Candida albicans aggravates duodenal ulcer perforation induced by administration of cysteamine in rats

BACKGROUND: Candida sp are frequently isolated from the ascitic fluid of patients with perforated ulcers. The present study was performed to examine whether Candida infection may be involved in the process of ulcer perforation. METHODS: Male Wistar rats were divided into a saline group (n = 15) and a Candida group (n = 17). Cysteamine-HCl (Sigma; 31 mg/100 g) was administered thrice on day 1 to both groups of animals. Candida albicans at a density of 10(8) in 0.5 mL of saline was administered 1 h before, and 12 h and 24 h after the first administration of cysteamine in the Candida group. RESULTS: Perforated duodenal ulcers were observed in 94.1% of the rats in the Candida group, but only 26.7% of the rats in the saline group (P < 0.01). The area of the duodenal ulcers in the Candida group was 40.89 +/- 33.07 mm2, whereas that in the saline group was 16.53 +/- 20.4 mm2 (P < 0.05). The mortality rate was significantly higher in the Candida group than in the saline group. In the Candida group, colonization by C. albicans was recognized at the ulcer base, surrounded by marked granulocytic infiltration. The number of eosinophils infiltrating the ulcer base was also significantly greater in the Candida group than in the saline group. Immunohistochemical analysis revealed the expression of secretory aspartyl protease (SAP) in the region of the ulcer showing colonization by C. albicans in the Candida group. CONCLUSION: Candida albicans aggravates duodenal ulcer perforation in the experimental model of cysteamine-induced duodenal ulcer perforation. The present findings suggest that SAP and host-parasite relationships, including granulocyte-dependent mechanisms, may be involved in the aggravation of ulcer perforation by C. albicans.     

Effect of cysteamine on gastroduodenal mucosal histamine in rat

Cysteamine administration to rats is followed by a high incidence of peptic ulceration. The aim of the present study was to investigate the effect of cysteamine on gastric and duodenal mucosal histamine and gastric mucosal histamine formation capacity. After a four hour fast, cysteamine in doses of 50, 100, 200, 300, 400, and 500 mg/kg bodyweight was injected subcutaneously to male Wistar rats; saline injection was used as control. After 24 hours the animals were killed; the stomach and duodenum were removed and examined for ulceration. Mucosal biopsies were taken for histamine studies. Gastric and duodenal ulceration tended to appear with increasing incidence with higher doses. A direct correlation was found between the dose of cysteamine and gastric mucosal histamine (p less than 0.02), and duodenal mucosal histamine (p less than 0.05). Further, a direct relationship was found between gastric mucosal histidine decarboxylase activity and the dose of cysteamine (p less than 0.05). Gastric mucosal histamine and histidine decarboxylase activity showed a direct correlation (p less than 0.001). Gastric and duodenal mucosal histamine and gastric mucosal histamine formation capacity were higher in rats with ulcers than in controls and rats without ulcers. In rat, cysteamine induces dose related changes in mucosal histamine and histidine decarboxylase activity. These changes are related to ulcer formation; histamine may be involved in the pathophysiology of cysteamine induced ulcer formation.     

An experimental study of adrenalin-stimulated gastric acid secretion and gastrin secretion in rats of cysteamine-induced duodenal ulcer]

It is known that cysteamine-induced duodenal ulcers in rats are similar to the human duodenal ulcers in some aspects. We investigated their similarities in view of adrenalin-stimulated gastric acid secretion and gastrin secretion in these rats. Acid outputs decreased in the control group by the administration of adrenaline, but in the cysteamine-administered group acid outputs increased dose dependently. Serum gastrin levels and plasma noradrenaline levels increased by cysteamine administration. The abnormal gastric acid secretion by the adrenalin infusion in the process of cysteamine-induced duodenal ulcers in rats, which was resembled to that of duodenal ulcer patients, was recognized.     

Pathogenesis of duodenal ulceration produced by cysteamine or propionitrile

Insight into the pathogenesis and etiology of experimental duodenal ulceration was sought by studying the modulation of this disease in rats by selective vagotomy, chemical sympathectomy, histamine depletion, histamine H-2 receptor antagonists (eg, metiamide, cimetidine), or endocrine ablations. Gastric secretion was examined in intact and pylorusligated animals. The formation of duodenal ulcers induced by the administration of propionitrile or cysteamine was abolished by vagotomy, decreased by sympathectomy, histamine depletion, histamine H-2 receptor antagonists, hypophysectomy, thyroidectomy, or adrenalectomy. Cimetidine and metiamide exerted a dose-dependent antiulcer effect, but metiamide enhanced the mortality of rats given propionitrile or cysteamine. The nonulcerogen derivative of cysteamine, ethanolamine, did not increase mortality when given in combination with metiamide. The gastric hyperacidity elicited by cysteamine was reduced by metiamide or vagotomy, the latter being more effective in this respect. Thus, the chemically induced duodenal ulcer in rats resembles the human peptic ulcer disease in sensitivity to therapeutic modalities and may serve as an appropriate model to study the role of neural, hormonal, and other factors in the etiology and pathogenesis of this disorder.     

Cysteamine-induced duodenal ulcer and the hepatoduodenal branch of the vagus nerve

We investigated the role of the autonomic nervous system in gastric acid secretion, somatostatin concentration and PAS-positive mucus production in Brunner's glands in cysteamine-induced duodenal ulcer. Vagotomized rats were used. No ulcers occurred in the groups with vagotomies of the hepatoduodenal, truncal or gastric branches after cysteamine administration. However, in the hepatoduodenal branch vagotomized group, there was an increase in gastric acid secretion after cysteamine administration. A similar increase was observed in the control group, but the decreases in somatostatin concentration and PAS-positive mucus seen in the control group were not found in the hepatoduodenal vagotomized group. These results suggest that the hepatoduodenal branch of the vagus nerve might play an important role in the ulcerogenic process of cysteamine-induced duodenal ulcer.     

Cysteamine-induced duodenal ulcer and the hepatoduodenal branch of the vagus nerve

We investigated the role of the autonomic nervous system in gastric acid secretion, somatostatin concentration and PAS-positive mucus production in Brunner’s glands in cysteamine-induced duodenal ulcer. Vagotomized rats were used. No ulcers occurred in the groups with vagotomies of the hepatoduodenal, truncal or gastric branches after cysteamine administration. However, in the hepatoduodenal branch vagotomized group, there was an increases in gastric acid secretion after cysteamine administration. A similar increase was observed in the control group, but the decreases in somatostatin concentration and PAS-positive mucus seen in the control group were not found in the hepatoduodenal vagotomized group. These results suggest that the hepatoduodenal branch of the vagus nerve might play an important role in the ulcerogenic process of cysteamine-induced duodenal ulcer.     

Candida albicans Infection Delays Duodenal Ulcer Healing in Cysteamine-Induced Duodenal Ulcers in Rats

A low curability of ulcers infected with Candida has been reported in the literature. The aim of the study reported here was to investigate experimentally whether Candida infection affects the healing of ulcers. Candida albicans (the Candida group) or saline (the control group) was administered intragastrically into rats with a cysteamine-induced duodenal ulcer. The duodenal lesions, vascular endothelial growth factor A (VEGF-A) and proliferating cell nuclear antigen (PCNA) were assessed. On Day 7 post-administration, 70.4% rats of the Candida group had a duodenal ulcer compared with 33.3% in the control group (P < 0.05). The duodenal ulcer in the Candida group was significantly larger and deeper than that in the control group. The number of VEGF-A- and PCNA-positive cells was smaller and the area of VEGF-A expression was lower in the Candida group. Using a rat model, we have demonstrated that Candida infection can delay the wound healing process of duodenal ulcers by means of a low expression of VEGF-A and PCNA.     

Gastrointestinal Damage Induced by Celecoxib and Rofecoxib in Rats

Five experimental models were developed in different groups of Wistar rats (N = 15) to study selective COX-2-inhibitor NSAIDs such as celecoxib and rofecoxib, as follows: (1) dose-dependent oral Celecoxib and Rofecoxib for 5 days, and 24 hr after oral indomethacin; (2) Same as 1 but subcutaneously; (3) gastric ulcer induced by glacial acetic acid; (4) duodenal ulcer induced by cysteamine; and (5) stress by immobilization and immersion in water at 15°C for 6 hr. Celecoxib and Rofecoxib, either orally or subcutaneously, did not produce necrotic lesions in healthy gastrointestinal mucosa (0%), showing normal histology. In contrast, previously indomethacin-induced lesions were aggravated (90%, P < 0.001). Total necrosis in the small intestine as well as increased ulcers and perforation of gastric and duodenal ulcers induced by acetic acid and cysteamine were observed. There was also aggravation of the necrotic gastric area in stress (60–90%, P < 0.05). Celecoxib and rofecoxib showed neutrophilia (5000/mm³) similar to that with indomethacin. In contrast, there was no leukocyte infiltration in the gastric mucosa; thus, we can consider it a selective COX-2 NSAID. In conclusion, celecoxib and rofecoxib at doses causing COX-2 but not COX-1 inhibition did not produce toxic lesions in healthy gastrointestinal mucosa, yielding a broad therapeutic margin. In contrast, when administered in altered gastrointestinal mucosa, they aggravated and complicated gastric ulcers as well as necrosis in the small intestine, consequently restricting their clinical use.     

Inhibition of cysteamine-induced duodenal ulcer in the rat by bile diversion. Enhancement of the ulcerogenic effect of cysteamine by taurocholic and glycocholic acids

Three groups of rats were twice given cysteamine subcutaneously in a dose of 20 mg/100 g body weight. Nine of 10 controls developed severe duodenal ulcers. In contrast, the ulcer formation was inhibited significantly in the rats submitted, before exposure to cysteamine, to a bile diversion operation consisting of jejunopylorostomy and Roux-en-Y anastomosis without gastric resection. However, rats submitted to the same operation but drinking a solution with 5 mmol/l sodium salts of taurocholic and glycocholic acid, 1:3, developed severe duodenal ulcers after cysteamine injections (8 of 10). The conclusion is that neither the chemical cysteamine nor hydrochloric acid alone can be made responsible for cysteamine-induced duodenal ulcer in the rat, but that bile salts clearly enhance the ulcerogenic property of cysteamine.     

Biphasic effect of duodenal ulcerogens on gastric emptying in the rat

The effect of the duodenal ulcerogen cysteamine on gastric emptying of a liquid meal was compared to that of two newly identified duodenal ulcerogens, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and mepirizole. Emptying rates after acute and chronic treatment with duodenal ulcerogens were obtained. Acute administration of cysteamine, MPTP, or mepirizole significantly delayed gastric emptying of the meal. Chronically treated rats, however, showed either no change or accelerated gastric emptying after cysteamine, MPTP, or mepirizole. Gastric emptying in chronically treated animals was faster in rats that developed the most severe duodenal ulcers. These results indicate that delayed gastric emptying instead of accelerated emptying is a more common abnormality during duodenal ulceration. After the ulcer develops, however, unaltered or accelerated gastric emptying is observed experimentally, thus suggesting that accelerated gastric emptying in duodenal ulcers is an acquired alteration. The implications that these experimental findings may have in the pathogenesis of duodenal ulcer, in light of the clinical data available, are discussed.This study was supported by NIH grant AM25229.     

Gastrointestinal damage induced by celecoxib and rofecoxib in rats

Five experimental models were carried out in different groups of Wistar rats (n = 15) in order to study selective (cyclo-oxygenase) COX-2 non-steroid antiinflammatory inhibitors, such as celecoxib and rofecoxib, as follows: 1) Dose-dependent oral celecoxib and rofecoxib for 5 days, and 24 hours after oral indomethacin. 2) Same as 1, but subcutaneously. 3) Gastric ulcer induced by means of glacial acetic acid. 4) Duodenal ulcer induced by means of cysteamine. 5) Stress due to being kept under restraint and immersion in water at 15 degrees C for 6 hours. Celecoxib and rofecoxib, either orally or subcutaneously, did not produce necrotic injuries in healthy gastrointestinal mucosa (0%), showing normal histology. On the other hand, the injuries previously induced by indomethacin worsened (90%, p < 0.001). Total necrosis of small intestine as well as increased ulcer and perforation of gastric and duodenal ulcers induced by acetic acid and cysteamine were observed. There was also worsening of gastric necrotic area with stress (60-90%, p < 0.05). Celecoxib and rofecoxib showed neutrophilia (5,000/mm3) similar to that presented by indomethacin, but there was no leukocyte infiltration in the gastric mucosa; thus we can consider it a COX-2 selective NSAID (non-steroidal anti-inflammatory drug). CONCLUSION: Dose-dependent administration of celecoxib and rofecoxib as COX-2 inhibitors and non-COX-1 inhibitors, respectively, did not produce toxic injuries on healthy gastrointestinal mucosa, thus providing a broad therapeutic spectre. On the other hand, when administered in presence of altered gastrointestinal mucosa, they worsened and complicated gastric ulcers, and also induced necrosis in the small intestine, thereby restricting their clinical use.     

Oral administration of synthetic human urogastrone promotes healing of chronic duodenal ulcers in rats

The effect of oral administration of synthetic human epidermal growth factor/urogastrone (EGF/URO) on healing of chronic duodenal ulcers induced by cysteamine in rats was investigated and compared with that of cimetidine, a H2-receptor antagonist. After 25 and 50 days of treatment, synthetic human EGF/URO significantly increased healing of chronic duodenal ulcers to the same extent as cimetidine. Combined treatment with synthetic human EGF/URO and cimetidine for 25 days was more effective than synthetic human EGF/URO given alone, whereas combined treatment for 50 days was significantly more effective than cimetidine alone. These results show that a combination of an agent inhibiting gastric acid secretion and the cytoprotective and growth-stimulating peptide EGF/URO seems to be more effective with regard to duodenal ulcer healing than individual administration of the two substances. Synthetic human EGF/URO is a potent inhibitor of gastric acid secretion when administered intravenously, but had no effect on acid secretion when given intraduodenally, which suggests that the effect of synthetic human EGF/URO is a direct action on the duodenal mucosa. In conclusion, this study showed that oral synthetic human EGF/URO has a significant effect on healing of duodenal ulcers in rats. The amount of synthetic human EGF/URO administered is comparable to that found in saliva during stimulation of the salivary glands. Our results, therefore, suggest that EGF/URO is one of the endogenous factors participating in healing of duodenal ulcers.     

Somatostatin in rat tissues is depleted by cysteamine administration

Administration of cysteamine (mercaptoethylamine) induces in rats severe perforating duodenal ulcers. Because the ulcerogenic properties of cysteamine are markedly reduced by treatment with somatostatin, we considered the possibility that cysteamine-induced duodenal ulcer might be mediated by depletion of tissue somatostatin, and thereby of its paracrine influences on gastrin and gastric acid secretion. To test this hypothesis, we measured the concentration of immunoreactive somatostatin (IR-somatostatin) in stomach and duodenal mucosa at intervals after administration of a single ulcerogenic dose (30 mg/kg by stomach tube). IR-somatostatin in these tissues fell rapidly to reach a minimum at 4 h (stomach 31%, duodenum 60% of control respectively). IR-somatostatin in hypothalamus and pancreas decreased gradually to a minimum at 7 h. Another duodenal ulcerogen, propionitrile (10 mg/100 g bw, s.c.) which is more toxic than cysteamine, and several stressful procedures including ether anesthesia, restraint and s.c. formalin did not lower stomach or duodenal IR-somatostatin. Gut, pancreas and hypothalamic VIP levels were not influenced by cysteamine. These findings suggest that cysteamine is a relatively specific depletor of tissue somatostatin. Because blood levels of somatostatin fell, and only trivial amounts of the peptide were found in the stomach lumen after cysteamine administration, it appears likely that this agent acts at the cellular level to cause breakdown of preformed somatostatin and/or to acutely reduce its synthesis.     

In vivo cell kinetics studies of the duodenum during and after healing of cysteamine-induced duodenal ulcer in rats using bromodeoxyuridine incorporation

The present study investigated the defect of duodenal defence responsible for the tendency of recurrence of duodenal ulcer. Male Wistar rats were treated with cysteamine-HCl subcutaneously to induce duodenal ulcer, and bromodeoxyuridine (BrdU) was given intraperitoneally 1 h before laparotomy. Serial tissue sections and immunocytochemical staining of BrdU were done to study the cell kinetics during and after healing. Deep ulcers developed in the proximal part of the duodenum 24 h after cysteamine injection, and the ulcer was replaced by scar tissue 1 week later. BrdU-labelling index of normal duodenal mucosa in control rats was 30-34%. On the peripheral part of the regenerative mucosa, BrdU-labelling index increased from 1.5% to 26-27%, 1-4 weeks after injection and remained at this level thereafter. On the central part, except the most central area, the labelling index remained at 0% until 3 weeks, and was 15% 6 weeks after cysteamine treatment. It never achieved the level seen in control normal mucosa. The labelling rate of fibrous cells in scar tissue decreased from 28% to nearly 0% 1-4 weeks after the injection. It is concluded that both the ulcer scar and the regenerative mucosa do not achieve a mature state in the initial scarred stage; they need more time to reach a relatively mature condition. Moreover, the regenerative mucosa will be the weak, easily damaged part of the duodenum.     

Effect of cysteamine on gastric nerve fibers containing gastrin-releasing peptide in the rat

In rats, changes in gastric nerve fibers containing gastrin-releasing peptide (GRP) in cysteamine-induced duodenal ulcer were investigated in relation to the dynamics of gastrin-producing cells (G-cells). Marked increases in gastric acid secretion and serum gastrin level were observed from 2h after the administration of cysteamine. The number of G-cells was significantly decreased from 2h after the injection of cysteamine. Two and 4h after the administration of cysteamine, the G-cells showed ultrastructural changes characterized by a markedly decreased number of secretory granules. Circulating GRP levels were significantly elevated from 2h after the administration of cysteamine. In the control group given vehicle only, nerve fibers showing immunoreaction for GRP formed a fine network in the gastric wall and were densely distributed in the oxyntic mucosa, located close to capillaries and demonstrated varicosities that contained either small clear vesicles or GRP-immunopositive vesicles with large cores. Eight h after the administration of cysteamine, there was depleted GRP immunoreactivity, evidenced by a markedly decreased number of vesicles, with large electron-dense cores, in the oxyntic mucosa. These findings suggest that, in cysteamine-induced doudenal ulcer, alterations in gastric nerve fibers containing GRP may be related to hypergastrinemia.     

Epidemiology of peptic ulcer disease

In the United States about four million people have active peptic ulcers and about 350,000 new cases are diagnosed each year. Four times as many duodenal ulcers as gastric ulcers are diagnosed. Approximately 3000 deaths per year in the United States are due to duodenal ulcer and 3000 to gastric ulcer. There has been a marked decrease in reported hospitalization and mortality rates for peptic ulcer in the United States. Changes in criteria for selecting the underlying cause of death might account for some of the apparent decrease in ulcer mortality rates. Hospitalization rates for duodenal ulcers decreased nearly 50 per cent from 1970 to 1978, but hospitalization rates for gastric ulcers did not decrease. Although this decrease in hospitalization rates may reflect a decrease in duodenal ulcer disease incidence, it appears that changes in coding practices, hospitalization criteria, and diagnostic procedures have contributed to the reported declines in peptic ulcer hospitalization and mortality rates. There is no good evidence to support the popular belief that peptic ulcer is most common in the spring and autumn. The most consistent pattern appears to be low ulcer rates in the summer. There is strong evidence that cigarette smoking, regular use of aspirin, and prolonged use of steroids are associated with the development of peptic ulcer. There is some evidence that coffee and aspirin substitutes may affect ulcers, but most studies do not implicate alcohol, food, or psychological stress as causes of ulcer disease. Genetic factors play a role in both duodenal and gastric ulcer. The first-degree relatives of patients with duodenal ulcer have a two- to threefold increase in risk of getting duodenal ulcer and relatives of gastric ulcer patients have a similarly increased risk of getting a gastric ulcer. About half of the patients with duodenal ulcer have elevated plasma pepsinogen I. A small increase in risk of duodenal ulcer is found in persons with blood group O and in subjects who fail to secrete blood group antigens into the saliva. In most Western countries, morbidity from duodenal ulcer is more common than from gastric ulcer, even though deaths from gastric ulcer exceed or equal those from duodenal ulcer. In Japan, both morbidity and mortality are higher for gastric ulcer than for duodenal ulcer.     

Prevalence of Peptic Ulcer in Dyspeptic Patients and the Influence of Age,Sex, and <Emphasis Type="Italic">Helicobacter pylori</Emphasis> Infection

We investigated the prevalence of peptic ulcer in dyspeptic patients in China to analyze the influence of age, sex, and Helicobacter pylori (H. pylori) infection. The results showed that the prevalence of gastric and duodenal ulcer increased with age. In patients under 60 years old, the prevalence of duodenal and gastric ulcers in females was markedly lower than that in males, especially the prevalence of duodenal ulcer. The prevalence of duodenal ulcer and gastric ulcer in H. pylori-infected patients was markedly higher than in patients without H. pylori infection. In the patients under 60 years old, sex differences were still seen in both H. pylori-positive and H. pylori-negative patients. The prevalence of gastric and duodenal ulcers was markedly increased with age in both H. pylori-positive and H. pylori-negative patients. Multivariate logistic regression analysis showed that age, male sex, and H. pylori infection were three independent risk factors for gastric and duodenal ulcers.     

Observations on peptic ulcer in Shan Dong, China

The study consisted of 10 994 inpatients with peptic ulcer in Shan Dong province. The ratio of duodenal to gastric ulcer was 1.59 : 1. The ratio of males to females was 6.8 : 1 for duodenal ulcer and 4.6 : 1 for gastric ulcer. The highest incidence was in adolescence and young adults and the presentation occurred more commonly in winter. A study of blood groups revealed that there was no relationship between blood group and duodenal or gastric ulcer. The majority (71.9%) of patients with peptic ulcer had complications of upper gastrointestinal bleeding, perforation or gastric outlet obstruction. Bleeding and obstruction were equally common in gastric and duodenal ulcer, but perforation was more common in gastric ulcer.     

Helicobacter pylori and perforated peptic ulcer. Prevalence of the infection and role of non-steroidal anti-inflammatory drugs

AIMS: To study the prevalence of Helicobacter pylori infection in patients with perforated peptic ulcer, to compare it with the prevalence in patients with uncomplicated ulcer, and to assess the role of non-steroidal anti-inflammatory drugs in this prevalence. METHODS: Consecutive patients with perforated peptic ulcer were included in this retrospective study. As a control group, patients undergoing elective outpatient evaluation for the investigation of dyspepsia during the same time period and found to have a peptic ulcer at endoscopy were included. A 13C-urea breath test was carried out in all patients to diagnose H. pylori infection. RESULTS: Sixteen patients with perforated peptic ulcer and 160 with non-complicated peptic ulcer were included. Sixty-two percent of the patients with perforated peptic ulcer were infected by H. pylori, while the microorganism was detected in 87% of the patients without this complication (P = 0.01). Non-steroidal anti-inflammatory drugs intake was more frequent (P = 0.012) in patients with perforated peptic ulcers (56%) than in those without perforation (26%). H. pylori prevalence in perforated peptic ulcers was of 44% in patients with non-steroidal anti-inflammatory drugs intake, but this figure increased up to 86% when only patients not taking non-steroidal anti-inflammatory drugs were considered (P = 0.09). In the multivariate analysis, non-steroidal anti-inflammatory drugs intake was the only variable that correlated with peptic ulcer perforation [odds ratio, 3.6 (95% confidence interval, 1.3-10); P = 0.016]. CONCLUSION: The mean prevalence of H. pylori infection in patients with perforated peptic ulcer is, overall, of only about 60%, which contrasts with the 90-100% figure usually reported in non-complicated ulcer disease. However, the most important factor associated with H. pylori-negative perforated peptic ulcer is non-steroidal anti-inflammatory drugs use, and if this factor is excluded, prevalence of infection is almost 90%, similar to that found in patients with non-perforating ulcer disease.     

Cysteamine induces duodenal ulcer in the mouse

A new model of duodenal ulcer disease has been developed in the mouse. The ulcers were produced after either oral or subcutaneous administration of cysteamine which has been shown to cause duodenal ulcer in the rat. Cysteamine induced duodenal ulcers in a time- and dose-dependent manner after oral administration. The new mouse model shares many similarities with both the rat model and human ulcer disease. Cysteamine caused a significant increase in gastric acidity and pepsin activity. The mouse can be protected against the cysteamine-induced duodenal ulcer by either the dopamine agonist lergotrile or histamine H2 receptor antagonist cimetidine. This new model of duodenal ulcer disease in the mouse may represent a simple and inexpensive way to screen for new antiulcerogenic drugs.