective activity and hypoglycemic principle showed better effect than SFT or GLC alone in NIDDM rats.

Gastroprotective effects of bitter principles isolated from Gentian root and Swertia herb on experimentally-induced gastric lesions in rats

Gentianae Radix, the dried root and rhizoma of Gentiana lutea L. (Gentianaceae), has long been used as a remedy for liver and stomach inflammation, eye troubles, etc. In this paper, the gastroprotective effects of the methanol extract of Gentian root (GM) were studied using different gastric lesion models. In pylorus-ligated rats, administration of GM in the duodenum suppressed gastric juice secretion and total acid output in a dose-dependent manner. Oral or duodenum administration of GM showed significant protection against acute gastric ulcer induced by aspirin plus pylorus ligation, water-immersion restraint stress-induced ulcers, and gastric mucosal injury induced by ethanol. Furthermore, four secoiridoid glycosides, amarogentin (A1), gentiopicroside (A2), amaroswerin (A3), and swertiamarin (A4), were obtained from Gentian root or Swertia herb, and their protective effects against stress-induced ulcers and ethanol-induced gastric mucosal injury were evaluated. The doses required for 50% inhibition (ID50) of A1, A3, and A4 on stress-induced ulcers were calculated to be 5.76, 2.58, and 167 mg/kg respectively. The protective effect of A2 at 250 mg/kg was 26.5%. On ethanol-induced gastritis, 5.0 mg/kg of A1 and A3 showed remarkable suppressive effects (33.7 and 45.4%, respectively), and 20 mg/kg of A4 exhibited a suppressive effect (30.8%). The effects of A1, A3, and A4 on ethanol-induced gastric lesions were canceled by 5.0 mg/kg indomethacin pretreatment. These results suggest that the therapeutic effects of Gentian root on gastric lesions are associated with enhanced mucosal defensive factors via the prostaglandin pathway in the cell membrane, and that secoiridoid glycosides contribute to this activity.

Review article: the pathophysiology of gastro‐oesophageal reflux disease − oesophageal manifestations

The pathogenesis of gastro-oesophageal reflux disease (GERD) is multifactorial, involving transient lower oesophageal sphincter relaxations (TLESRs) as well as other lower oesophageal sphincter (LES) pressure abnormalities. GERD is associated with a decrease in LES pressure, which can be provoked by factors such as foods (fat, chocolate, etc.), alcohol, smoking and medications. These factors have also been shown to increase TLESRs. As a result, reflux of acid, bile, pepsin and pancreatic enzymes occurs, leading to oesophageal mucosal injury, which can potentially progress to oesophageal adenocarcinoma in a minority of patients with Barrett's metaplasia. In addition, duodenogastric contents can also contribute to oesophageal injury. Other factors contributing to the pathophysiology of GERD include hiatal hernia, poor oesophageal clearance, delayed gastric emptying and impaired mucosal defensive factors. Hiatal hernia has a permissive role in the pathogenesis of reflux oesophagitis by promoting LES dysfunction. Delayed gastric emptying, resulting in gastric distension, can significantly increase the rate of TLESRs, contributing to postprandial GER. The mucosal defensive factors have an important role in GERD. When excessive acid causes a breakdown in oesophageal epithelial defenses, epithelial resistance may be reduced. Nocturnal GERD is associated with prolonged acid exposure and proximal extent of acid contact, which elevates the risk for oesophageal damage and GERD-related complications. In sum, GERD is a complex problem caused by many factors that are exacerbated when the patient is in the supine position.

Effect of Cissus quadrangularis on gastric mucosal defensive factors in experimentally induced gastric ulcer-a comparative study with sucralfate.

Cissus quadrangularis is an indigenous plant commonly mentioned in Ayurveda for treatment of gastric ulcers. The ulcer-protective effect of a methanolic extract of C. quadrangularis (CQE) was comparable to that of the reference drug sucralfate. Further, gastric juice and mucosal studies showed that CQE at a dose of 500 mg/kg given for 10 days significantly increased the mucosal defensive factors like mucin secretion, mucosal cell proliferation, glycoproteins, and life span of cells. The present investigation suggests that CQE not only strengthens mucosal resistance against ulcerogens but also promotes healing by inducing cellular proliferation. Thus, CQE has potential usefulness for treatment of peptic ulcer disease.

Effect of <I> Cissus quadrangularis</I> on Gastric Mucosal Defensive Factors in Experimentally Induced Gastric Ulcer—A Comparative Study with Sucralfate

Effect of <I> Cissus quadrangularis</I> on Gastric Mucosal Defensive Factors in Experimentally Induced Gastric Ulcer—A Comparative Study with Sucralfate

Gastroduodenal ulcer protective activity of Asparagus racemosus: an experimental, biochemical and histological study

Asparagus racemosus is an Ayurvedic rasayana, which finds mention in ancient Indian texts for treatment of gastric ulcers. The ulcer protective effect of methanolic extract of fresh roots of A. racemosus (ARM), 25–100 mg/kg given orally, twice daily for 5 days, was studied on different gastroduodenal ulcer models. ARM 50 mg/kg, twice daily, orally (total saponins 0.9%) showed significant protection against acute gastric ulcers induced by cold restraint stress (CRS), pyloric ligation, aspirin plus pyloric ligation, and duodenal ulcers induced by cysteamine. ARM in the above dose also significantly healed chronic gastric ulcers induced by acetic acid after 10 days treatment. However, ARM was ineffective against aspirin- and ethanol-induced gastric ulcers. Further, gastric juice and mucosal studies showed that ARM significantly increased the mucosal defensive factors like mucus secretion, cellular mucus, life span of cells and also possessed significant anti-oxidant effect, but had little or no effect on offensive factors like acid and pepsin.

Gastro‐oesophageal reflux disease – pathophysiological issues of clinical relevance

SummaryGastro‐oesophageal reflux disease is a multifactorial disorder in which the pathophysiological mechanisms are variably combined in different patients. Motor dysfunction of the lower oesophageal sphincter (LOS) and, possibly, the proximal stomach is a major cause of the increase in the number of reflux episodes. Transient LOS relaxation is the main mechanism of reflux in many patients with endoscopically negative disease, whereas a hypotensive LOS becomes relevant only in patients with oesophagitis. Alterations in primary and secondary peristalsis contribute to the increased oesophageal acid exposure by delaying clearance. The presence of a hiatus hernia, especially when voluminous and/or non‐reducible, increases the number of reflux episodes by mechanically weakening the oesophago‐gastric junction, and impairs oesophageal clearance. Hypersensitivity to acid is often present and contributes to the clinical manifestations of the disease, whereas oesophageal hypersensitivity, both to chemical and mechanical stimuli, plays a predominant role in a subset of patients. Increased concentrations of noxious compounds in the oesophageal refluxate may contribute to the development of anatomical lesions, but this is still a matter for debate. The clinical relevance of Helicobacter pylori infection and of mucosal defensive factors still needs to be fully elucidated.

Effect of Ecabet Sodium Enema on mildly to moderately active ulcerative proctosigmoiditis: an open-label study

OBJECTIVES: Ecabet sodium (ES), a nonabsorbable antigastric ulcer agent, has been shown to adhere to the region of an ulcer. It topically enhances gastric mucosal defensive factors such as the endogenous prostaglandins, capsaicin-sensitive sensory nerves, nitric oxide, and mucin. All of these mucosal defensive factors play an important role in maintaining the mucosal integrity of the colon and rectum. Therefore, we investigated the effect of ES in patients with mildly to moderately active ulcerative proctosigmoiditis. METHODS: In an open-label study, seven patients with mildly to moderately active ulcerative colitis (UC) who had an inflamed mucosa in the rectum and/or sigmoid and were resistant to 4-wk topical and systemic standard treatment were treated with an ES enema b.i.d. for 14 days. The enema consisted of ES (1 g) and tepid water (20 or 50 ml). These patients were assessed by the Clinical Activity Index, colonoscopically, and histologically before and after the ES therapy. The ES therapy was started after obtaining informed consent from the patients. RESULTS: Six of the seven patients responded to therapy and achieved clinical, endoscopic, and histological remissions. One patient was withdrawn because of increased stool frequency. All six patients who completed the study showed a significant change in the mean Clinical Activity Index score from 5.3 ± 1.4 (mean ± SD) to 0.5 ± 0.8 ( p < 0.05), in the colonoscopic score from 3.0 ± 0.9 to 0.8 ± 0.4 ( p < 0.05), and in the histological score from 2.7 ± 0.5 to 0.5 ± 0.6 ( p < 0.05), and achieved remission at the end of the study. There were no side effects attributable to the ES therapy. Five of the six patients are still in clinical remission after a median follow-up period of 5 months. CONCLUSIONS: The ES enemas proved to be a safe and potentially useful adjuvant therapy currently available for treating patients with mildly to moderately active ulcerative proctosigmoiditis. A controlled study is necessary to confirm our results.

Prophylactic and curative effects of in gastric ulcer models

Bacopa monniera Wettst. (BM, syn. Herpestis monniera L; Scrophulariaceae), is an Ayurvedic drug used as a rasayana. Its fresh juice was earlier reported to have significant antiulcerogenic activity. In continuation, methanolic extract of BM (BME) standardized to bacoside-A content (percentage-38.0 +/- 0.9), when given in the dose of 10-50 mg/kg, twice daily for 5 days, showed dose-dependent anti-ulcerogenic on various gastric ulcer models induced by ethanol, aspirin, 2 h cold restraint stress and 4 h pylorus ligation. BME in the dose of 20 mg/kg, given for 10 days, twice daily showed healing effects against 50% acetic acid-induced gastric ulcers. Further work was done to investigate the possible mechanisms of its action by studying its effect on various mucosal offensive acid-pepsin secretion and defensive factors like mucin secretion, mucosal cell shedding, cell proliferation and antioxidant activity in rats. BME 20 mg/kg showed no effect on acid-pepsin secretion, increased mucin secretion, while it decreased cell shedding with no effect on cell proliferation. BME showed significant antioxidant effect per se and in stressed animals. Thus, the gastric prophylactic and curative effects of BME may be due to its predominant effect on mucosal defensive factors.

Pediatric gastritis and peptic ulcer disease.

Inflammation of the gastric and duodenal mucosa is the end result of an imbalance between mucosal defensive and aggressive factors. The degree of inflammation and imbalance between defensive and aggressive factors can then result in varying degrees of gastritis and/or mucosal ulceration. Gastritis and ulcers of the duodenum or stomach can be classified as primary or secondary. The majority of children with chronic gastritis and ulcers in the stomach or duodenum have secondary inflammation or mucosal ulceration. These secondary ulcers generally occur due to a systemic condition like head trauma or overwhelming sepsis, or as sequelae to drug ingestion (i.e. non-steroidal anti-inflammatory agents), but secondary gastroduodenal ulcers can also occur in specific disease conditions such as Zollinger-Ellison syndrome or Crohn's disease. In almost all children with primary duodenal or gastric ulcers mucosal inflammation and, less frequently, ulceration is caused by a spiral shaped, gram-negative, microaerobic rod Helicobacter pylori. Recent epidemiological evidence has linked chronic H. pylori infection with the development of gastric carcinomas.

Gastritis and peptic ulcer disease in childhood.

Inflammation of the gastric and duodenal mucosa is the end result of an imbalance between mucosal defensive and aggressive factors. The degree of inflammation and imbalance between defensive and aggressive factors can then result in varying degrees of gastritis and/or frank mucosal ulceration. Gastritis and ulcers of the duodenum or stomach can be classified either as primary or secondary. The majority of children with chronic active or chronic gastritis and ulcers in the stomach or duodenum have secondary inflammation or mucosal ulceration. These ulcers generally occur due to a systemic condition like head trauma or overwhelming sepsis, or, as sequelae to drug ingestion (i.e., non-steroidal anti-inflammatory agents), but secondary gastroduodenal ulcers can also occur in specific disease conditions such as Zollinger-Ellison syndrome or Crohn's disease. The different causes of gastritis and peptic ulcer disease will be discussed in this paper. In almost all children presenting to their treating pediatric gastroenterologist with duodenal or gastric ulcers of these patients, mucosal inflammation and less frequently, ulceration is caused by a spiral shaped, gram-negative, microaerobic rod, properly named Helicobacter pylori. Recent epidemiological evidence has linked chronic H. pylori infection with the development of gastric carcinomas.

Effects of the common cold and intranasal fluticasone propionate treatment on mucosal host defense assessed by human saliva

Objective. The purpose of this investigation was to study the effect of a potent topical steroid, fluticasone propionate, on patients with early signs and symptoms of the common cold. To characterize the mucosal inflammatory response, salivary defense factors and flow rate in these patients were analyzed. Study Design. Forty patients with symptoms of the common cold were randomized into 2 groups to receive either high-dose fluticasone propionate (100 μg per nostril) or placebo 4 times daily for 6 days. Paraffin-stimulated whole saliva was collected on day 1 (before the onset of medication), day 7 (posttreatment), and day 21 (follow-up). Results. Salivary flow rate, innate host defense factors, and total protein content were not affected by the common cold. IgA increased between day 7 and day 21 ( P ≤ .01; Student 2-tailed t test), and the relative proportions of salivary peroxidase and IgA increased on day 7 ( P = .01) and day 21 ( P = .05). In patients receiving fluticasone, saliva flow rate was lower on day 21 ( P ≤ .05) than on days 1 and 7. The innate salivary defense factors were not affected, but IgA increased both on day 7 ( P ≤ .001) and on day 21 ( P ≤ .001) in comparison with day 1. Conclusions. Of the oral mucosal defense factors, only IgA is activated during the common cold. Intranasally administrated fluticasone propionate does not have a suppressive effect on salivary antimicrobial capacity. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999;87:695-9)

Oral anti-inflammatory and anti-ulcerogenic activities of a hydroalcoholic extract and partitioned fractions of Turnera ulmifolia (Turneraceae)

Anti-inflammatory studies were conducted on rats or mice using a crude hydroalcoholic extract of the aerial parts of Turnera ulmifolia and it's partitioned fractions, i.e. the aqueous, ethyl acetate and ethanolic fractions. The hydroalcoholic extract and it's fractions (aqueous and ethanolic) inhibited carrageenan-induced edema. However, only the ethanolic fraction was used in the other experiments due to it's yield. The extract also inhibited the cotton pellet granuloma and the increase of vascular permeability induced by histamine, 5-hydroxytryptamine and prostaglandin E 2, but not that produced by bradykinin. The extract or the fraction did not present analgesic activity in the writhing test using acetic acid and did not reduce croton oil-induced ear edema in mice. When the ethanolic fraction and LPS were administered i.p. to Balb/C mice 72 h before blood or peritoneal fluid collection, no changes were observed in the white or total blood cell counts in the peripheral blood. On the other hand, changes were observed in both total and differential cell counts in the peritoneal exudate since all doses of the fraction reduced the number of total leukocytes (mainly lymphocytes) obtained from the peritoneal exudate. In contrast to nonsteroidal anti-inflammatory drugs, the administration of the hydroalcoholic extract or the ethanolic fraction alone did not potentiate gastric mucosal lesions induced by aspirin. The extract and the fraction inhibited the appearance of gastric lesions induced by indomethacin, ethanol and pylorus ligature, but not those induced by stress. As also observed with carbenoxolone, the ethanolic fraction increased the wall mucus in hypothermical-restraint stress-induced gastric lesions. The anti-ulcerogenic effect of the extract and of the ethanolic fraction may be related to an increase of mucosal defensive factors, such as prostaglandin and mucus. The anti-inflammatory actions of the extract and the fraction may be due to an inhibitory effect on histamine and cyclooxygenase II, but not on cyclooxygenase I, because the extract and it's fraction present both anti-inflammatory and anti-ulcerogenic effects. The major substances present in the ethanolic fraction are flavonoids which will be isolated and identified.

Suppressive effect of tetraprenylacetone on gastric atrophy induced by short-term administration of N-methyl-N'-nitro-N-nitrosoguanidine in rats.

Several studies have been reported on the effects of various therapeutic agents in enhancing or suppressing the carcinogenic activity of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). However, it is still unknown whether a mucosal protective agent could suppress its carcinogenic activity. Twenty-five Wistar male rats were divided into four groups: group 1, MNNG alone; group 2, MNNG + tetraprenylacetone; group 3, control; group 4, tetraprenlacetone alone. MNNG 100 mg/mL, was freely given to groups 1 and 2, and tetraprenylacetone (200 mg/kg intraperitoneal) was additionally administered every other day to the rats in groups 2 and 4. The animals were sacrificed at 10 weeks and the gastric mucosa examined. Atrophic changes were observed in the antrum after 8 weeks of oral administration of MNNG. Furthermore, using immunohistological analysis with 5-bromo-2'-deoxyuridine (BrdU), the proliferative zone was found to be enlarged and shifted upward, although the BrdU labelling index of the proliferative zone was unaltered. Intraperitoneal administration of tetraprenylacetone every other day suppressed the MNNG-induced atrophic change and the alterations proliferative markers. Tetraprenylacetone alone did not have an effect either on morphological or proliferative markers. These observations suggest that gastric mucosal defensive factors may play critical roles in suppressing atrophic change inducing carcinogenesis by an exogenic carcinogen.