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Hintergrund: Eine Akkumulation von eosinophilen Granulozyten (EG) am Gastrointestinaltrakt (GIT) kann aus verschiedenen pathogenetischen Ursachen erfolgen (Allergie, Autoimmunitat, idiopathische eosinophile Gastroenteritis, Neoplasie, Parasitose, Vaskulitis etc). Die eosinophile Infiltration kann von der Speiserohre bis zum Rektum jeden Organabschnitt isoliert oder kontinuierlich betreffen. Die eosinophile Osophagitis (Eo E) wurde in den letzten beiden Jahrzehnten wesentlich haufiger diagnostiziert und stellt eine wichtige Differenzialdiagnose von Patienten mit Dysphagie, refluxartigen Beschwerden, Motilitatsstorungen oder bei Thorax- und Abdominalschmerzen dar. Methodik: Die zur Diagnostik der Eo E benutzten Kriterien wurden aus dem Interdisziplinaren Datenregister fur chronisch entzundliche und allergische Magen-Darm-Erkrankungen der Universitat Erlangen analysiert extrahiert und mit einer selektiven Literaturrecherche zum Zeitpunkt Dezember 2012 zusammengefasst. Ergebnisse und Schlussfolgerung: Die Diagnostik der Eo E verlangt bei der Anamnese (z. B. veranderte Nahrungsaufnahme, Schluckstorungen, Thoraxdruck, allergische Vorerkrankungen) und bei der Endoskopie hochste Aufmerksamkeit, denn nicht selten finden sich nur diskrete Hinweise oder Auffalligkeiten der Osophagusmukosa. Typische Zeichen sind Bolusobstruktion bei jungen Mannern, erhohte Verletzbarkeit der Schleimhaut oder Ringbildungen. Die Eo E zeigt in nur ca. einem Drittel aller Falle typische endoskopische Zeichen (weise Papeln, Ring- oder Langsfurchen, Strikturen), ein Drittel zeigt verdachtige Befunde (Odem, Kontaktvulnerabilitat, blasse Mukosa) und ein Drittel ist endoskopisch unauffallig. Die endoskopische Diagnostik muss obligat histologisch durch Stufenbiopsien aus dem Osophagus erganzt werden. Die Diagnose ist gesichert, wenn mehr als 15 – 20 Eosinophile pro hochauflosendes Blickfeld (HPF) im proximalen und distalen Osophagus nachgewiesen werden konnen. Als fakultative Diagnostikmodalitaten gelten pH-Metrie, Manometrie, radiologischer KM-Schluck, Endosonografie und Thorax-Computertomografie, die nur bei speziellen Fragestellungen hinzugezogen werden mussen. Bei thorakalem Druckgefuhl sind kardiale Grunderkrankungen zu uberprufen. Weitere wichtige Differenzialdiagnosen sind die Refluxerkrankung, Mitbeteiligung des Osophagus bei Systemerkrankungen (Autoimmunopathie) oder eosinophile Gastro-Enterocolitiden und hypereosinophiles Syndrom.

Insulin resistance, oxidative stress, and an abnormal production of adipokines and cytokines are implicated in the pathogenesis of nonalcoholic steatohepatitis (NASH). Recently, we reported a significant improvement in plasma liver enzymes among patients with NASH treated with melatonin. In this study, we investigated the effect of melatonin, administered at a dose of 10 mg/day for 28 days to 16 patients with histologically proven NASH on insulin resistance (HOMA-IR), on the plasma levels of adiponectin, leptin, ghrelin, and resistin. Additionally, plasma levels of aminotransferases and gamma glutamyltranspeptidase as well as plasma concentrations of melatonin were evaluated. Median baseline values of HOMA-IR, leptin (ng/mL), and resistin (pg/mL) in patients with NASH were significantly higher in comparison with controls: 4.90 versus 1.60, 10.70 versus 4.30, and 152 versus 91, respectively. Median adiponectin level (μg/mL) was decreased in patients compared to controls: 6.40 versus 16.25; no significant difference in ghrelin levels between patients and controls was found. After melatonin treatment, the median value of HOMA-IR was significantly reduced by 60% as compared to baseline values, whereas adiponectin, leptin, and ghrelin plasma levels rose significantly by 119%, 33%, and 20%, respectively; the difference between pre-/posttreatment in plasma resistin levels was not significant. These findings make melatonin a suitable candidate for testing in patients with NASH in the large controlled clinical trials.

Melatonin and L-tryptophan (Trp) are highly gastroprotective in humans, but no study has assessed their impact on healing of chronic gastroduodenal ulcers in humans. Three groups (A, B and C) of 14 idiopathic patients in each treatment group with gastroduodenal chronic ulcers were treated with omeprazole (20 mg twice daily) combined either with placebo (group A), melatonin (group B) or with Trp (group C). The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after initiation of therapy. Plasma melatonin, gastrin, ghrelin and leptin were measured by RIA. On day 7, omeprazole by itself (group A) had not healed any ulcers, but four ulcers were healed with omeprazole plus melatonin and two with omeprazole plus tryptophan. At day 21, all ulcers were healed in patients treated with melatonin or Trp, but only 10-12 ulcers were healed in placebo-treated patients. After treatment with omeprazole plus melatonin (group B) or Trp (group C), plasma melatonin levels rose several-fold above initial values. Plasma gastrin level also rose significantly during treatment with omeprazole plus melatonin or Trp, but it was also significantly increased in patients treated with omeprazole plus placebo. Plasma ghrelin levels did not change significantly after treatment with melatonin or Trp, while plasma leptin increased significantly in patients treated with melatonin or Trp but not with placebo. We conclude that melatonin or Trp, when added to omeprazole treatment, accelerates ulcer healing and this likely depends mainly upon the significant increments in plasma melatonin.

Lymphoid hyperplasia of the intestine has been associated with multiple diseases and symptoms. This study was undertaken to analyze the number and topographical distribution of the lymphoid follicles. A total of 302 adult consecutive patients were enrolled when they underwent elective colonoscopy. Standardized pictures from terminal ileum and colon were taken using video colonoscopes. In each picture, the number, size, and mucosal elevation of lymphoid follicles were analyzed in relation to histological and immunological findings and medical history. Lymphoid hyperplasia was found to be most extensive in the terminal ileum and cecum. Patients with untreated gastrointestinally mediated allergy (GMA) showed the highest number of lymphoid follicles per visible field in the terminal ileum ( P < 0.001) and cecum ( P = 0.003) vs. the control group. Patients with infectious colitis also showed a high number of lymphoid follicles per endoscopic visible field in the transverse colon ( P = 0.020). The presence of lymphoid hyperplasia is a frequent finding during colonoscopy. It may indicate an enhanced immunological mucosal response to antigenic stimulation such as GMA or infection.

This investigation was designed to assess the effects of oral administration of melatonin (10 mg) and tryptophan (Trp) (500 mg) on fasting and postprandial plasma levels of melatonin, gastrin, ghrelin, leptin and insulin in 10 healthy controls and in age-matched patients with liver cirrhosis (LC) and portal hypertension. Fasting plasma melatonin levels in LC patients were about five times higher (102 +/- 15 pg/mL) than in healthy controls (22 +/- 3 pg/mL). These levels significantly increased postprandially in LC patients, but significantly less so in controls. Treatment with melatonin or L-Trp resulted in a further significant rise in plasma melatonin, both under fasting and postprandial conditions, particularly in LC patients. Moreover, plasma gastrin, ghrelin, leptin and insulin levels under fasting and postprandial conditions were significantly higher in LC subjects than in healthy controls and they further rose significantly after oral application of melatonin or Trp. This study shows that: (a) patients with LC and portal hypertension exhibit significantly higher fasting and postprandial plasma melatonin levels than healthy subjects; (b) plasma ghrelin, both in LC and healthy controls reach the highest values under fasting conditions, but decline postprandially, especially after oral application of melatonin or Trp; and (c) plasma melatonin, gastrin, ghrelin and insulin levels are altered significantly in LC patients with portal hypertension compared with that in healthy controls possibly due to their portal systemic shunting and decreased liver degradation.

The formation of acute gastric lesions depends upon the balance between the aggressive factors promoting mucosal damage and the natural defense mechanisms. Previous studies have shown that melatonin inhibits gastric acid secretion, enhances the release of gastrin, augments gastric blood flow (GBF), increases the cyclooxygenase-2 (COX-2)-prostaglandin (PG) system and scavenges free radicals, resulting in the prevention of stress-induced gastric lesions. Besides the pineal gland, melatonin is also generated in large amounts in the gastrointestinal tract and due to its antioxidant and anti-inflammatory properties; this indole might serve as local protective endogen preventing the development of acute gastric damage. The results of the present study indicate that stress-induced gastric lesions show circadian variations with an increase in the day time and a decline at night. These changes are inversely related to plasma melatonin levels. Following pinealectomy, stress-induced gastric mucosal lesions were more pronounced both during the day and at night, and were accompanied by markedly reduced plasma melatonin levels with a pronounced reduction in mucosal generation of prostaglandin E(2) (PGE(2)), GBF and increased free radical formation and by small rise in plasma melatonin during the dark phase. We conclude that stress-induced gastric ulcerations exhibit a circadian variation with an increase in the day and attenuation at night and that these fluctuations of gastric stress ulcerogenesis occur also after pinealectomy, depending upon the interaction of COX-PG and free radicals, probably mediated by the changes in local gastric melatonin.

Hormonal fluctuations are known to predispose ulceration of the upper gastrointestinal tract, but to date no comparative study of their effects on the healing of pre-existing ulcers in the oral cavity and stomach has been made. We studied the effects of depletion of testosterone and of EGF on the healing of acetic acid-induced ulcers using rats having undergone bilateral orchidectomy and/or salivectomy respectively. We measured alterations in gastric acid secretion and blood flow at ulcer margins, as well as plasma levels of testosterone, gastrin and the proinflammatory cytokines IL-1 beta and TNF-alpha. Testosterone (0.01-10 mg/kg/day i. m.) dose-dependently delayed oral and gastric ulcer healing. When applied in an optimal dose of 1 mg/kg/day, this hormone significantly raised gastric acid secretion and plasma IL-1 beta and TNF-alpha levels. Attenuation of plasma testosterone levels via bilateral orchidectomy inhibited gastric acid secretion and accelerated the healing of oral and gastric ulcers, while increasing plasma gastrin levels and these effects were reversed by testosterone. Salivectomy raised plasma testosterone levels, and delayed oral and gastric ulcer healing. Treatment of salivectomised animals with testosterone further inhibited ulcer healing, and this effect was counteracted by EGF. We propose that testosterone delays ulcer healing via a fall in blood flow at the ulcer margin, a rise in plasma levels of IL-1 beta and TNF-alpha and, in the case of gastric ulcers, an increase in gastric acid secretion. EGF released from the salivary glands plays an important role in limitation of the deleterious effects of testosterone on ulcer healing.

Summary Background Ghrelin stimulates food intake and body weight gain. The stomach is the major source of circulating ghrelin, but controversy exists over the relationship between ghrelin release and Helicobacter pylori infection. Aim To assess the relationship between H. pylori infection and ghrelin, leptin and gastrin release in adult shepherds and their children, and to measure the effect of H. pylori eradication on gastric ghrelin content. Methods H. pylori prevalence was compared in 42 shepherds with full contact with sheep, 148 farmers without sheep contact and in 61 age-matched urban adult controls as well as in 58 shepherd children with sheep contact, 88 mountain children without contact and 141 urban children controls. Serum levels of ghrelin, leptin and gastrin in adult shepherds and their children with and without H. pylori infection were measured. Results The major source of circulating ghrelin was gastric corpus mucosa, as ghrelin content was severalfold higher than that in antral mucosa and was significantly higher in the H. pylori-eradicated than that in H. pylori-infected mucosa. Serum levels of ghrelin were greatly increased, while gastrin levels were significantly decreased in H. pylori-negative as compared with H. pylori-positive subjects. In mountain children, serum levels of ghrelin and leptin were about twofold higher in H. pylori-negative than in H. pylori-positive children, whereas gastrin levels were significantly reduced in H. pylori-negative children. Conclusions The high incidence of H. pylori infection in shepherds and their children seems to contribute to the decreased serum levels of ghrelin and increased levels of gastrin in H. pylori-infected mountain children and to their decreased appetite and dyspeptic symptoms.

Ghrelin, identified in the gastric mucosa has been involved in control of food intake and growth hormone (GH) release but little is known about its influence on gastric secretion and mucosal integrity. The effects of ghrelin on gastric secretion, plasma gastrin and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous ghrelin (5, 10, 20, 40 and 80 μg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS and this was accompanied by the significant rise in plasma ghrelin level, gastric mucosal blood flow (GBF) and luminal NO concentrations. Ghrelin-induced protection was abolished by vagotomy and attenuated by suppression of COX, deactivation of afferent nerves with neurotoxic dose of capsaicin or CGRP8–37 and by inhibition of NOS with l -NNA but not influenced by medullectomy and administration of 6-hydroxydopamine. We conclude that ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol and WRS, and these effects depend upon vagal activity, sensory nerves and hyperemia mediated by NOS-NO and COX-PG systems.

Serum leptin and ghrelin levels were investigated in patients with obstructive sleep apnoea (OSA) syndrome before and during continuous positive airways pressure (CPAP) treatment and compared with body mass index (BMI)-matched controls without OSA. Male patients (n=30) with OSA (apnoea/hypopnoea index=58+/-16, BMI=32.6+/-5.3 kg x m(-2)) underwent CPAP treatment. Fasting leptin and ghrelin were measured at baseline and 2 days, and in the case of leptin 2 months after initiation of treatment. Baseline plasma ghrelin levels were significantly higher in OSA patients than in controls. After 2 days of CPAP treatment, plasma ghrelin decreased in almost all OSA patients (n=9) to levels that were only slightly higher than those of controls (n=9). Leptin levels did not change significantly from baseline after 2 days of CPAP treatment, but were higher than in the control group. After 8 weeks, leptin levels decreased significantly, although the BMI of the patients showed no change. The decrease in leptin levels was more pronounced in patients with a BMI30 kg x m(-2). These data indicate that the elevated leptin and ghrelin levels are not determined by obesity alone, since they rapidly decreased during continuous positive airways pressure therapy.

Gastric cancer is one of the most common malignant tumors of the gastrointestinal tract. However, the molecular pathways involved in the regulation of gastric carcinogenesis are not completely elucidated. In the last decade, basic cancer research has been focused on the deregulation of apoptosis as a central event in the process of carcinogenesis. Caspase-3 and survivin are regulators of apoptosis and have been implicated in the development of gastric cancer. The aim of the present study was to compare the expression of mRNA and protein for survivin and caspase-3 in the gastric cancer and in the cancer margin with that in normal human gastric mucosa. Fifteen patients with advanced gastric cancer (all H. pylori-positive) and 15 matched control subjects with normal gastric mucosa were included in this study. The biospy specimens for histology and for molecular analyses were taken from gastric tumor, tumor surrounding gastric mucosa and in normal patients from the mucosa of antrum and corpus. Survivin mRNA expression was very weak, but detectable, in the normal gastric mucosa. However, at the protein level, no expression for survivin was detected in the normal gastric mucosa. In the biopsy specimens from tumor and surrounding gastric mucosa, a significant increase in survivin mRNA and protein expression was observed. The expression of survivin was higher in the tumor than in the tumor margin. The mRNA and protein expression of caspase-3 was detected in the gastric mucosa of normal subjects. In gastric cancer only the expression of procaspase-3 was observed, while the expression of active caspase-3 was completely undetectable. In the gastric mucosa surrounding gastric cancer, no gene and protein expression for caspase-3 was detected. We conclude that the changes in the level of caspase-3 and survivin play an important role in the transformation from normal gastric mucosa to gastric career.

Helicobacter pylori, NSAID and cigarette smoking are major risk factors for gastroduodenal ulcers. However, the results of studies on the interaction between these factors on ulcerogenesis are controversial. This study was designed to examine the association between gastroduodenal ulcers and H. pylori infection, NSAID use, smoking and age.5967 dyspeptic patients underwent 13C-urea breath test (UBT) and upper endoscopy, while age and dyspeptic symptoms were reported.Out of 5967 patients, 31.8% were ulcerated; 9.2% had gastric, 17.2% duodenal and 5.4% both gastric and duodenal ulcers. H. pylori was found in 72.5% of gastric ulcer patients, in 83.6% of duodenal ulcer patients, in 76.9% of gastroduodenal ulcer patients and in 64.8% of dyspeptic patients. The gastric, duodenal and gastroduodenal ulcers were related to H. pylori significantly and the respective ORs were: 1.44, 2.77 and 1.81. NSAID alone was used by 6.2%-12.7% of ulcer patients, tending to raise only the risk of gastric ulcer but reducing that of duodenal and gastroduodenal ulcers. The H. pylori prevalence was significantly higher in smokers (76%) than in non-smokers (67%) and the ulcer risk was also significantly higher in smokers than in non-smokers. About 20% of ulcers were 'idiopathic', i.e. without NSAID and H. pylori and the ratio of these ulcers to all ulcers significantly increased during the 5 years of the study.Based on multivariable logistic regression analysis we conclude that: 1) H. pylori infection, NSAID use, smoking and age play major roles in the pathogenesis of peptic ulcerations; 2) there is a negative interaction between H. pylori and NSAID on duodenal ulcers, suggesting that H. pylori reduces the development of these ulcers in NSAID users, and 3) about 20% of peptic ulcers in the Polish population are unrelated to H. pylori and NSAID use (idiopathic ulcers).

The peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-dependent nuclear receptor that has been implicated in the control of metabolism and numerous cellular processes, including cell cycle control, carcinogenesis, and inflammation. The present study was designed to investigate the effect of the specific PPARγ ligand, pioglitazone, on the mucosal lesions induced by ischaemia and reperfusion (I/R) in rats.I/R lesions were induced in Wistar rats by applying a small clamp to the coeliac artery for 30 min (ischaemic phase), followed by the removal of the clamp for 3 h (reperfusion phase). Vehicle (saline) or increasing doses of pioglitazone (2.5, 10, and 30 mg/kg i.g.) were given 30 min before exposure to I/R. The animals were killed immediately after the end of the reperfusion phase (time 0) and at 12 and 24 h after I/R. The area of gastric lesions was measured by planimetry, and the gastric blood flow was determined by the H[Formula: See Text] gas clearance method. The gastric mucosal gene expressions of PPARγ, interleukin-1beta (IL-1β), tumour necrosis factor alpha (TNF-α), leptin, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) were examined by RT-PCR. In addition, protein expression of COX-2 and leptin was assessed by Western blot.The pretreatment with pioglitazone reduced in a dose-dependent manner the mean lesion area induced by I/R, and this effect was accompanied by a significant increase in the gastric blood flow. The decrease in gastric ulcerations by pioglitazone was also observed 12 and 24 h after the I/R. The PPARγ mRNA was weakly expressed in the intact gastric mucosa, but significantly up-regulated after exposure to I/R at each time interval studied. The expression of IL-1β was not changed significantly after pioglitazone applied i.g. at doses 2.5 and 10 mg/kg, but it was down-regulated at the dose 30 mg/kg. TNFα mRNA was strongly increased after the exposure to I/R, but it was down-regulated after pioglitazone pretreatment. In contrast, both leptin and COX-2 mRNA and protein expression were increased in the gastric mucosa after exposure to I/R. The pretreatment with pioglitazone caused a significant up-regulation of mRNA and protein expression of leptin, reaching its peak at the dose 30 mg/kg i.g. In contrast, COX-2 expression did not change significantly after the 2.5 and 10 mg/kg of pioglitazone, but it significantly decreased after pioglitazone at dose 30 mg/kg given to rats before exposure to I/R.Pioglitazone reduces the acute erosions and deeper gastric lesions induced by I/R. The beneficial effect of this PPARγ ligand on I/R-induced gastric damage may be due to its anti-inflammatory properties, especially to the reduction in TNF-α expression and to up-regulation of leptin mRNA in the gastric mucosa. The inhibition of COX-2 expression by pioglitazone may reflect the anti-inflammatory properties of this compound.

Background. Chronic infections have been proposed to play a role in the aetiology or progression of atherosclerotic plaques. Increased risk of coronary artery disease has been suggested in patients seropositive for Helicobacter pylori. Aim. To analyse coronary specimens in patients with severe (coronary artery disease) for Helicobacter pylori specific DNA. Patients and Methods. Atherosclerotic plaques were obtained in 46 consecutive patients (9 female, 37 male, mean age 62.7±9.17 years) during coronary bypass procedures. Serum was analysed for IgG-/ca-gA-antibodies specific for Helicobacter pylori. Polymerase chain reaction and sequence analysis were used to identify bacterial DNA. Coronary artery biopsies from 19 autopsies without coronary artery disease were examined as a control group. Results. Of the 46 coronary artery disease patients, 32 (69.60 were Helicobacter pylori seropositive. Positive results for Helicobacter pylori DNA showed 18 seropositive and 4 seronegative (with anamnesis of eradication therapy). A total of 22 patients (47.8%) of the coronary artery disease group but none of controls revealed positive DNA. In the coronary artery disease group, a correlation between DNA presence and prior myocardial infarction (p=0.008) and unstable angina (p

Background: Leptin is a pleiotropic hormone that is involved in the regulation of food intake and body weight. Recent findings demonstrated that leptin receptors are present in the pancreas but the involvement of leptin in pancreatitis remains unknown. The aim of the present study was: (1) to assess plasma leptin levels in rats with caerulein-induced pancreatitis (CIP) and humans with acute pancreatitis; and (2) to determine the effects of exogenous leptin on the course of acute CIP in rats Methods: CIP was produced in Wistar rats by s.c. infusion of 5 µg of caerulein for 5 h. Plasma leptin was measured by specific RIA and leptin expression in the pancreas was determined at the transcriptional and protein levels. In addition, the effects of exogenous leptin at the doses of 1 or 10 µg/kg i.p. on the course of CIP and the plasma levels and mRNA expression in pancreas of cytokines TNFα and IL-4 were studied. Furthermore, pancreatic cNOS and iNOS expression at mRNA level were measured in rats with CIP and pretreated with leptin. Parallel to these studies, the plasma levels of leptin were measured in 15 patients with acute edematous pancreatitis and in 30 healthy controls of comparable age and body mass index. Results: In rats, plasma leptin rose significantly from the median of 0.14 (0.03–0.3 ng/ml) in the control group to 0.56 (0.2–3.2 ng/ml) in rats with CIP. The CIP was associated with an upregulation of mRNA and protein for leptin in the pancreas. The administration of exogenous leptin significantly reduced the weight of pancreas, histological manifestations of pancreatitis, plasma TNFα and mRNA expression for iNOS in the pancreatic tissue. The assessment of leptin plasma level in humans demonstrated significantly higher median values of plasma leptin in patients with acute pancreatitis [7.5 (4.3–18.4 ng/ml)] than in healthy controls [2.1 (1.0–11.8 ng/ml)]. Conclusions: (1) Acute pancreatitis in rats and in humans is associated with a marked increase in the plasma level of leptin. (2) The transcriptional upregulation of leptin in the pancreas after induction of pancreatitis indicates that the inflammed pancreas could be the source of local production of leptin. (3) Exogenous leptin protects the pancreas against development of acute CIP in rats and one possible mechanism of action of leptin might be attributed to the activation of nitric oxide pathway.

Background and Aims: Mast cells, which are important effector cells in food allergy, require a special histologic treatment for quantification in endoscopic gastrointestinal samples. The objective of this study was to investigate whether mast cell tryptase (T), a typical mast cell-associated marker, may help to detect patients with food allergy. Methods: Mast cell T was investigated from 289 colorectal samples of 73 controls, 302 samples from 43 patients with food allergy and gastrointestinal symptoms, and 72 samples from 12 patients with partial or complete remission of allergic symptoms. Endoscopically taken samples were immediately put into liquid nitrogen, mechanically homogenized by a micro-dismembrator with three homogenization steps and tissue T content (ng T/mg wet weight) was measured by fluoroenzyme immunoassay. Results: Tissue T levels from the lower gastrointestinal tract were significantly elevated (p < 0.0001) in patients with manifest gastrointestinal allergy (median: 55.7, range: 9.3–525.0) compared with controls (median: 33.5, range: 8.0–154.6). A subgroup of 12 patients with remission of allergy showed markedly decreased symptom scores and mucosal T levels after more than 1 year of antiallergic therapy (pretreatment median: 54.1, range: 37.0–525.0 and posttreatment median: 28.4, range: 19.8–69.1; p = 0.01). Conclusions: High T levels in the gut of food-allergic patients support the role of stimulated mast cells or an increased mast cell number.

Helicobacter pylori (HP) infection is usually accompanied by an increased plasma level of gastrin, a potent mitogen able to induce cyclooxygenase (COX)-2. This study examined (a) the seroprevalence of HP, its cytotoxic protein, CagA, and cytokines (tumor necrosis factor alpha, interleukins 1beta and 8) in 80 patients with colorectal cancers, before and after the removal of tumor, compared with 160 age- and gender-matched controls; (b) the gene expression of gastrin and its receptors (CCKB-R) in the cancer tissue, (c) the plasma levels and tumor tissue contents of gastrin, and (d) the mRNA expression of COX-1, COX-2, and apoptotic proteins (Bax and Bcl2) in cancer tissue and intact colonic mucosa. Anti-HP IgG, anti-CagA IgG seroprevalence, and cytokine levels were analyzed by enzyme-linked immunosorbent assay tests; gene expressions of gastrin, CCKB-R, COX-1, COX-2, Bax, and Bcl2 by reverse transcriptase polymerase chain reaction; and gastrin by radioimmunoassay. The seroprevalence of HP, especially that expressing CagA, was significantly higher in cancer patients than in controls and did not change 1 week after tumor resection while plasma cytokines were significantly reduced after this operation. Both gastrin and CCKB-R mRNA were detected in the cancer tissue and the resection margin; similarly, COX-2 mRNA was expressed in most of cancers and their resection margin but not in intact colonic mucosa, where only COX-1 was detected. The colorectal cancer tissue contained several folds more immunoreactive gastrin than cancer resection margin and many folds more than the intact colonic mucosa. We conclude that colon adenocarcinoma and its resection margin overexpress gastrin, its receptors, CCKB-R, and COX-2, and that HP infection may contribute to colonic cancerogenesis via overexpression of gastrin and COX-2, which may account for the stimulation of the tumor growth and the reduction in apoptosis as documented by enhanced mRNA expression of anti-apoptotic Bcl2 over proapoptotic Bax proteins.

Background: Gastric cancer is one of the most frequent neoplasms and a leading cause of the death world-wide. In recent years, epidemiological and animal studies demonstrated a link between gastric cancer and chronic infection with H. pylori. The exact mechanism responsible for the development of gastric cancer in H. pylori-infected patients still remains unclear. There is evidence that the up-regulation of certain growth factors could play an important role in the promotion of the gastric carcinogenesis. Aims: The present study was designed to determine the gene expression of major known growth factors such as transforming growth factor alpha (TGFα), hepatocyte growth factor (HGF) and gastrin in the gastric cancer tissue, the surrounding mucosa and, for comparison, in the normal gastric mucosa. Furthermore, the luminal and plasma levels of gastrin in patients with gastric cancer were determined. In addition, the gene and protein expressions of apoptosis-related proteins such as Bax and Bcl-2 were investigated by reverse transcription-polymerase chain reaction and Western blot. Twenty-five gastric cancer patients and 40 age- and gender-matched control subjects hospitalized with non-ulcer dyspepsia were included into this study. Results: An overall H. pylori-seropositivity among gastric cancer patients was about 72% and was significantly higher than in the controls (56%). The prevalence of CagA-positive strains was also significantly higher among gastric cancer patients than in controls (56% vs. 32%). The gene expression of HGF and TGFα was detected more frequently in gastric cancer tissue samples than in normal gastric mucosa (52% vs. 12% for HGF and 48% vs. 24% for TGFα). The extent of protein expression in Western blotting analysis for HGF and TGFα correlated with the mRNA expression of these factors. Gene expression of gastrin was detected in the antrum of all tested patients and in the majority (84%) of gastric cancer patients. The median plasma and luminal concentrations of gastrin in gastric cancer patients were significantly higher than in controls. The gene expression of bcl-2 was detected in all (100%) and that of proapoptotic bax only in 56% of gastric cancer samples. In comparison to the surrounding non-tumorous tisssue, the gene expression of bax was significantly down-regulated and the gene expression of bcl-2 was up-regulated in gastric cancer tissue. At the protein level, Bax was not detectable and Bcl-2 was seen in 80% of gastric cancer samples. Conclusions: It is concluded that the patients infected with H. pylori, especially with CagA-positive strains, are at a higher risk of developing a gastric cancer. An increased production and release of gastrin, as well as an over-expression of growth factors such as HGF and TGFα, might contribute to the gastric carcinogenesis. In addition, a dysregulation of the Bax/Bcl-2 system with significant up-regulation of Bcl-2 is observed in gastric cancer.

Background. Gastric infection caused by Helicobacter pylori has recently been associated with increased risk of coronary artery disease. Aim. To: 1) determine seroprevalence of Helicobacter pylori and its cytotoxin associated gene A in patients with/without coronary artery disease (group A), 2) assess influence of Helicobacter pylori eradication on coronary artery lumen reduction after percutaneous coronary angioplasty (group B) and 3) determine influence of Helicobacter pylori eradication on plasma cytokines, lipids and coagulation factors in patients subjected to percutaneous coronary angioplasty (group B). Patients and methods. Group A included 100 patients with coronary artery disease (subgroup I) and 100 patients without (subgroup II). For Helicobacter pylori seroprevalence, plasma anti-Helicobacter pylori and anti-cytotoxin associated gene A IgG were examined. Group B included 40 patients with significant single-vessel coronary arterial disease and Helicobacter pylori infection confirmed by 13C-urea breath test and serologically using anti-Helicobacter pylori and anti-cytotoxin associated gene A IgG. Six months after percutaneous coronary angioplasty and triple anti-Helicobacter pylori therapy, the Helicobacter pylori status reassessed by urea breath test was negative in all but two patients of subgroup I subjected to Helicobacter pylori therapy. Coronary angiography and laboratory tests were repeated in both subgroups of group B included in the trial and reduction in coronary artery lumen in these subgroups was compared to baseline after percutaneous coronary angioplasty considered as 100%. Results. Helicobacter pylori seropositivity reached 81.5% of coronary artery disease (subgroup 1) and was significantly higher than that in controls without coronary artery disease (subgroup 11) the odds ratio being 4.3 for Helicobacter pylori in coronary artery disease. Cytotoxin associated gene A IgG detection was also significantly higher (47.3%) in coronary artery disease than in controls (28%) giving the odds ratio about 2.3. Mean coronary artery lumen reduction in patients undergoing percutaneous coronary angioplasty + Helicobacter pylori eradication therapy (subgroup I) was significantly (p

Background: There is accumulating evidence for the role of Helicobacter pylori in the development of gastric cancer as well as of lymphomas that arise in mucosa-associated lymphoid tissue (MALT). We reported recently that gastric cancer patients show high prevalence of cagA-positive H. pylori and express gastrin and gastrin receptors enabling them to stimulate tumour growth in autocrine fashion. Aims: Since the H. pylori infection is considered to be more strongly associated with MALT lymphoma than with gastric cancer, we decided to determine the gastrin and its receptors’ mRNA expression and gastrin content in this tumour as well as the release of this hormone both into plasma and gastric lumen. Twenty MALT lymphoma patients were compared with 100 age- and gender-matched controls with similar dyspeptic symptoms. Results: The overall H. pylori seropositivity in MALT lymphoma was about 90% and CagA positivity was 70%, compared to 56% and 33%, respectively, in controls. The serum gastrin in MALT lymphoma was about sixfold higher than in controls while gastric luminal gastrin in these patients was over 70 times higher than in controls. Gastrin content in tumour was about 10-fold higher than in antral mucosa. Gastrin and gastrin-receptor (CCKB-receptor) mRNA were detected by reverse transcriptase–polymerase chain reaction in cancer tissue whilst in the fundic and antral mucosa, only enhanced expression of CCKB-receptor mRNA and gastrin mRNA was detected, respectively. Histamine stimulation in MALT lymphoma induced acid secretion that was only about 30% of control value due to atrophic gastritis. This study confirms an important role of CagA-positive H. pylori in the pathogenesis of MALT lymphoma and shows that this lymphoma is capable of synthesizing and releasing potent growth promoting gastrin, possibly due to the action on G-cells of H. pylori-originated Nα-methyl histamine and cytokines (tumour necrosis factor alpha and interleukin-8). Conclusions: Gastric MALT lymphoma is closely linked to CagA-positive H. pylori infection. Gastrin and its receptors may be implicated in the pathogenesis of gastric lymphoma.

Ischemia followed by reperfusion is known to produce gastric lesions due to oxidative stress, but the role of gastric H(+) secretion in the formation of this mucosal injury remains unknown. We studied alterations in gastric acid secretion and gastric histamine content, as well as the expression of histidine-decarboxylase and interleukin-1beta during the mucosal recovery from ischemia-reperfusion erosions. Gastric secretion was studied in rats (series A) with gastric fistula before, during and after the ischemia induced by clamping of celiac artery for 0.5 h followed by reperfusion in animals pretreated with vehicle (saline), omeprazole, a proton pump inhibitor, or ranitidine, a histamine (H(2)) receptor antagonist. In series B, the animals were submitted to 0.5 h of ischemia followed by 1 h of reperfusion and then anesthetized at 0, 3, 12 and 24 h or 3, 5, 10 or 15 days after the end of ischemia-reperfusion to determine gastric blood flow by H(2)-gas clearance technique, area of gastric lesions, plasma gastrin and interleukin-1beta levels, histamine content by radioimmunoassay (RIA) and expression of histidine-decarboxylase and interleukin-1beta mRNA by reverse transcription polymerase chain reaction. Clamping of celiac artery caused cessation of gastric blood flow and almost complete suppression of basal gastric acid secretion (series A) that returned gradually to the control value at day 3 after ischemia-reperfusion, accompanied by the rise in plasma gastrin levels, pronounced expression of histidine-decarboxylase mRNA and increased mucosal histamine content. Ischemia, followed by 1 h of reperfusion, produced gastric erosions (series B) that reached maximum at 12 h, but then declined at 24 h. These erosions progressed at day 3 into deeper ulcers whose area declined progressively within the next 5-15 days. The gastric blood ceased to flow (series B) during 30 min of clamping and was reduced throughout the period of healing of acute erosions, being accompanied by a gradual rise in mucosal interleukin-1beta mRNA content and in plasma interleukin-1beta levels. Treatment with omeprazole or ranitidine, which completely suppressed gastric acid secretion and significantly raised plasma gastrin level, greatly reduced the formation of erosive lesions preventing the progression of these lesions to chronic gastric ulcers, and this was accompanied by the rise in gastric blood flow and plasma gastrin levels and the significant attenuation of plasma interleukin-1beta levels. The ranitidine and omeprazole-induced suppression of ischemia-reperfusion erosions were abolished by the instillation of exogenous 0.2 N HCl into the stomach of these rats. The histidine-decarboxylase was faintly expressed in the intact gastric mucosa, but strongly upregulated during mucosal recovery from the damage induced by ischemia-reperfusion. We conclude that following ischemia-reperfusion: (1) gastric acid secretion, gastric microcirculation and histamine production markedly decline, while interleukin-1beta release significantly increases, probably playing an important role in the progression of acute lesions into chronic gastric ulcerations; (2) the suppression of gastric acid secretion by omeprazole and ranitidine, that induces hypergastrinemia, prevents the progression of gastric erosions into ulcers; and (3) the addition of exogenous acid restores the progression of the acute lesions into gastric ulcers, indicating that gastric acid plays a key role in ulcerogenesis induced by ischemia-reperfusion.

Lipopolysaccharides (LPS), the component of the cell wall of gram-negative bacteria, have been implicated in the pathogenesis of acute pancreatitis, but the mechanism of their action on the pancreas has not been fully explored. The aim of this study was to investigate the effects of various doses of LPS on the integrity of intact pancreas and that involved in acute caerulein-induced pancreatitis (CIP) in the rat and to compare these effects with those of nitric oxide (NO) donor, S-nitrose-acetylpenicillamine (SNAP). The expression of constitutive NO synthase (cNOS) and inducible NO synthase (iNOS) mRNA was also examined in the isolated pancreatic acini obtained from the inflamed pancreas of rats treated with LPS. CIP was produced by subcutaneous (s.c.) infusion of caerulein (5 μg/kg·h for 5 h) to conscious rats. Bolus injections of various doses of LPS (0.1, 1, 10, 20 or 40 mg/kg) or SNAP (1.5, 3 or 6 mg/kg) were made intraperitoneally (i.p.) either alone or 30 min prior to s.c. infusion of caerulein to induce CIP. Infusion of caerulein produced acute pancreatitis confirmed by histological examination and manifested by an increase of pancreatic mass (by about 200%). Blood levels of amylase and lipase were augmented by 400 and 800% respectively, whereas the pancreatic blood flow (PBF) was decreased by 50% in rats with CIP. Injection of low doses of LPS (0.1–1 mg/kg i.p.) or SNAP (1.5–3 mg/kg i.p.) 30 min prior to caerulein infusion reversed the harmful effects of pancreatic overstimulation with caerulein and reduced significantly the histological manifestations of CIP such as edema, neutrophil infiltration and vacuolization of the acinar cells. These protective effects of low doses of LPS pretreatment on the pancreas were completely antagonized by the suppression of the activity of NO synthase (NOS) with NG-nitro-L-arginine (L-NNA) applied (20 mg/kg i.p.) 15 min prior to the LPS injection. Combination of L-arginine (100 mg/kg i.p.), a substrate for NOS, with L-NNA given prior to low doses of LPS, restored the LPS-induced protection of the pancreas in rats with CIP. In contrast, higher doses of LPS (20–40 mg/kg i.p.) or SNAP (6 mg/kg i.p.), which produced a significant fall of the PBF, did not protect the pancreas against CIP. Administration of various doses of LPS to rats with CIP resulted in significant and dose-dependent stimulation of NO biosynthesis in the isolated acini obtained from the pancreas of these animals. LPS enhanced the expression of both cNOS and iNOS in the pancreatic acini obtained from rats subjected to CIP. The signal for cNOS mRNA was detected in all samples, reaching peak at the protective dose of LPS (1 mg/kg i.p.), while iNOS was overexpressed only at the highest doses of LPS that failed to exhibit the protective activity. We conclude that the pretreatment with low doses of LPS protects the pancreas against the damage provoked by CIP and this effect could be attributed, at least in part, to the activation of L-arginine-NO system in the pancreas.

Leptin, detected recently in the stomach, is a product of the ob gene released by cholecystokinin (CCK) and plays an important role in the control of food intake but its influence on gastroprotection against the damage caused by noxious agents has not been studied. This study was designed to compare the effects of leptin and cholecystokinin-8 (CCK-8) on gastric mucosal lesions induced by topical application of 75% ethanol or acidified aspirin. Four series of Wistar rats (A, B, C and D) were used to determine the effects of: (A) suppression of prostaglandin biosynthesis by indomethacin (5 mg/kg i.p.); (B) inhibition of nitric oxide (NO)-synthase by nitro-L-arginine methyl ester (L-NAME) (5 mg/kg i.v.); (C) blockade of sensory nerves by capsaicin (125 mg/kg s.c.) and (D) bilateral vagotomy, on the gastric lesions induced by intragastric (i.g.) application of ethanol with or without pretreatment with CCK-8, a known gastroprotective substance or leptin. CCK-8 (1-100 microg/kg i.p.) and leptin (0.1-50 microg/kg i.p.) dose dependently attenuated gastric lesions induced by 75% ethanol; the dose reducing these lesions by 50% being about 10 microg/kg and 8 microg/kg, respectively. The protective effects of CCK-8 and leptin were accompanied by a significant rise in gastric blood flow (GBF) and luminal NO concentration. Leptin was also effective to attenuate aspirin-induced damage and the accompanying fall in the GBF, whereas CCK-8 dose dependently worsened aspirin damage and failed to influence GBF. CCK (1-100 microg/kg i.p.), given in graded doses, produced a dose-dependent increase in the plasma leptin level and a rise of the expression of ob messenger RNA (mRNA) in gastric mucosa, the maximum being reached at a dose of 100 microg/kg. Pretreatment with CCK-8 (10 microg/kg i.p.) or with 8% peptone, that is known to stimulate CCK release, also produced a significant rise in plasma leptin levels and up-regulation of ob mRNA while reducing significantly the gastric lesions induced by 75% ethanol to the same extent as that induced by exogenous leptin (10 microg/kg i.p.). Indomethacin, which suppressed prostaglandin generation by approximately 90%, failed to influence leptin- or CCK-8-induced protection against ethanol, whereas L-NAME attenuated significantly CCK-8- and leptin-induced protection and hyperemia but addition to L-NAME of L-arginine, but not D-arginine, restored the protective and hyperemic effects of both hormones. The ob mRNA was detected as a weak signal in the intact gastric mucosa and in that exposed to ethanol alone but this was further enhanced after treatment with graded doses of CCK-8 or peptone meal applied prior to ethanol. We conclude that: (1) exogenous leptin or that released endogenously by CCK or meal exerts a potent gastroprotective action depending upon vagal activity, and involving hyperemia probably mediated by NO and sensory nerves but unrelated to endogenous prostaglandins; (2) leptin mimics the gastroprotective effect of CCK and probably mediates the protective and hyperemic actions of CCK in the rat stomach.

Pancreatic secretory trypsin inhibitor (PSTI) is an inhibitor of serine-proteinases including pancreatic trypsin that prevents excessive digestion of the gastrointestinal mucus, but its role in the mechanism of mucosal defense has been little studied. This study was designed to determine the effect of base variant of human PSTI (R44S-PSTI) on gastric secretion, healing of gastric lesions induced by stress and the expression of PSTI during mucosal recovery from stress lesions. Recombinant R44S-PSTI was obtained using by site-directed mutagenesis due to replacement of arginine by serine that led to longer half life of this peptide than its natural form. Stress ulcerations were induced by exposure of rats to a standard 3.5 h of water immersion and restraint stress with or without pretreatment with vehicle or R44S-PSTI (0.1 mg/kg) applied s.c. 30 min before and immediately after the end of stress. Rats were then sacrificed immediately (time 0) and at 6 h or 12 h after the termination of stress. The gastric blood flow (GBF) was measured by H 2 -gas clearance technique at each time period and gastric mucosal samples were excised for assessment of PSTI immunohistochemical expression and PSTI messenger RNA by reverse transcriptase polymerase chain reaction (RT-PCR) and Southern hybridization. Stress produced numerous gastric lesions and decreased the GBF by about 30% as compared to the respective value in vehicle-treated non-stressed gastric mucosa. R44S-PSTI given s.c. in graded doses (0.01–1 mg/kg) inhibited dose-dependently gastric acid and pepsin outputs, in rats with gastric fistula and accelerated the healing of stress-induced gastric lesions significantly. The healing effects of R44S-PSTI (0.1 mg/kg s.c.) recorded at 6 h and 12 h after the end of stress were accompanied by a significant rise in the GBF. The expression of PSTI mRNA in the intact mucosa was weak, but following exposure to stress it was significantly augmented to reach the highest observed value at 6 h after the stress. We conclude that (1) base variant of human PSTI accelerates healing of stress-induced gastric lesions probably due to its antisecretory activity and enhancement of mucosal blood flow and (2) the expression of genes for PSTI plays an important role in the mechanism of mucosal recovery from gastric lesions induced by stress.

Background: NSAIDs, such as aspirin (ASA), cause widespread mucosal damage, but repeated ASA insults appear to induce mucosal tolerance (adaptation) to this␣injury. The mechanism of the gastric adaptation to the damage induced by ASA has not been fully explained. Aim: To determine the role of the mucosal gene expression for spasmolitic peptide (SP) (a member of trefoil peptides) and transforming growth factor alpha (TGFα) as well as for cyclooxygenase (COX)-1 and COX-2 during gastric adaptation to ASA in rats. Methods: Gastric lesions were produced by ASA (100 mg/kg in 1.5 mL of 0.2 M HCl) applied intragastrically (i.g.) as a single dose, every day for 5 days. Control rats were given 1.5 mL of vehicle (0.2 M HCl i.g.) as a single dose, during 5 consecutive days. Gastric blood flow (GBF) was measured by H2-gas clearance technique and gastric mucosal specimens were taken for the assessment of cell␣proliferation rate in gastric mucosa by bromodeoxyuridine (BrdU) uptake, mucosal generation of prostaglandin E2 measured by radioimmunoassay, and for expression of SP, TGFα COX-1 and COX-2 mRNA as determined by RT-PCR. To quantify the relative amounts of mRNA for SP and TGFα, southern blotting analysis of the PCR products was performed and the intensity of PCR products was compared with that of β-actin used as a standard. Results: ASA applied once produced numerous gastric erosions, but with repeated ASA doses the adaptation to this NSAID developed, the area of gastric lesions being reduced by 86% after six consecutive ASA insults. This adaptation to ASA was accompanied by approximately a 90% reduction in prostaglandin E2 biosynthesis, by a significant rise in BrdU uptake by glandular cells predominantly in the neck region of gastric glands and by expression of SP (SP/β-actin ratio; 0.96 ± 0.08 in ASA-adapted mucosa vs. 0.38 ± 0.05 in the control mucosa) and TGFα (TGFα/β-actin ratio: 0.97 ± 0.07 in ASA-adapted mucosa vs. 0.77 ± 0.06 in the control mucosa). COX-1 expression was detected in vehicle-control gastric mucosa and after single exposure to ASA or after six consecutive ASA insults, while COX-2 mRNA was not detected in vehicle-control gastric mucosa, but appeared after single ASA insult and was sustained after subsequent ASA doses. Conclusions: (i) Gastric adaptation to aspirin injury involves enhanced cell proliferation which appears to be mediated by increased expression of SP and TGFα, and (ii) rapid upregulation of COX-2 expression following single and repeated ASA insults may represent a compensatory response to suppression of prostaglandin generation by this NSAID.

Background Epidermal growth (EGF) and transforming growth factor alpha (TGFalpha) are potent gastric secretory inhibitors, mitogens, and mucosal protectors, but the impact of Helicobacter pylori infection on their mucosal expression and luminal release has not been clarified. Methods In this study, gene and immunoreactive and immunohistochemical expressions of EGF and TGFalpha were assessed in the gastric mucosa of 15 H. pylori-negative healthy normals, in 22 H. pylori-positive duodenal ulcer patients (DU) and in 24 H. pylori-positive non-ulcer dyspepsia patients (NUD). All studies in DU and NUD patients were repeated after 2 weeks of triple therapy (amoxicillin + clarithromycin + omeprazole) and 4 weeks and 2 years later. Results Immunohistochemical expression of EGF and TGFalpha in H. pylori-positive DU and NUD was significantly higher than in H. pylori-negative normals, and this increase persisted at 2 and 4 weeks after therapy but normalized 2 years later. EGF mRNA was detected in the gastric mucosa of H. pylori-positive DU before and at 2 and 4 weeks after H. pylori eradication, but it was not found 2 years after the eradication of H. pylori or in gastric mucosa of H. pylori-negative control subjects. TGFalpha mRNA was detected in the gastric mucosa independently of H. pylori status, with the stronger expression observed in the gastric mucosa of H. pylori-positive DU and NUD before eradication than after this procedure. Plasma gastrin, which was significantly increased in H. pylori-positive DU, normalized already after 2 weeks of triple therapy. The eradication rate as determined by histology after triple therapy reached 86.3% in DU patients and 90.5% in NUD patients. Two years after the eradication the H. pylori reinfection rate was 4.5% among DU patients and 4.2% among NUD. Treatment of DU patients with triple therapy resulted in complete ulcer healing. Conclusions 1) Chronic H. pylori infection and resulting antral gastritis are associated with increased plasma gastrin and increased mucosal cell proliferation, probably due to enhanced expression of EGF and TGFalpha, and 2) the H. pylori eradication results in a decrease in plasma gastrin, but the increase in gastric TGFalpha and EGF content is sustained, suggesting that they may be involved in ulcer healing.

Overexpression of transforming growth factors (TGF) in acute pancreatitis (AP) suggested that these substances play an important role in pancreatic repair and remodeling but the contribution of epidermal growth factor (EGF), that is well known to promote cell growth and regeneration, has not been investigated. The aim of this study was to compare the gene and immunohistochemical expression of EGF and TGF-β1, cell proliferation, and biochemical parameters in AP induced by infusion of a supramaximal dose of caerulein in rats. The rats were sacrificed at 0, 12, 24, 48, 72 h, 5 and 10 days after the termination of caerulein infusion. Pancreatic tissue DNA synthesis, cell proliferation, histological and immunohistochemical assessments and plasma amylase were estimated following induction of AP. The mRNA expression for EGF and TGF-β1 was evaluated by reverse transcription-polymerase chain reaction. During 10 days of the study after induction of AP a gradual normalization of biochemical and histological parameters was observed. DNA synthesis and cell proliferation which were significantly decreased at 0 and 24 h, increased significantly at 48 and 72 h, and then gradually decreased reaching at day 10 the values similar to those of vehicle-treated control rats. In these control rats the EGF mRNA or immunohistochemical expression was not detected, while the TGF-β1 expression was weak. After induction of AP, the mRNA and immunohistochemical expression of EGF showed an increase during the initial 5 days, while those of TGF-β1 showed a marked increase between 0 and 48 h and then again at day 10. We confirm that: (1) the expression of TGF-β1 during AP is biphasic with an initial increase probably related to pancreatic damage and inhibition of cell proliferation and with the later phase of increase accompanied by the stimulation of the synthesis of extracellular matrix components and (2) AP is accompanied by an induction of synthesis of EGF that occurs in the initial phase of AP, probably limiting the extent of AP, and enhancing the stimulation of the pancreatic repair and regeneration.

Background: Autoantibodies against epitopes located at the canaliculi of human parietal cells occur in about 30% of Helicobacter pylori-infected patients. This has led to the hypothesis that gastric secretory function could be inhibited by anticanalicular autoantibodies in H. pylori gastritis. Methods: Forty-four H. pylori-infected patients with and without duodenal ulcers were screened for anticanalicular autoantibodies by means of immunohistochemistry. Plasma gastrin levels and basal and maximal gastric acid output were determined. Results: Fasting gastrin levels were significantly increased in the group with anticanalicular autoantibodies. In the group of patients with non-ulcer dyspepsia the presence of anticanalicular autoantibodies was significantly correlated with an impaired basal acid secretion. Conclusions: Antigastric autoimmunity in H. pylori gastritis seems to be relevant for gastric hyposecretion either directly by inhibiting the proton pump or indirectly through the development of gastric m...

Melatonin, a pineal hormone that is biosynthesized from L-tryptophan, is known to scavenge oxygen free radicals and to be present in the gut, but little is known about the role of this hormone and its precursor, L-tryptophan, in protecting the gastric mucosa from damage accompanied by increase in the generation of oxygen radicals.This study was designed to determine the effects of melatonin and L-tryptophan on the formation of acute gastric lesions induced by stress and ischaemia reperfusion and, for comparison, by topical irritants such as 100% ethanol or acidified acetylsalicylic acid.It was found that pretreatment with melatonin in doses ranging from 1.2 to 10 mg/kg dose-dependently reduced the stress-induced gastric lesions and was accompanied by a reduction in blood-free radicals and by attenuation of the fall in gastric blood flow. L-tryptophan applied intragastrically in doses ranging from 1 to 100 mg/kg also reduced dose-dependently the lesions induced by stress; this effect too was accompanied by a rise in gastric blood flow. Pretreatment with indomethacin, to block the biosynthesis of prostaglandins, significantly augmented the lesions produced by stress and completely abolished the protective effects of melatonin or L-tryptophan. Both melatonin and tryptophan reduced the formation of acute gastric lesions provoked by ischaemia reperfusion; this was accompanied by an increase in gastric blood flow. In contrast, melatonin and L-tryptophan failed to influence acute gastric lesions induced by topical irritants such as 100% ethanol or acidified aspirin.Melatonin and L-tryptophan protect the gastric mucosa from damage by stress and ischaemia reperfusion, and this action is mediated, at least in part, by the limitation in the free radicals, the stimulation of mucosal generation of PG and by the increase in gastric blood flow.

BACKGROUND: Application of neutralising antibodies (NAs) to transforming growth factor beta 1 (TGF beta 1) improves wound healing in experimental glomerulonephritis and dermal incision wounds. TGF beta 1 has been detected in the stomach, but despite the fact that this cytokine plays a central part in wound healing no information is available to determine if modulation of the TGF beta 1 profile influences the healing of gastric ulcers. This study examines gastric ulcer healing in the rat after local injection of NAs to TGF beta 1. METHOD: Chronic gastric ulcers were induced in Wistar rats by the application of 100% acetic acid to the serosal surface of the stomach. Immediately after ulcer induction and on day 2, NAs to TGF beta 1 (50 micrograms), TGF beta 1 (50 ng), saline or control antibodies (IgG; 50 micrograms) were locally injected into the subserosa. Controls received no subserosal injections. Animals were killed on day 5 or 11, the ulcer area was measured planimetrically, sections were embedded in paraffin wax, and stained with trichrome or haematoxylin and eosin. Depth of residual ulcer was assessed on day 11 by a scale of 0-3, the percentage of connective tissue was determined by a semiquantitative matrix score and granulocytes and macrophages in the ulcer bed were also assessed. RESULTS: The application of NAs to TGF beta 1 led to a significant acceleration of gastric ulcer healing on day 11 (0.6 (SD 0.8) v 3.7 (SD 2.6) mm2), a reduction in macrophages (23.7 (SD 22.6) v 38 (26) per 40 x power field) and granulocytes (8.5 (SD 5.6) v 20 (10) per 40 x power field), fewer histological residual ulcers (mean 1 (SD 0.9) v 2 (1.1)), a reduced matrix score, and a regenerative healing pattern. Excessive scarring was seen in the TGF beta 1 treated group. CONCLUSION: Further treatment of gastric ulcers may induce a new treatment modality by local injection of NA to TGF beta 1 in an attempt to accelerate and improve ulcer healing.

The urease-ammonia (NH4OH) system has been proposed to play a major role in the pathogenesis of the Helicobacter pylori-associated gastritis, but the mechanism of the mucosal damage has not been fully explained. This study was designed to examine possible adaptive cytoprotection and the adaptation of rat gastric mucosa to the irritant action of NH4OH and urease.Single application of NH4OH alone in various concentrations (15-500 mM) caused concentration-dependent mucosal damage starting with 30 mM and reaching a maximum at 250 mM NH4OH, similar to that obtained with 100% ethanol; it was accompanied by a decrease in gastric blood flow (GBF) to approximately 30% of the normal value. When the mucosa was first exposed to the low, non-damaging concentration (15 mM) of NH4OH and then insulted with 100% ethanol, the extent of ethanol damage was greatly attenuated as compared with that caused by ethanol alone. This adaptive cytoprotection was accompanied by the rise in GBF and reversed, in part, by the pretreatment with indomethacin, an inhibitor of prostaglandin (PG)-cyclooxygenase; with L-NAME, a blocker of NO-synthase; or with capsaicin deactivating the sensory nerves. Damaging concentrations of NH4OH (125 mM) caused widespread mucosal damage after the first application, but with repeated insults with 125 mM NH4OH a gradual reduction in the mucosal lesions, accompanied by enhanced mucosal cell proliferation and over-expression of epidermal growth factor (EGF) (using immunocytochemistry) and mRNA of EGF (using trans-reverse polymerase chain reaction), were observed.NH4OH alone damages gastric mucosa only at the concentration exceeding that found in H. pylori-infected stomachs, whereas at lower concentrations it acts as 'mild' irritant to induce adaptive cytoprotection. This adaptive cytoprotection appears to be mediated, in part, by endogenous PG, sensory nerves, and an arginine-NO-dependent pathway, and repeated applications of NH4OH induce gastric adaptation, probably mediated by enhanced expression of EGF and its receptors and by an increased cell proliferation.

Nitric oxide (NO) was shown to mediate gastric hyperemia following secretory stimulation but its role in the control of gastric secretion has not been clarified. Secretory studies were carried out on conscious dogs with chronic gastric fistula, Heidenhain pouch and esophageal fistula, while changes in gastric blood flow were measured in the mucosa of Heidenhain pouuch by laser Doppler flowmetry. Plasma gastrin was determined by radioimmunoassay. Infusion of N G - nitro- l -arginine ( l -NNA) (bolus i.v. injection of 2.5 mg/kg followed by infusion of 0.5 mg/kg/h), a potent inhibitor of nitric oxide synthase, failed to affect basal gastric secretion or plasma gastrin level but suppressed an increase of this secretion induced by sham-feeding, ordinary meat feeding or i.v. infusion of bombesin (0.5 μg/kg/h), pentagastrin (4 μg/kg/h) or histamine (40 μg/kg/h). In tests with feeding and bombesin infusion, l -NNA caused a significant and dose-dependent reduction in plasma gastrin levels. The inhibition by l -NNA of gastric acid secretory response to pentagastrin, histamine or feeding was accompanied by a decline in blood flow. Addition of l -arginine (bolus i.v. dose of 50 mg/kg followed by infusion of 5 mg/kg/h) significantly attenuated the l -NNA induced inhibition of gastric secretion and the reduction in plasma gastrin response as well as in the fall of gastric blood flow. We conclude that endogenous nitric oxide affects the gastric secretion and that this effect is mediated, at least in part, by the changes in the gastrin release and gastric blood flow.

Melatonin and its precursor, l-tryptophan, have been shown to exert gastroprotective effects in animals, but their influence on the gastric damage by aspirin (ASA) in humans has been sparingly investigated. In this study, we designed to determine the effects of melatonin and l-tryptophan on ASA-induced gastric mucosal damage, gastric microbleeding, mucosal generation of prostaglandin E(2), and plasma melatonin, and gastrin levels. Three groups of healthy male volunteers (n = 30) with intact gastric mucosa received daily for 11 days either ASA alone or that combined with melatonin or tryptophan. Gastric blood loss and mucosal damage were evaluated at 3rd, 7th, and 11th days of ASA administration by endoscopy using Lanza score. ASA alone caused a marked rise of gastric damage and gastric blood loss, mainly at day 3rd and 7th, but they were significantly reduced at 11th day. Pretreatment with melatonin or tryptophan remarkably reduced ASA induced gastric lesions and microbleeding. Gastric mucosal generation of PGE(2) was suppressed by about 90% in all subjects treated with ASA alone without or with addition of melatonin or tryptophan. Plasma melatonin was markedly increased after treatment with melatonin or tryptophan plus ASA, but it was also raised significantly after application of ASA alone. Plasma gastrin levels were raised in subjects given melatonin or tryptophan plus ASA, but not in those with ASA alone. We conclude that melatonin and its precursor tryptophan given orally significantly reduce gastric lesions induced by ASA possibly due to (a) direct gastroprotective action of exogenous melatonin or that generated from tryptophan and (b) gastrin released from the gastric mucosa by melatonin or tryptophan.

Histamine is not only a potent stimulator of gastric acid secretion, but it also plays a central role in gastroduodenal ulcerogenesis. In the present study we tested the effect of pre-treatment with exogenous prostaglandin E(2) (PGE(2)) in a new rat model of experimental gastric ulcers induced by combination of histamine and gastric ischemia.In male Wistar rats, a chronic ischemia of gastric mucosa was induced via the clamping of the left gastric artery and vein (L-AV) in combination with pylorus ligation. The following treatment groups of rats (6 rats/group) were investigated: 1) histamine alone (40 mg/kg twice s.c.); 2) vehicle (saline) followed 30 min later by gastric mucosal L-AV ischemia and pylorus ligation combined with histamine (40 mg/kg twice s.c.) and 3) PGE(2) (5 microg/kg i.g.) followed 30 min later by gastric mucosal L-AV ischemia combined with histamine (40 mg/kg twice s.c.) and pylorus ligation. At 4 hr after the clamping of L-AV and pylorus ligation, the area of gastric lesions and gastric acid secretion was determined.Histamine treatment failed to produce gastric lesions, but when it was combined with ischemia, the widespread gastric lesions in the corpus mucosa, but not in the antrum, were observed. This damaging effect and decrease in the GBF were significantly attenuated by pretreatment with PGE(2).The present study demonstrates that gastric hypersecretion induced by histamine in combination with gastric mucosal ischemia results in gastric lesions which progress into chronic gastric ulcers.

Ghrelin, identified in the gastric mucosa, is involved in control of food intake and growth hormone (GH) release. Besides being an appetite hormone, central and peripheral ghrelin exerts a potent protective action against gastric mucosal experimental injury induced by stress, an effect dependant on vagal activity and hyperemia mediated by nitric oxide synthase (NOS)-nitric acid (NO) and cyclo-oxygenase (COX)-prostaglandin (PG) systems and calcitonin gene related peptide (CGRP) released from sensory afferent nerves.

We describe the first detailed case of eosinophilic esophagitis associated with esophageal intramural pseudodiverticulosis and gastro-esophageal reflux disease in a 24-year-old man, who suffered from recurrent dysphagia since the age of 3 years. He presented with symptoms of dysphagia, food impaction and malnutrition. An esophagogram revealed a high-grade stenosis in the proximal part of the esophagus. Histological evaluation of esophageal mucosal biopsies demonstrated more than 20 eosinophil granulocytes per high power field, indicative of eosinophilic esophagitis. Additionally, esophago-gastro-duodenoscopy showed pseudodiverticulosis in the distal portion of the esophagus. A therapeutic regimen consisting of topical steroid intake, antihistamines, proton-pump-inhibition and specific food avoidance led to significant clinical improvement within 6 weeks.

Gastrin and its precursor, progastrin, are synthesized in the stomach, particularly when infected with Helicobacter pylori, and they are metabolized, at least in part, in the liver. However, little is known about their levels in various hepatic diseases.This study was carried out on 147 patients including chronic hepatitis B (n = 35), hepatitis C (n = 52) and liver cirrhosis (n = 60) of class A (n = 38), class B (n = 15) and class C (n = 7) (Child-Pugh classification) and age- and sex-matched healthy controls (n = 65). The diagnosis of chronic hepatitis was confirmed by liver biopsy in all patients, whereas the diagnosis of liver cirrhosis was based on clinical and laboratory findings. Liver biopsy was done in 38 out of 60 patients. Blood samples were collected under basal conditions and separated plasma samples were kept frozen at -70 degrees C until radioimmunoassay of progastrin and its products, including bioactive amidated gastrins.Median (range) plasma concentrations of total progastrin product and amidated gastrin in control subjects were 147.5 (73-345) pM and 33 (15-65), respectively. These concentrations in hepatitis B and C were not significantly different from those in controls. In cirrhosis (classes A, B and C), the concentrations of the progastrin and of gastrin were significantly (P0.05) higher than in controls reaching, respectively, 253.5 (135-683 pM) and 47.5 (17-385) pM. Both progastrin and gastrin levels were significantly higher in H. pylori-positive than in negative cirrhotic patients. Antibodies against H. pylori were present in about 50% of controls, 68% of hepatitis B, 57% of hepatitis C and in 83% in cirrhosis patients. The difference in H. pylori prevalence between cirrhosis and controls was statistically significant.Plasma levels of progastrin and gastrin are significantly increased in cirrhotic patients and this could be attributed to reduced metabolism of these peptides in liver cirrhosis and to their increased release due to H. pylori infection rate in this disease.

Despite numerous epidemiological studies, the association between Helicobacter pylori infection and gastric cancer (GC) remains unexplained. This study was designed to determine the seropositivity of H. pylori and cytotoxin-associated gene A (CagA), serum gastrin and interleukin-8 (IL-8) levels as well as basal intragastric pH and maximal histamine-induced gastric acid outputs (MAO) in a large series of GC patients and controls.337 GC patients (118 men and 219 women; median age 59.4; range 21-87) and 337 controls randomized for sex and age entered the study. Serum IgG antibodies to H. pylori and CagA and serum levels of IL-8 were measured by enzyme-linked immunosorbent assay, while serum-amidated gastrin was determined by specific radioimmunoassay and correlated with gastric luminal pH.The numbers of GC patients and controls involved in the study in various age groups, ranging from 20 to70 years, were similar, but overall H. pylori IgG seropositivity in GC patients was significantly higher (90.8%) than in controls (79.2%). The overall CagA seropositivity in GC patients was about double (58.2%) that in controls (25.2%). Serum gastrin levels over the calculated cut-off value (38.88 pM/L) were found in several-fold larger number in GC patients (48%) than in controls (8.3%) and. similarly, serum IL-8 values over the cut-off point (1.77 pg/mL) occurred in almost all (99.7%) GC patients but in only a few controls (0.3%). Basal intragastric pH above the cut-off point (pH = 4.50) was observed in about 58.2% of GC patients compared to 15.1% in controls, and strong correlation between the serum gastrin and gastric pH was found in GC but weak in controls. The cut-off value for MAO was 12.3 mml/h; MAO below this cut-off value occurred in 89.9% of GC patients and in only 4.7% of controls. A summary odds ratio (SOR) in GC for H. pylori IgG was 2.59 (95% Cl: 1.61-4.22) for CagA - 4.12 (95% Cl; 2.93-5.8), for serum gastrin - 10.25 (95%; 6.47-16.47) and for MAO - 15.2 (95% Cl; 9.45-39.82). Multivariable analysis of serum gastrin, IgG and CagA, and luminal pH and MAO values revealed that only gastrin and CagA have significant influence on GC formation (OR1 in logistic regression).1. CG patients show significantly higher H. pylori IgG and CagA seropositivity than dyspeptic age- and gender-matched controls, confirming that gastric infection with CagA expressing H. pylori greatly increases the risk of GC. 2. Serum gastrin levels in GC but not in controls are correlated with the rise in intragastric pH, indicating that excessive gastrin release in GC is affected by lower intragastric pH. 3. Serum gastrin level and CagA seropositivity are significantly increased in the majority of GC patients, and are the only variables in multivariable analysis to have a predominant influence on GC formation, which suggests that both these parameters may be implicated in H. pylori-related gastric carcinogenesis. 4. H. pylori-infected GC patients produce significantly more IL-8 than do non-GC controls, probably reflecting CagA-positive H. pylori-associated gastritis.

Lipopolysaccharides (LPS) are major components of the outer membrane of Gram-negative bacteria, which play a central role as potent endotoxins in the pathogenesis of the Gram-negative septicaemia. Although it is well known that large amounts of endotoxin may produce haemorrhagic lesions in the stomach, the effect of LPS on ulcer healing has not been fully clarified. The aim of the present study was to examine the effect of parenteral injection of LPS at different doses on the course of ulcer healing in rats.Gastric ulcers were induced in Wistar rats by serosal application of an acetic acid area. After ulcer induction, vehicle (saline) or E. coli-LPS was injected at various doses (0.1, 1 and 5 mg/kg i.p.) for 7 days. The animals were sacrificed on day 8 after ulcer induction and the following parameters were analysed; ulcer area (planimetry), gastric blood flow (GBF) (H2 gas clearance method), gastric secretion, plasma levels of proinflammatory cytokines such as IL-1beta and TNFalpha, mucosal gene expression for cyclooxygenases (COX-1/-2), apoptosis-related proteins (Bax, Bcl-2), TNFalpha, IL-1beta and vascular endothelial growth factor (VEGF).Daily parenteral challenge with LPS resulted in a dose-dependent delay in ulcer healing with maximum observed at a dose of 5 mg/kg (12.14 +/- 1.2 mm2 versus 5.18 +/- 0.8 mm2 in the control group). The impairment of ulcer healing in LPS-treated rats was associated with a significant decrease in GBF, increased mRNA expression for IL-1beta, TNFalpha, the rise in plasma IL-1beta and TNFalpha levels, an overexpression of COX-2 and VEGF and imbalance in the ratio between pro-apoptotic Bax and antiapoptotic Bcl-2. The daily administration of 50 mg/kg pentoxifylline by itself failed to accelerate the ulcer healing but attenuated the deleterious effects of LPS on this healing.1) Bacterial endotoxin impairs ulcer healing through the decrease in gastric mucosal blood flow, increased expression and release of proinflammatory cytokines IL-1beta and TNFalpha, the imbalance between pro- and anti-apoptotic members of Bcl-2 family via downregulation of antiapoptotic bcl-2, and 2) endotoxin leads to upregulation of genes for VEGF and COX-2, which fail to accelerate the ulcer healing.

The repair of damaged gastric mucosa is a complex process involving prostaglandins (PG) and mucosal growth factors such as epidermal growth factor (EGF). Recently, we postulated that the increased occurrence of apoptosis in the gastric epithelium might be of pathophysiological importance in the development of stress lesions. The aim of the present study was to assess the effect of the pretreatment of rats, exposed to 3.5 h of water immersion and restraint stress (WRS), with EGF and PG (16,16 dmPGE(2)) on the number of stress lesions, recovery of gastric mucosa from stress and the expression of apoptosis related genes such as caspase-3 and antiapoptotic bcl-2. Rats were divided in following groups: (1) vehicle; (2) EGF 100 microg/kg i.p.; (3) 16,16 dm-PGE(2) (5 microg/kg i.g.) and caspase-1 inhibitor (ICE-I; 100 microg/kg i.p.). One hour later, the rats were exposed to 3.5 h of WRS and then sacrificed immediately (0 h) or at 6, 12, or 24 h after WRS. The number of acute gastric lesions was determined. Gastric epithelial apoptosis was assessed by TUNEL staining. In addition, mRNA expression of caspase-3, Bcl-2 and proinflammatory cytokines (IL-1 beta, TNFalpha) was assessed by RT-PCR. PGE(2) generation in gastric mucosa and luminal EGF were determined by RIA. Exposure to WRS resulted in the development of multiple acute stress erosions ( approximately 18) which almost completely healed during 24 h. The gastric blood flow was significantly reduced (approximately 70% of intact mucosa) immediately after WRS. The expression of mRNA for IL-1 beta and TNF alpha reached their peak at 12 h after stress exposure. The apoptosis rate was highest at 6 h after WRS and was accompanied by the highest caspase-3 expression. In rats pretreated with EGF or 16,16 dm-PGE(2), a significant decrease in caspase-3 mRNA and upregulation of bcl-2 mRNA as observed as compared to vehicle controls. Caspase-1 inhibitor significantly reduced the number of stress lesions. We conclude that EGF and PGE(2) accelerate healing of stress-induced lesions due to the attenuation of apoptosis via upregulation of bcl-2 in gastric mucosa. Inhibitors of apoptosis accelerate healing of stress lesions and may be potentially effective agents in the healing of damaged gastric mucosa.

Gastroduodenal ulcerations have worldwide distribution and the infection with Helicobacter pylori (HP) has been implicated in pathogenesis of this disease. The HP infection is usually accompanied by hypergastrinemia and enhanced generation of prostaglandins (PG), both implicated in the pathogenesis of peptic ulcerations but no study has been undertaken to assess the relationship between the HP infection and coexpression of gastrin and cyclooxygenases (COX), the rate limiting enzymes in the PG production. Since HP infection, usually accompanying peptic ulcerations, results in increased release of gastrin, a potent gastric mitogen that might be capable to induce COX-2 and to generate PG, we decided 1) to compare the seroprevalence of HP and its cytotoxic protein, CagA, in gastric ulcer patients with those in age- and gender-matched controls; 2) to determine the gene expression of gastrin and its receptors (CCK B -R) at the margin of gastric ulcer and in the mucosa of antrum and corpus before and after successful eradication of HP, 3) to assess the plasma levels and gastric luminal contents of gastrin before and after HP eradication and 4) to examine the mRNA and enzyme protein expression of COX-1 and COX-2 as well as the PGE 2 generation in ulcer margin tissue and gastric antral and fundic mucosa before and after the HP eradication. The trial material included 20 patients with gastric ulcer and 40 age- and gender-matched controls. Anti-HP and anti-CagA IgG seroprevalence was estimated by specific antisera using ELISA tests. Gene expressions of gastrin, CCK B -R, COX-1 and COX-2 were examined using RT-PCR with β-actin as a reference and employing Western blotting for COX-2 expression, while gastrin and PGE 2 were measured by RIA. All gastric ulcers were located at smaller curvature within the antral mucosal area. The seroprevalence of HP, especially that expressing CagA, was significantly higher in gastric ulcers (85%) than in controls (62.5%). Both gastrin and CCK B -R mRNA were detected by RT-PCR in ulcer margin and gastrin mRNA was overexpressed in remaining antral mucosa, while CCK B -R mRNA was overexpressed in fundic mucosa of HP infected patients. Similarly, COX-2 mRNA and protein were found in margin of gastric ulcer and in the HP infected antral and fundic mucosa but not in the mucosa of HP eradicated patients in whom ulcers completely healed and gastrin was expressed only in antrum, CCK B -R only in corpus, while COX-1 was detected both in antrum and corpus. HP positive gastric ulcer patients showed about three times higher levels of plasma immunoreactive gastrin and about 50% higher luminal gastrin contents than the HP negative controls and this increased plasma and luminal gastrin was normalized following the HP eradication. A significant fall in gastrin and CCK B -R mRNA expression was noticed six weeks after HP eradication in gastric antral and fundic mucosa, while COX-2 mRNA completely disappeared after this treatment. We conclude that 1) HP infected gastric ulcer margin coexpresses gastrin, its receptors (CCK B -R), and COX-2; 2) HP infection may be implicated in gastric ulceration via increased release of gastrin that could be responsible for the overexpression of COX-2 that in turn could help ulcer healing through the stimulation of mucosal cell growth, restoration of the glandular structure and angiogenesis in the ulcer area and 3) gastrin produced in HP infected antral mucosa seems to be involved in the induction of COX-2 and PG production by this enzyme and this may contribute to the ulcer healing.

Background Ischemia followed by reperfusion (I/R) induces gastric lesions, probably due to excessive formation of free radicals, but the role of the scavenger of these radicals, proinflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), in the healing of these lesions has not been extensively studied. It is also unknown whether expression of intercellular adhesion molecule-1 (ICAM-1), which mediates neutrophil-induced injury and neutrophil infiltration, is involved in the recovery from I/R lesions. Methods I/R lesions were induced in Wistar rats by applying a small clamp to the celiac artery for 30 min (ischemia phase), followed by the removal of the clamp for 60 min (reperfusion phase). The influence of I/R on gastric secretion was also tested in rats equipped with a gastric fistula (GF) without or with the exposure to a standard period of I/R. Two series of rats (A and B) were used to determine the effects of exogenous and endogenous superoxide dismutase SOD (series A) and allopurinol, a xanthine oxidase inhibitor (series B), on the mucosal recovery from the gastric lesions induced by I/R. The animals were killed immediately after the exposure to I/R (0 h) and at 3 h, 24 h, or 3, 5, or 10 days after this I/R, the area of gastric lesions being measured by planimetry, and the gastric blood flow (GBF) determined by the H2 gas clearance method. Blood was withdrawn for measurement of plasma IL-1beta and TNF-alpha levels with enzyme-linked immunosorbent assay, and plasma gastrin with radioimmunoassay. Biopsy samples of oxyntic mucosa were taken for the assessment of SOD, IL-1beta, TNF-alpha, and ICAM-1 mRNAs by reverse-transcription polymerase chain reaction and Southern blot. Results Exposure to I/R resulted in acute gastric erosions, with the maximal increase of the area of these lesions observed 3 h after the end of I/R. This effect was accompanied by a decrease in the GBF, a significant increase in blood free radicals and plasma gastrin increments, and almost complete suppression of gastric secretion. Starting 24 h after I/R, the gastric superficial lesions progressed into deeper ulcers that healed progressively within 10 days, and this was accompanied by gradual restoration of the gastric secretion and the GBF. Treatment with SOD and allopurinol accelerated significantly the healing of I/R erosions, and this effect was accompanied by a significant increase in the GBF and the attenuation of blood free radicals. At 0, 3, and 12 h after I/R a significant decrease in SOD mRNA was observed, whereas expression of TNF-alpha, IL-1beta, and ICAM-1 showed a progressive increase starting immediately after I/R, reaching a maximum on day 3. The plasma level of TNF-alpha and IL-1beta started to increase on day 3 and peaked on day 5 after I/R, being still significantly higher at day 10 than that measured in the vehicle-treated control gastric mucosa. On day 10 the gastric ulcers were almost completely healed, and a decrease in the expression for TNF-alpha, IL-1beta, and ICAM-1 mRNA and an increase in the expression of SOD mRNA were observed. Conclusions 1) exposure to I/R produces gastric lesions mediated by the excessive formation of free radicals, resulting in suppression of both gastric microcirculation and secretory activity of the stomach; 2) SOD and allopurinol accelerate the healing of I/R lesions, probably due to suppression of oxygen free radicals and improvement of gastric microcirculation; and 3) the upregulation of SOD mRNA, with subsequent increase in the SOD production and local release of IL-1beta and TNF-alpha, may activate ICAM-1 expression and neutrophil infiltration, which appear to play an important role in the progression of I/R-induced acute gastric erosions into chronic ulcers.

We examined the influence of endogenous and exogenous epidermal growth factor (EGF) on pancreatic repair after acute pancreatitis. Caerulein-induced pancreatitis was evoked in rats with intact or removed salivary glands and EGF (10 microg/kg) was administered starting 24 h after cessation of caerulein infusion. The dose of EGF 10 microg/kg was chosen because it was the most effective in preliminary experiments when 1, 10 or 50 microg/kg of EGF was used. Caerulein administration caused acute edematous pancreatitis with biochemical and histological manifestation of pancreatic damage, followed by spontaneous regeneration. The effect of salivectomy on the course of acute pancreatitis was slight, resulting in additional reduction in pancreatic blood flow, DNA synthesis and in an increase in plasma interleukin 1beta level. Treatment with EGF accelerated the healing of pancreatic damage, causing an increase in pancreatic blood flow and DNA synthesis. EGF caused faster normalization of plasma amylase and lipase activity and plasma interleukin 1beta concentration, as well as, this peptide accelerated the restoration of pancreatic amylase activity. On histological examination, EGF caused reduction of pancreatic damage and acceleration of tissue repair. We conclude that EGF reduces the severity of pancreatic damage evoked by caerulein-induced pancreatitis-related pancreatic damage and accelerates tissue repair. The beneficial effects of EGF appear to depend, at least in part, on the improvement of pancreatic blood flow, as well as on an increase of pancreatic cell growth and limitation of the activation cytokine release.

In this study, ischemia–reperfusion produced in rats by clamping the celiac artery for 0.5 h followed by 1 h of reperfusion was used to develop a new model of superficial gastric erosions progressing to deeper ulcers. Ischemia alone resulted in an immediate fall in gastric blood flow but no gross mucosal lesions were observed. When ischemia was followed by reperfusion, gastric erosive lesions occurred, reached a maximum at 12 h and then declined after 24 h. These acute erosions progressed into deeper lesions 24 h after ischemia–reperfusion and reached a peak after 3 days. Gastric blood flow and the mucosal generation of prostaglandin E2 were significantly suppressed immediately following ischemia–reperfusion, but with the healing of deeper gastric ulcers, both gastric blood flow and prostaglandin E2 generation were gradually restored. Cyclooxygenase-1 mRNA was detected by reverse transcription-polymerase chain reaction in intact gastric mucosa and throughout the recovery of the mucosa from acute ischemia–reperfusion lesions, whereas cyclooxygenase-2 mRNA, was recorded only after ischemia–reperfusion. NS-398 and rofecoxib, selective inhibitors of cyclooxyganase-2, failed to affect prostaglandin E2 generation in the non-ulcerated gastric mucosa but inhibited it significantly in the ulcer area. The two cyclooxygenase-2 inhibitors as well as resveratrol, a specific cyclooxygenase-1 inhibitor and indomethacin and meloxicam, non-specific inhibitors of cyclooxygenase, augmented acute gastric erosions induced by ischemia–reperfusion and delayed significantly the progression of these lesions into deeper ulcers at each time interval after ischemia–reperfusion. We conclude that prostaglandins generated by both cyclooxygenase-1 and cyclooxygenase-2 contribute to the healing of gastric lesions induced by ischemia–reperfusion.