Melatonin and its precursor L-tryptophan prevent acute gastric mucosal damage induced by aspirin in humans.

Melatonin (MT) and its precursor L-tryptophan (Trp) are implicated in the protection of gastric mucosa against noxious agents. However, the role of MT and Trp on the gastric mucosal injury induced by aspirin (ASA) in human has not been investigated. Studies in animals showed that both MT and Trp given intragastrically prevents the formation of gastric mucosal lesions induced by ASA. The aim of the present study was to determine the influence of MT and Trp given orally to healthy humans on gastric mucosal lesions induced by ASA. The present study included 21 healthy, Hp-negative male volunteers with intact gastro-duodenal mucosa aging 20-50 yr. They were divided in 3 groups; group 1: 7 volunteers receiving daily 2 x 1g ASA (Polfa, Rzeszow) during 11 days; group 2: 7 healthy volunteers receiving 2x1 g ASA and MT (Lekam, Zakroczyn) (5 mg 30 min prior to ASA) during 11 days and group 3: 7 healthy volunteers receiving 2x1 g ASA and Trp (Ardeytropin, Germany) (0.5 g 30 min prior to ASA) during 11 days. Mucosal damage was evaluated at 3(rd), 7(th) and 11(th) days of ASA administration by endoscopy using Lanza score. Plasma melatonin was measured using RIA and gastric mucosal generation of PGE(2) was assessed also by RIA. ASA caused marked mucosal injury at all days of its administration except day 11(th) when only moderate lesions were evident. Pretreatment with MT or Trp alone was accompanied by a significant decrease in gastric mucosal lesion score. Gastric mucosal generation of PGE(2) was suppressed by about 90% in subjects treated with ASA without or with MT or Trp. We concluded that: MT and its precursor Trp significantly attenuate gastric mucosal lesions induced by aspirin. The action of Trp may be be mediated by MT produced in gastrointestinal tract from Trp. The gastroprotective action of MT and Trp is independent on gastric mucosal PGE2 generation.

Helicobacter pylori and its involvement in gastritis and peptic ulcer formation.

Modern gastroenterology started in early 19(th) century with the identification by W. Prout of the inorganic (hydrochloric) acid in the stomach and continued through 20(th) century with the discoveries by I.P. Pavlov of neuro-reflex stimulation of gastric secretion for which he was awarded first Nobel Prize in 1904. When concept of nervism or complete neural control of all digestive functions reached apogeum in Eastern Europe, on the other side of Europe (in United Kingdom), E. Edkins discovered in 1906 that a hormone, gastrin, may serve as chemical messenger in stimulation of gastric acid secretion, while L. Popielski revealed in 1916 that histamine is the most potent gastric secretagogue. K. Schwartz, without considering neural or hormonal nature of gastric secretory stimulation, enunciated in 1910 famous dictum; "no acid no ulcer"; and suggested gastrectomy as the best medication for excessive gastric acid secretion and peptic ulcer. In early 70s, J.W. Black, basing on earlier L. Popielski's histamine concept, identified histamine-H(2) receptors (H(2)-R) and obtained their antagonists, which were found very useful in the control of gastric acid secretion and ulcer therapy for which he was awarded in 1972 second Nobel Prize in gastrology. With discovery by G. Sachs in 1973 of proton pumps and their inhibitors (PPI), even more effective in gastric acid inhibition and ulcer therapy than H(2)-R antagonists, gastric surgery, namely gastrectomy, practiced since first gastric resection in 1881 by L. Rydygier, has been considered obsolete for ulcer treatment. Despite of the progress in gastric pharmacology, the ulcer disease remained essentially "undefeated" and showed periodic exacerbation and relapses. The discovery of spiral bacteria in the stomach in 1983 by B.J. Marshall and R.J. Warren, Australian, clinical researches, awarded in 2005 the Nobel Prize for the third time in gastrology, has been widely considered as a major breakthrough in pathophysiology of gastritis and peptic ulcer, which for the first time can be definitively cured by merely eradication of germ infecting stomach. This overview presents the mechanism of induction of gastritis and peptic ulcer by the H. pylori infection and describes accompanying changes in gastric acid and endocrine secretion as well as the effects of germ eradication on gastric secretory functions and gastroduodenal mucosal integrity.

Helicobacter pylori infection in coronary artery disease.

The role of inflammation in the pathogenesis and progression of coronary artery disease (CAD) has been increasingly discussed, but still remains unclear. Inflammatory changes in the vessel wall play an important role in the pathogenesis of atherosclerosis. Systemic inflammatory reaction can be detected by showing increased plasma levels of different proinflammatory cytokines and acute-phase proteins. Infectious agents have been linked to coronary heart disease on epidemiological and pathogenetic grounds. The prevalent condition and the exact mechanism of initiation of atherosclerotic vascular disease remain unclear. Nevertheless, many similarities exist between the processes of inflammation and atherogenesis, and the evidence is growing for the role of an active inflammation in the atherosclerosis in the coronary circulation and elsewhere. Although the seroepidemiological and eradication studies have suggested a causal relationship between Helicobacter pylori (Hp) infection and coronary heart disease; the issue is still controversial. The detection of Hp specific DNA in atheromatous plaque material from coronary arteries, but more important, the reduction in restenosis of coronary vessels after Hp eradication could be interpreted as an evidence for the involvement of a Hp infection in the progression of CAD induced by a local inflammatory process.

Ascorbic acid attenuates aspirin-induced gastric damage: role of inducible nitric oxide synthase.

Aspirin (ASA) represents an important risk factor for gastric mucosal injury. Recently, vitamin C releasing aspirin (ASA-VitC) has been shown to reduce gastric toxicity of ASA in animal model of gastric injury. The aim of the present study was to compare the effect of ASA and ASA-VitC on the gastric mucosal damage before and after Helicobacter pylori (Hp) eradication in 10 young healthy Hp-positive volunteers. All subjects underwent endoscopy at day 0 (before ASA or ASA-VitC treatment) and at day 3 following treatment (1.6 g ASA/day or 1.6 g ASA + 0.96 g Vit C/day). In addition, in vitro experiments were performed in which gastric mucosal cell line (MKN-45 cells) was incubated with ASA or ASA-VitC alone or in combination with H.pylori. Expression of constitutive and inducible NO synthase (cNOS, iNOS) was analyzed by Western blot. Moreover, COX-2 expression was analyzed in gastric biopsies at mRNA and protein level by RT-PCR and Western blot, respectively. In humans, treatment with ASA-VitC induced significantly less gastric mucosal lesions than plain ASA. Furthermore, in comparison to plain ASA, ASA-VitC caused stronger inhibition of cNOS and increase in iNOS expression in the gastric mucosa. In vitro studies demonstrated a significant increase in iNOS expression in MKN-45 cells incubated with Hp. This effect was aggravated by the addition of ASA, but not ASA-VitC, to MKN-45 cells incubated with H.pylori. Both ASA and ASA-VitC stimulated the COX-2 expression in the gastric mucosa. We conclude that ASA-VitC in comparison with ASA induces less gastric mucosal damage and this protective effect may be due to its inhibitory effect on iNOS expression.

Neuro-hormonal control of food intake: basic mechanisms and clinical implications.

Obesity is one of the most common metabolic diseases and the greatest threats of the health because of possibility of numerous complications. In order to design effective drugs or apply the helpful surgical procedure it is essential to understand physiology of appetite control and pathophysiology of obesity. According to the first law of thermodynamics, the energy input in the form of food, equals energy expenditure through exercise, basal metabolism, thermogenesis and fat biosynthesis. The control of body weight actually concerns the control of adipose tissue with the key role of hypothalamus, possessing several neuronal centers such as that in lateral hypothalamic nuclei considered to be "hunger" center and in ventromedial nuclei serving as the "satiety" center. In addition, paraventricular and arcuate hypothalamic nuclei (ARC) are the sites where multiple hormones, released from the gut and adipose tissue, converge to regulate food intake and energy expenditure. There are two distinct types of neurons in ARC that are important in control of food intake; (1) preopiomelanocortin (POMC) neurons activated by an orexigenic hormones and releasing alpha-melanocyte-stimulating hormone (alpha-MSH) in satiety center and (2) neurons activated by orexigenic peptides such as ghrelin that release the substances including neuropeptide Y (NPY) and Agouti-Related Peptide (AgRP) in hunger center. ARC integrates neural (mostly vagal) and humoral inputs such as enteropeptides including orexigenic (ghrelin and orexins) and an orexigenic peptides (cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin and others) that exert a physiological role in regulating appetite and satiety. The peripherally (gut, adipose tissue) and centrally expressed modulators of appetitive behavior act through specific receptors in the afferent (mostly vagal) nerves and hypothalamic neurons implicated in adiposity signaling and regulation of food intake.

Gastric electrical stimulation results in improved metabolic control in diabetic patients suffering from gastroparesis.

AIMS/HYPOTHESIS: Symptoms of gastroparesis possess a heavy impact on the quality of life; delayed gastric emptying may result in poor metabolic control in diabetics. Gastric electrical stimulation (GES) has recently been introduced as a treatment option in patients with drug refractory gastroparesis to increase the quality of life by alleviating nausea and vomiting frequencies. However, the effect of GES on metabolic control has not been assessed yet. METHODS: We performed a prospective single center study on the long-term effect (12 months) of continuous high-frequency/low-energy GES on symptoms, gastric emptying (measured scintigraphically), and metabolic control (HbA1c) in insulin-dependent diabetic subjects suffering from drug-refractory gastroparesis for more than one year. RESULTS: Seventeen (12 female, 5 male) patients entered the study; all were available for analysis at all time points. No therapy-associated adverse events occurred. Weekly vomiting and nausea frequencies decreased significantly at 6 and 12 months. Gastric retention rates improved significantly from 83 % (2 h) and 38 % (4 h) to 35 % (2 h)/14 % (4 h) and 25 % (2 h)/17 % (4 h) at 6 and 12 months, respectively. HbA1c values were lowered in all 17 subjects; initially, all HbA1c values were above 7.5 %; at 6 and 12 months, mean values had significantly decreased from 8.6 % to 6.2 % and 6.5 %, respectively. CONCLUSIONS/INTERPRETATION: Gastric electrical stimulation offers symptom control in diabetics with drug-refractory gastroparesis and decreases gastric retention. This study, for the first time, documents a positive effect of this therapy on metabolic control as indicated by HbA1c, a surrogate marker of the risk of diabetic complications.

From nerves and hormones to bacteria in the stomach; Nobel prize for achievements in gastrology during last century.

Rapid progress in gastroenterological research, during past century, was initiated by the discovery by W. Prout in early 18th century of the presence of inorganic, hydrochloric acid in the stomach and by I.P. Pavlov at the end of 19th century of neuro-reflex stimulation of secretion of this acid that was awarded by Nobel prize in 1904. Then, J. W. Black, who followed L. Popielski's concept of histamine involvement in the stimulation of this secretion, was awarded second Nobel prize in gastrology within the same century for the identification of histamine H2-receptor (H2-R) antagonists, potent gastric acid inhibitors, accelerating ulcer healing. The concept of H2-R interaction with other receptors such as muscarinic receptors (M3-R), mediating the action of acetylocholine released from local cholinergic nerves, and those mediating the action of gastrin (CCK2-R) on parietal cells, has been confirmed both in vivo studies and in vitro isolated parietal cells. The discovery of H2-R antagonists by Black and their usefulness in control of gastric secretion and ulcer healing, were considered as real breakthrough both in elucidation of gastric secretory mechanisms and in ulcer therapy. Discovery of even more powerful gastric acid inhibitors, proton pump inhibitors (PPI), also highly effective in acceleration of ulcer healing was, however, not awarded Nobel prize. Unexpectedly, two Australian clinical researchers, R.J. Warren and B.J. Marshall, who discovered in the stomach spiral bacteria, named Helicobacter pylori, received the third in past century Nobel prize in gastrology for the finding that this bacterium, is related to the pathogenesis of gastritis and peptic ulcer. They documented that eradication of H. pylori from the stomach, using antibiotics and potent gastric inhibitors, not only accelerates healing of ulcer but also prevents its recurrence, the finding considered as greatest discovery in practical gastrology during last century. Thus, the outstanding achievements in gastroenterology during last century have been awarded by three Nobel prizes and appreciated by millions of ulcer patients all over the world.

Brain-gut axis and its role in the control of food intake.

Gastrointestinal tract (GIT) and nervous system, both central (CNS) and enteric (ENS), are involved in two-way extrinsic communication by parasympathetic and sympathetic nerves, each comprising efferents fibers such as cholinergic and noradrenergic, respectively, and afferent sensory fibers required for gut-brain signaling. Afferent nerves are equipped with numerous sensors at their terminals in the gut related to visceral mechano- chemo- and noci-receptors, whose excitations may trigger a variety of visceral reflexes regulating GIT functions, including the appetitive behaviour. Food intake depends upon various influences from the CNS as well as from the body energy stores (adipocytes) that express and release the product of Ob gene, leptin, in proportion to fat stored and acting in long-term regulation of food intake. Leptin acts through receptors (Ob-R) present in afferent visceral nerves and hypothalamic arcuate nucleus (ARC), whose neurons are capable of expressing and releasing neuropeptide Y (NPY) and agouti related protein (AgRP) that activate the ingestive behaviour through paraventricular nucleus (PVN) (iVfeeding centerli). In addition, to this long-term regulation, a short-term regulation, on meal-to-meal basis, is secured by several gut hormones, such as cholecystokinin (CCK), peptides YY (PYY) and oxyntomodulin (OXM), released from the endocrine intestinal cells and acting via G-protein coupled receptors (GPCR) either on afferent nerves or directly on ARC neurons, which in turn inhibit expression and release of food-intake stimulating NPY and AgRP, thereby inducing satiety through inhibition of PVN. In contrast, during fasting, the GIT, especially oxyntic mucosa, expresses and releases appetite stimulating (orexigenic) factors such as ghrelin and orexins (OX) -A and OX-B, and cannabinoid CB1 agonist. Ghrelin activates growth-hormone secretagogue receptor (GHS-R) in hypothalamic ARC and stimulates growth hormone (GH) release and in vagal afferents to promote the expression and release of hypothalamic NPY and AgRP stimulating PVN and driving ingestive behaviour. The balance and interaction between anorexigenic (CCK, PYY, OXM) and orexigenic (ghrelin and OX) factors originating from GIT appears to play an important role in short-term regulation of food intake and growth hormone (GH) release. An impairment of this balance may result in disorders of feeding behaviour and weight gain (obesity) or weight loss (cachexia).

Spontaneous flow of bile through the human pancreatic duct in the absence of pancreatitis: nature's human experiment.

One hundred years ago E. L. Opie proposed two distinct hypotheses to address the pathogenesis of gallstone-induced pancreatitis. These hypotheses appear mutually exclusive. The first predicts that impediment to the flow of pancreatic juice causes pancreatitis (the pancreatic duct obstruction hypothesis), whereas the second predicts that bile flow into the pancreatic duct behind an impacted gallstone would trigger the onset of acute pancreatitis (the common-channel hypothesis). One of the more convincing arguments against the latter hypothesis is the observation that bile, when experimentally perfused through the pancreatic duct of dogs, does not induce pancreatitis. This experimental situation had spontaneously developed in the patient we describe here: a biliopancreatic fistula had permitted the continuous flow of bile through a large portion of the pancreas, which was associated with cholangitis but had apparently never led to pancreatitis. This patient's case would suggest that in humans, just as in experimental animals, bile flow through the pancreatic duct is not necessarily involved in the onset of gallstone-induced pancreatitis and lends further support to Opie's pancreatic duct obstruction hypothesis.

Discovery by Jaworski of Helicobacter pylori and its pathogenetic role in peptic ulcer, gastritis and gastric cancer.

The presence of spiral-shaped micro-organisms in the human stomach was described over 100 years ago by Polish clinical researcher, Professor W. Jaworski at Cracow Jagiellonian University. Their presence was then confirmed in animals by G. Bizzazero, but was not really taken seriously until the late 1970s, when J.R. Warren, a pathologist in Perth, Australia, noted the appearance of spiral bacteria overlaying gastric mucosa, chiefly over inflamed tissue. Warren and B.J. Marshall cultured these organisms in 1982 from 11 patients with gastritis and were able to demonstrate a strong association between the presence of Helicobacter pylori (H. pylori) and the finding of inflammation in gastric biopsies. People, who did not exhibit gastritis, also did not have the organism, a finding which was confirmed in a number of studies. Originally called Campylobacter pyloridis, the name was changed to Campylobacter pylori, and then later to Helicobacter pylori (H. pylori) as specific morphologic, structural, and genetic features indicated that it should be placed in a new genus. Marshall elegantly fulfilled Koch's postulates for the role of H. pylori in antral gastritis with the self administration of H. pylori, and also showed that it could be cured by use of antibiotics and bismuth salts. Most persons who are infected with H. pylori never suffer any symptoms related to the infection; however, H. pylori causes chronic active, chronic persistent, and atrophic gastritis in adults and children. Infection with H. pylori also causes duodenal and gastric ulcers. Infected persons have a 2- to 6-fold increased risk of developing gastric cancer and mucosal-associated-lymphoid-type (MALT) lymphoma compared with their uninfected counterparts. The role of H. pylori in non-ulcer dyspepsia remains unclear. These practical aspects of H. pylori were subjects of two international symposia organized by us in 1995 and 1997 in Cracow, helping to promote research and Polish consensus regarding treatment of H. pylori infection.

Detection of Helicobacter pylori specific DNA in human atheromatous coronary arteries and its association to prior myocardial infarction and unstable angina.

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 -/cagA-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 (69.6%) 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<0.001) was found. CONCLUSION: Identification of DNA in atherosclerotic plaques of patients with severe coronary artery disease supports the hypothesis that Helicobacter pylori infection may influence the development of atherosclerosis. Our results may indicate an direct involvement of Helicobacter pylori in the progression and instability of plaques in these patients.

Gastric electrical stimulation in intractable symptomatic gastroparesis.

BACKGROUND: The treatment of gastroparesis remains unsatisfactory despite prokinetic and anti-emetic drugs. Gastric electrical stimulation has been proposed as a therapeutic option. We have assessed the effect of gastric electrical stimulation on symptoms, medical treatment, body weight and gastric emptying in patients with intractable symptomatic gastroparesis in a non-placebo-controlled study. METHODS: In this multicenter study, 38 highly symptomatic patients with drug-refractory gastroparesis were enrolled. Patients first received temporary electrical stimulation using percutaneous electrodes. The 33 responders to temporary stimulation then underwent surgical implantation of a permanent stimulator. Severity of vomiting and nausea was assessed before and after stimulation. Patients were reassessed 3, 6, and 12 months after permanent implantation. RESULTS: With stimulation, 35/38 patients (97%) experienced >80% reduction in vomiting and nausea. This effect persisted throughout the observation period (2.9-15.6 months, 341 patient-months). Gastric emptying did not initially change, but improved in most patients at 12 months. At 1 year, the average weight gain was 5.5% and 9/14 patients initially receiving enteral or parenteral nutrition were able to discontinue it. CONCLUSION: Electrical stimulation of the stomach has an immediate and potent anti-emetic effect. It offers a safe and effective alternative for patients with intractable symptomatic gastroparesis.

Leptin in the control of gastric secretion and gut hormones in humans infected with Helicobacter pylori.

BACKGROUND: Leptin, a protein product of obese gene expressed primarily by adipocytes, provides feedback information on the size of energy stores to central OB receptors controlling the food intake, energy expenditure and body weight homeostasis. It has recently been detected in the rat stomach, especially after cholecystokinin (CCK) administration and in human stomach infected with Helicobacter pylori, but its role in gastric secretory functions in humans has not been revealed. This study was designed to determine the involvement of leptin in the control of basal, CCK- and meal-induced gastric H+ secretion and plasma gastrin and CCK levels in humans before and after an eradication of H. pylori. METHODS: Two groups (A and B) of subjects were used; group A (n = 7), for comparison of the effects of CCK and leptin on basal gastric H+ and plasma hormone (leptin, gastrin and CCK) levels, and group B (n = 6), for studies on the involvement of leptin in gastric secretory and plasma hormonal responses to vagal stimulation and gastric peptone meal before and after H. pylori eradication. RESULTS: In H. pylori-positive subjects, CCK (12-200 pmol kg(-1) h(-1)) given i.v. caused a dose-dependent increase of gastric H+ accompanied by a dose-dependent rise in plasma CCK and leptin levels. In contrast, leptin administered i.v. in graded doses (5-80 pmol kg(-1) h(-1)) resulted in a gradual inhibition of basal gastric H+ secretion and in adose-dependent increment in plasma leptin accompanied by an increase in plasma gastrin without alteration of plasma CCK level. Following eradication of H. pylori by 1-week triple therapy in group B patients, the infusion of CCK produced a significantly smaller increase in gastric H+ secretion and significantly smaller rise in plasma leptin as compared to those before the eradication. Cephalic phase stimulation of gastric secretion induced by modified sham-feeding in group B H. pylori-positive subjects increased gastric H+ secretion to about 40% of pentagastrin maximum without affecting plasma leptin, gastrin, or CCK level, while gastric peptone meal resulted in the increase in gastric H+ response reaching about 70% of pentagastrin maximum accompanied by a marked rise in plasma leptin, gastrin and CCK. The treatment with a standard dose of leptin (20 pmol kg(-1) h(-1)) failed to affect sham-feeding-induced gastric H+ secretion but reduced significantly the peptone meal-stimulated H+ secretion, while raising plasma gastrin in response to this meal. Plasma CCK under basal conditions and after sham-feeding was not affected, but plasma CCK response to gastric meal was significantly reduced by leptin infusion. Eradication of H. pylori did not affect basal or sham-feeding-induced H+ secretion but resulted in a significant fall in gastric meal-induced H+ and plasma leptin, gastrin and CCK levels. CONCLUSIONS: 1) The gastric meal and CCK enhance the release of leptin in H. pylori-positive patients and this leptin is capable of inhibiting basal and meal-stimulated gastric H+ secretion, while raising plasma gastrin and reducing the plasma CCK levels, and 2) the eradication of H. pylori reduces the postprandial gastric H+ and plasmagastrin responses as well as the release of leptin in response to CCK and meal.

Remodeling of extracellular matrix in gastric ulceration.

The quality of ulcer repair remains crucial for the stability of the injured tissue and for preventing recurrence. Therefore, we studied the temporo-spatial expression of the fibrillar and basement membrane collagens (types I, III, and IV), the collagenase MMP-2 as well as its inhibitor TIMP-1 before and after oral administration of basic fibroblast growth factor (b-FGF) over 30 days in acetic acid-induced rat gastric ulcers. The alterations and the exact location of the mRNA transcripts and their precipitated proteins were visualized by means of radioactive in situ hybridization and immunohistochemistry. Our data show that hybridization signals of procollagen I could first be identified 2 hours after ulcer induction. After 12 hours the ulcer was established and the mRNA was enhanced at the ulcer margin. After 24-48 hours the other procollagen transcripts were detected and all were further upregulated over the mesenchymal cells of all gastric layers up to 21 days, then declined at 30 days. In contrast, MMP-2 became prominent after 48 hours and up to 21 days. TIMP-1 was enhanced at 72 hours. After oral administration of b-FGF the transcriptional activity of the procollagens and MMP-2 was not significantly altered, while ulcer diameter was significantly reduced. We conclude that the early onset and long duration of collagens' expression points to their central structural and functional role in gastric ulcer healing. MMP-2 seems to be involved in both active ulceration and ECM remodeling. The timing of TIMP/MMP expression may be critical for proper restoration of gastric wall integrity.

Expression of decorin and biglycan in rat gastric tissue: effects of ulceration and basic fibroblast growth factor.

BACKGROUND: The small chondroitin/dermatan sulphate proteoglycans decorin and biglycan participate in organizing the network of collagen fibrils and interact with non-collagenous matrix proteins. In addition, via interactions with cytokines they are directly or indirectly involved in signalling, growth and cell differentiation. We aimed to analyse their expression in normal gastric tissue and during gastric ulcer healing. METHODS: Proteoglycan expression was studied by immunohistochemistry and in situ hybridization in acetic acid-induced gastric ulcers in rat during early phases and during chronic ulceration. The effects of treatment with an acid stable mutein of FGF-2 (bFGF) were also studied. RESULTS: In normal gastric tissue, both proteoglycans were most strongly expressed in the submucosal layer. However, some epithelial cells were positive for biglycan and, surprisingly, also for decorin. In the early phase after ulcer induction exclusively decorin became induced in the muscularis mucosae, while biglycan became detectable in this layer only after 2 weeks. There was no up-regulation of either proteoglycan in other layers, nor could an effect of FGF-2 treatment be seen. CONCLUSIONS: The expression of decorin could be observed for the first time in epithelial cells. Decorin, but not biglycan, appears as an early phase reactant in the muscularis mucosae in accordance with its putative role during angiogenesis and the prevention of apoptosis.

Role of reactive oxygen metabolites in aspirin-induced gastric damage in humans: gastroprotection by vitamin C.

BACKGROUND: The roles of active oxygen metabolites and anti-oxidative defenses in aspirin (ASA)-induced gastric damage have been little studied. AIM: We determined the effects of aspirin (400 mg b.d.) with or without vitamin C (480 mg b.d.) for 3 days on gastric mucosa in human volunteers. METHODS: Gastric injury was assessed endoscopically; gastric blood flow, reactive oxygen release (quantified by chemiluminescence), lipid peroxidation, myeloperoxidase, superoxide dismutase and glutathione peroxidase activity and intragastric vitamin C content were measured. Expression of superoxide dismutase and glutathione peroxidase mRNAs was assayed semi-quantitatively. RESULTS: ASA produced erosions, a marked increase in chemiluminescence, lipid peroxidation, and myeloperoxidase activity. It also resulted in a suppression of gastric blood flow, intragastric vitamin C levels, superoxide dismutase and glutathione peroxidase activities. The addition of vitamin C significantly attenuated gastric damage and reversed the effects of ASA on these parameters. Superoxide dismutase and glutathione peroxidase mRNAs were decreased in ASA-treated subjects; the addition of vitamin C restored their regular levels. CONCLUSIONS: (i) free radical-induced lipid peroxidation and suppression of antioxidizing enzymes play an important role in gastric damage induced by aspirin; (ii) increased myeloperoxidase activity suggests activated neutrophils to be the major source of these radicals; (iii) vitamin C protects against ASA-induced damage due to its anti-oxidizing activity.

Effect of Helicobacter pylori eradication on cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) expression during gastric adaptation to aspirin (ASA) in humans.

Gastric adaptation to aspirin is impaired in Helicobacter pylori infection, but the mechanisms underlying this phenomenon are unclear. In this study, we compared gastric mucosal expression of iNOS and COX-2 during 14 days of aspirin ingestion in the same subjects before and 3 months after eradication of H. pylori. Compared to non-infected controls, mucosal expression of COX-2 and iNOS was enhanced before and 3 months after eradication of H. pylori. During aspirin ingestion, mucosal expression of COX-2 remained unchanged before eradication of H. pylori, but increased gradually after successful antimicrobial treatment. Independent of H. pylori status, expression of iNOS increased at the beginning of aspirin intake, but then returned to initial values. We conclude that COX-2 but not iNOS might be involved in gastric adaptation to aspirin in humans and that this mechanism appears to be impaired in H. pylori infection.

Aspirin effects on gastric epithelial cell proliferation and cytokine expression.

Aspirin is known to cause gastric injury and to delay ulcer healing. The effects of aspirin on gastric epithelial cell function are heterogeneous; in contrast to injuring the mucosa, aspirin may also act beneficially by inducing adaptation; a mechanism that is poorly understood. We aimed to document the effects of different doses of aspirin on gastric epithelial cell function defined as proliferation, and secretion as well as mRNA expression of cytokines. Furthermore, we studied the effects of aspirin pretreatment on cytokine secretion as a potential element of gastric adaptation. The proliferative activity of three different gastric epithelial cell lines (AGS, KATO III, RGM-1) was assessed by (3)H-thymidine incorporation; secretion of growth factors PDGF-AB and VEGF into culture supernatant was documented by ELISA. mRNA transcripts of both cytokines were quantified by real time RT-PCR. Low doses of aspirin did not alter the proliferative dynamics in two of the three studied cell lines; high doses abolished proliferation. Secretion of PDGF-AB and VEGF increased during the first days of low dose aspirin exposition; higher concentrations led to a depletion of cytokines after an initial liberation in the case of VEGF, mRNA of which was also dose-dependently increased by aspirin. Seven-day pretreatment with low amounts of aspirin did not alter the secretory response of the epithelia caused by higher doses of this drug. The secretion of cytokines and proliferation of gastric epithelial cells are adversely effected by aspirin in a similarly dose-dependent fashion as the intended effects of this drug on platelet function and pain relief.

Eradication of Helicobacter pylori restores the inhibitory effect of cholecystokinin on gastric motility in duodenal ulcer patients.

BACKGROUND: Increased gastric emptying and defective action of endogenous cholecystokinin (CCK), that is known to inhibit this emptying, have been implicated in the pathogenesis of duodenal ulcer (DU). The aim of this double blind study was to assess whether CCK and somatostatin participate in the impairment of gastric motility in active DU patients before and after Helicobacter pylori eradication. METHODS: Tests were undertaken in 10 DU patients without or with elimination of the action of endogenous CCK using loxiglumide, a selective CCK-A receptor antagonist, before and 4 weeks after eradication of H. pylori with 1 week triple therapy that resulted in healing of all DUs tested. The gastric emptying rate after feeding was determined using the 13C-acetate breath test. Before each test, samples of gastric juice were obtained by aspiration using a nasogastric tube for determination of somatostatin using specific radioimmunoassay. RESULTS: Prior to H. pylori eradication gastric emptying half-time was 31 +/- 6 min in placebo-treated DU patients and this emptying rate was not significantly affected in tests after pretreatment with loxiglumide (10 mg/kg i.v.). Following eradication of H. pylori, in tests with placebo gastric emptying half-time was significantly longer (48 +/- 9 min) compared to that prior to H. pylori eradication. Pretreatment with loxiglumide in H. pylori eradicated DU patients significantly enhanced the gastric emptying rate with an emptying half-time of only 33 +/- 4 min. Eradication of H. pylori resulted in a significant increase in somatostatin concentration in gastric juice and loxiglumide significantly reduced this luminal somatostatin in H. pylori-eradicated subjects compared to values before anti-H. pylori therapy. CONCLUSIONS: 1) H. pylori infection in DU patients is accompanied by enhanced gastric emptying and reduction in luminal release of somatostatin; 2) the failure of loxiglumide to affect gastric emptying in H. pylori-infected DU patients might be attributed, at least in part, to the failure of endogenous CCK to control gastric motility due to deficient release of somatostatin; and 3) H. pylori-infected patients appear to exhibit a deficient somatostatin release by endogenous CCK that can be reversed by the eradication of H. pylori indicating that both CCK and somatostatin may contribute to normalization of gastric emptying following H. pylori eradication in DU patients.