Hydrogen sulfide (H2S) plays an important role in human physiology, exerting vasodilatory, neuromodulatory and anti-inflammatory effects. H2S has been implicated in the mechanism of gastrointestinal integrity but whether this gaseous mediator can affect hemorrhagic lesions induced by stress has been little elucidated. We studied the effect of the H2S precursor L-cysteine, H2S-donor NaHS, the H2S synthesizing enzyme (CSE) activity inhibitor- D,L-propargylglycine (PAG) and the gastric H2S production by CSE/CBS/3-MST activity in water immersion and restraint stress (WRS) ulcerogenesis and the accompanying changes in gastric blood flow (GBF). The role of endogenous prostaglandins (PGs) and sensory afferent nerves releasing calcitonin gene-related peptide (CGRP) in the mechanism of gastroprotection induced by H2S was examined in capsaicin-denervated rats and those pretreated with capsazepine to inhibit activity of vanilloid receptors (VR-1). Rats were pretreated with vehicle, NaHS, the donor of H2S and or L-cysteine, the H2S precursor, with or without the concurrent treatment with 1) nonselective (indomethacin) and selective cyclooxygenase (COX)-1 (SC-560) or COX-2 (rofecoxib) inhibitors. The expression of mRNA and protein for COX-1 and COX-2 were analyzed in gastric mucosa pretreated with NaHS with or without PAG. Both NaHS and L-cysteine dose-dependently attenuated severity of WRS-induced gastric lesions and significantly increased GBF. These effects were significantly reduced by pretreatment with PAG and capsaicin denervation. NaHS increased gastric H2S production via CSE/CBS but not 3-MST activity. Inhibition of COX-1 and COX-2 activity significantly diminished NaHS- and L-cysteine-induced protection and hyperemia. NaHS increased expression of COX-1, COX-2 mRNAs and proteins and raised CGRP mRNA expression. These effects of NaHS on COX-1 and COX-2 protein contents were reversed by PAG and capsaicin denervation. We conclude that H2S exerts gastroprotection against WRS-induced gastric lesions by the mechanism involving enhancement in gastric microcirculation mediated by endogenous PGs, sensory afferent nerves releasing CGRP and the activation of VR-1 receptors.

Naproxen belongs to commonly used NSAIDs associated with less cardiovascular toxicity than selective COX-2 inhibitors and other NSAIDs but its use is limited due to serious gastrointestinal (GI)-tract adverse effects. Novel H2S-releasing derivative of naproxen (ATB-346) was shown to inhibit COX-1 and prostaglandins (PGs) generation without causing mucosal damage unlike parent drug but whether ATB-346 can affect stress-induced gastric damage remains unknown. We compared ATB-346 vs naproxen and celecoxib and determined the role of reactive oxygen species and cytokines in the action of these NSAIDs against water immersion restraint stress (WRS)-induced gastric lesions in rats. WRS exposed animals were pretreated with (1) naproxen, (2) ATB-346 (0.5–40 m/kg i.g.), and (3) celecoxib (10 mg/kg i.g.) with or without ODQ (5 mg/kg i.p.), selective guanylate cyclase inhibitor or BCA (10 mg/kg i.p.), the inhibitor of H2S-synthesizing enzyme CSE. The number of gastric lesions was assessed by planimetry, the gastric blood flow (GBF) by H2-gas clearance technique, the malonyldialdehyde (MDA) concentration, MPO and PGE2 generation, the plasma level of IL-1beta and TNF-alpha and the expression of SOD and glutathione peroxidase (GPx) were determined by ELISA and RT-PCR. Pretreatment with ATB-346 dose-dependently reduced WRS-induced gastric lesions; the dose inhibiting these lesions by 50% being 29 mg/kg, caused significant rise in GBF and fall in MPO and MDA content. These effects of ATB-346 were reversed by cotreatment with ODQ but not BCA (p

acid-induced hyperemia, further declined by IND pretreatment (10 mg/kg, sc). These results suggest that although GPR43 activation enhances duodenal mucosal defenses by increased DBS via 5HT4 activation, GPR43 activation combined with COX inhibition may increase vulnerability of duodenal mucosa to gastric acid via 5HT3 activation and reduction of blood flow. Excess 5-HT release via GPR43 activation with accompanying acid exposure may be implicated in functional dyspepsia symptoms.

Melatonin is a potent reactive oxygen metabolite scavenger and antioxidant that has been shown to influence many physiological functions of the gastrointestinal (GI) tract including secretion, motility, digestion and absorption of nutrients. The role of melatonin in gastroduodenal defense and ulcer healing has been the subject of recent investigations. Melatonin produced in the GI mucosa plays an important role in protection against noxious agents thus contributing to the maintenance of GI integrity and to esophageal protection, gastroprotection and ulcer healing. This review was designed to summarize the involvement of melatonin, conventionally considered as a major hormone of the pineal gland, in the maintenance of gastric mucosal integrity, gastroprotection, ulcer healing and intestinal disorders. Melatonin was originally shown to attenuate gastric mucosal lesions but controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole, or rather gastrointestinal melatonin plays predominant role in gastroprotection. Intragastric and central administration of exogenous melatonin and L-tryptophan, this indoleamine precursor, affords protection against gastric hemorrhagic damage caused by the exposure of gastric mucosa to variety of non-topical and topical ulcerogens such as stress, ethanol and ischemia-reperfusion. The speed of ulcer healing in experimental animals and humans is accelerated by melatonin. This indoleamine could be also effective against the esophageal lesions provoked by reflux esophagitis in animal models and prevents the incidence of GERD in humans. The melatonin-induced gastroprotection is accompanied by an increase in gastric blood flow, plasma melatonin concentration, enhancement in mucosal generation of PGE2, luminal NO content and plasma gastrin levels. Melatonin scavenges reactive oxygen metabolites, exerts anti-oxidizing and anti-inflammatory actions and inhibits the formation of metalloproteinases- 3 and -9; both implicated in the pathogenesis of gastrointestinal injury and formation of gastric ulcers. Blockade of MT2 receptors by luzindole, significantly attenuated melatonin- and L-tryptophan-induced protection and increased the speed of ulcer healing and these effects were accompanied by an increase in the GBF and luminal content of NO suggesting that melatonin exhibits gastroprotection and hyperemia via activation of MT2 receptors and release of NO. The accumulated evidence indicates that the melatonin-induced gastroprotection and the enhancement in healing rate of gastric ulcers may involve the gastroprotective factors derived from the activation of PG/COX and NO/NOS systems as well as gastrin which also was shown to exhibit protective and trophic effects in the upper GItract. Interestingly, pinealectomy, which suppressed plasma melatonin levels, markedly exacerbated gastric lesions induced by topical and non-topical ulcerogens and these effects are counteracted by a concurrent supplementation with melatonin. Evidence is provided that exogenous melatonin and that converted from its precursor, L-tryptophan, attenuates acute gastric lesions and accelerates ulcer healing via interaction with MT2 receptors due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from NOS and COX-1 and COX-2 overexpression and activity. The pineal gland plays an important role in the limitation of gastric mucosal injury and the acceleration of ulcer healing via releasing endogenous melatonin, which attenuates oxidative stress and exerts anti-inflammatory action.

concentration (0.1 mM) declined blood flow.Co-superfusion of PA1 (0.1 mM) inhibited acid-induced hyperemia, further declined by IND pretreatment (10 mg/kg, sc).These results suggest that although GPR43 activation enhances duodenal mucosal defenses by increased DBS via 5HT 4 activation, GPR43 activation combined with COX inhibition may increase vulnerability of duodenal mucosa to gastric acid via 5HT 3 activation and reduction of blood flow.Excess 5-HT release via GPR43 activation with accompanying acid exposure may be implicated in functional dyspepsia symptoms.

Hydrogen sulfide (H 2 S) modulates a number of physiological actions including vasodilatation, inhibition of oxidant stress and apoptosis.H 2 S which is formed in gastric epithelium by the activity of two enzymes cysthationine γ-lyase (CSE) and cystathionine β-synthetase (CBS) has been shown to protect the gastric mucosa from ethanol-induced gastric lesions but whether its efficacy against acid-dependent stress-induced damage has been little studied.It also remains unknown how the expression of CSE and CBS contribute to the mucosal damage induced by stress in the presence or absence of H 2 S. We studied the effect of NaHS, a H 2 S-donor and L-cysteine, a H 2 S precursor on 1) gastric acid secretion in rats equipped with chronic gastric fistulas (GF) and water immersion restraint stress (WRS)-induced gastric lesions with intact and capsaicin-denervated sensory nerves (large dose 125 mg/kg s.c for 3 days).Rats were pretreated 30 min before the WRS with A) NaHS (5 mg/kg i.g); B) Lcysteine (10 mg/kg i.g.) with or without the combination with inhibitors of CSE activity, beta-cyano-L-alanine (BCA, 50 mg/kg i.g.) and D,L-propargylglycine (PAG 15 -80 mg/kg i.g.).The number of gastric lesions was measured by planimetry, the gastric blood flow (GBF) by H 2 -gas clearance technique and the mRNA expression of CSE, CBS, HIF-1 α and antioxidizing enzymes SOD and GPx was assessed by RT-PCR and Western Blot.NaHS (1-20 mg/kg) and cysteine (5-40 mg/kg) dose-dependently inhibited basal and histaminestimulated gastric acid secretion in GF rats.Exposure to WRS caused mucosal hemorrhagic lesions accompanied by the fall in GBF and upregulation of mRNA expression of CSE and CBS.Pretreatment with NaHS and L-cysteine significantly reduced WRS-induced gastric damage and significantly raised GBF and these effects were completely lost in animals with capsaicin denervation.BCA and PAG which dose-dependently augmented the number of WRS lesions, reversed the NaHS and L-cysteine-induced protection and hyperemia against WRS-induced gastric damage.Upregulation of mRNA expression for HIF-1 α mRNA, CSE and CBS in the gastric mucosa exposed to WRS was diminished by NaHS and L-cysteine and these effects were further enhanced in capsaicin-denervated rats treated with NaHS and L-cysteine.The increased expression of SOD and GPx mRNA was observed in NaHS-and L-cysteine-pretreated rats but not in those with capsaicin-denervation.We conclude that: 1) an increase in the expression of CSE and CBS, key enzymes in H 2 S biosynthesis, could compensate for the stress-induced impairment of gastric mucosal defense; 2) antisecretory activity of H 2 S donors contributes to the attenuation of acid-dependent injury caused by WRS, and 3) sensory mediators and antioxidizing enzymes SOD and GPx play an important role in H 2 S-induced gastroprotection against WRS-induced ulcerogenesis.

This review was designed to provide an update on the role of asymmetric arginine (ADMA), the endogenous inhibitor of nitric oxide (NO) synthase in the pathophysiology of the upper gastrointestinal (GI) tract. Numerous studies in the past confirmed that NO is a multifunctional endogenous gas molecule involved in most of the body organs’ functional and metabolic processes including the regulation of gastrointestinal (GI) secretory functions, motility, maintenance of GI integrity, gastroprotection and ulcer healing. NO is metabolized from L-arginine by enzymatic reaction in the presence of constitutive NO synthase. In upper GI tract, NO acts as a potent vasodilator known to increase gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, inhibits the gastric secretion and protects the gastric mucosa against the damage induced by a variety of damaging agents and corrosive substances. In contrast, ADMA first time described by Vallance and coworkers in 1992, is synthesized by the hydrolysis of proteins containing methylated arginine amino acids located predominantly within the nucleus of cells. This molecule has been shown to competitively inhibit NO synthase suggesting its regulatory role in the functions of vascular endothelial cells and systemic circulation in humans and experimental animals. Nowadays, ADMA is a potentially important risk factor for coronary artery diseases and a marker of cardiovascular risk. Increased plasma levels of ADMA have been documented in several conditions that are characterized by endothelial dysfunction, including hypertension, hypercholesterolemia, hyperglycemia, renal failure and tobacco exposure. The role of ADMA in other systems including GI-tract has been so far less documented. Nevertheless, ADMA was shown to directly induce oxidative stress and cell apoptosis in gastric mucosal cells in vitro and to contribute to the inflammatory reaction associated with major human pathogen to gastric mucosa, Helicobacter pylori (H.pylori). Infection of gastric mucosa with this germ or H. pylori water extract led to marked increase in the plasma concentration of ADMA and significantly inhibited bicarbonate secretion, considered as one of the important components of upper GI-tract defense system. When administered to rodents, ADMA aggravated gastric mucosal lesions injury induced by cold stress, ethanol and indomethacin and this worsening effect on gastric lesions was accompanied by the significant increase in the plasma level of ADMA. This exaggeration of gastric lesions by ADMA was coincided with the inhibition of NO, the suppression of gastric blood flow and excessive release of proinflammatory cytokine TNF-α. This metabolic analog of L-arginine applied to rats was exposed to water immersion and restraint stress and ischemiareperfusion, causing an elevation of plasma levels of ADMA and gastric MDA content, which is the marker of lipid peroxidation. These effects, including the rise in the plasma levels of ADMA in rats with stress and ischemia-reperfusion-induced gastric lesions, were attenuated by concomitant treatment with L-arginine, the substrate for NO-synthase, and superoxide dismutase (SOD), a reactive oxygen metabolite scavenger added to ADMA. We conclude that ADMA could be considered as an important factor contributing to the pathogenesis of gastric mucosal damage and inflammatory reaction in H. pylori-infected stomach due to inhibition of NO, suppression of GI microcirculation, and the proinflammatory and proapoptotic actions of this arginine analog. Keywords: Asymmetric dimethylarginine, nitric oxide, gastric damage, gastroprotection, Helicobacter pylori, stress, nonsteroidal antiinflammatory drugs, upper gastrointestinal (GI) tract, vascular endothelial cells, gastric mucosa

Melatonin (N-acetyl-5-methoxytryptamine) is a hormon secreted mostly by the pineal gland in the brain which maintains the body's circadian rhythm. Interestingly, this indol derivative is produced by enterochromaffin-like cells (ECL) in the gastrointestinal tract (GIT) in amount about 400 fold greater than detected in the pinealocytes. Previous studies revealed that melatonin exerts beneficial action against acute gastric damage induced by stress ethanol, aspirin and ischemia-reperfusion. Hyperglycemia, which is the main symptom of diabetes mellitus, is known to induce mitochondrial dysfunction and endoplasmic reticulum stress, both promoting the generation of reactive oxygen species (ROS). ROS were shown to exhibit higher activity than molecular oxygen under basal conditions due to unpaired electron in its outermost shell of electrons. ROS lead to damage of cellular proteins, nucleic acids and membrane polyunsaturated fatty lipids. In this study, we induced diabetes mellitus by the application of strep. tozocin in presence of gastric ulcers. Male Wistar rats were used in this model. 9 days after gastric ulcers and diabetes mellitus induction, groups of rats were treated with saline or melatonin (20 mg/kg i.g.). At the termination of the experiment, rats were anesthetized, abdomen was opened and gastric blood flow (GBF) was measured. Stomachs were removed for determination of gastric ulcers area by planimetry. Tissue samples were collected for biochemical assays. We demonstrated that melatonin significantly accelerates gastric ulcers healing with and without coexistence of diabetes mellitus. This effect was accompanied by increase of GBF level. Moreover, we observed an increase in superoxide dismutase (SOD) activity and an decrease in lipid peroxidation products concentration within gastric tissue homogenates of animals treated with melatonin, as compared with control group. Melatonin application accelerates gastric ulcers healing with and without presence of diabetes mellitus. We conclude that melatonin can physiologically regulate anti-oxidative enzymes activity and increase GBF level.

Nesfatin-1 belongs to a family of anorexigenic peptides, which are responsible for satiety and are identified in the neurons and endocrine cells within the gut. These peptides have been implicated in the control of food intake; however, very little is known concerning its contribution to gastric secretion and gastric mucosal integrity. In this study the effects of nesfatin-1 on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and restraint stress (WRS) were determined. Exogenous nesfatin-1 (5-40 mu g/kg i.p.) significantly decreased gastric acid secretion and attenuated gastric lesions induced by WRS, and this was accompanied by a significant rise in plasma NUCB2/nefatin-1 levels, the gastric mucosal blood flow (GBF), luminal NO concentration, generation of PGE(2) in the gastric mucosa, an overexpression of mRNA for NUBC2 and cNOS, as well as a suppression of iNOS and proinflammatory cytokine IL-1 beta and TNF-alpha mRNAs. Nesfatin-1-induced protection was attenuated by suppression of COX-1 and COX-2 activity, the inhibition of NOS with L-NNA, the deactivation of afferent nerves with neurotoxic doses of capsaicin, and the pretreatment with capsazepine to inhibit vanilloid VR1 receptors. This study shows for the first time that nesfatin-1 exerts a potent protective action in the stomach of rats exposed to WRS and these effects depend upon decrease in gastric secretion, hyperemia mediated by COX-PG and NOS-NO systems, the activation of vagal and sensory nerves and vanilloid receptors. (C) 2013 Elsevier Inc. All rights reserved.

The term cytoprotection pioneered by Robert and colleagues has been introduced to describe the remarkable ability of endogenous and exogenous prostaglandins (PGs) to prevent acute gastric hemorrhagic lesions induced by noxious stimuli such as ethanol, bile acids, hiperosmolar solutions and nonsteroidal anti-inflammatory agents such as aspirin. Since that time many factors were implicated to possess gastroprotective properties such as growth factors including epidermal growth factor (EGF) and transforming factor alpha (TGFα), vasodilatory mediators such as nitric oxide (NO) and calcitonin gene related peptide (CGRP) as well as appetite gut hormones including gastrin and cholecystokinin (CCK), leptin and recently ghrelin. This protective action of gut peptides has been attributed to the release of PG but question remains whether another peptide angiotensin, the classic component of the systemic and local renin-angiotensin system (RAS) could be involved in the mechanism of gastric integrity and gastroprotection. After renin stimulation, the circulating angiotensin I is converted to angiotensin II (ANG II) by the activity of the Angiotensin Converting Enzyme (ACE). The ANG II acting via its binding to two major receptor subtypes the ANG type 1 (AT1) and type 2 (AT2) has been shown be activated during stress and to contribute to the pathogenesis of cold stress- and ischemia-reperfusion-induced gastric lesions. All bioactive angiotensin peptides can be generated not only in systemic circulation, but also locally in several tissues and organs. Recently the new functional components of RAS, such as Ang-(1-7), Ang IV, Ang-(1-12) and novel pathways ACE2 have been described suggesting the gastroprotective role for the novel ANG II metabolite, Ang-(1-7). The fact that Ang-(1-7) is produced in excessive amounts in the gastric mucosa of rodents and that pretreatment by Ang-(1-7) exhibits a potent gastroprotective activity against the gastric lesions induced by cold-restraint stress suggests that this and possibly other vasoactive metabolites of ANG II pathway could be involved in the mechanism of gastric integrity and gastroprotection. This review summarizes the novel gastroprotective factors and mechanisms associated with metabolic fate of systemic and local RAS activation with major focus to recent advancement in the angiotensin pathways in the gut integrity.

The renin-angiotensin system (RAS) plays an important role in the maintenance of blood pressure, cardiovascular functions, body fluids homeostasis and kidney reabsorption process but little is known whether angiotensin derivative metabolites, the classic component of the systemic and local RAS exhibit gastroprotective and ulcer healing properties. Angiotensin II (Ang II) formed from angiotensin I due to angiotensin-converting enzyme (ACE) binds to the Ang type 1 (AT1) and type 2 (AT2) receptors, both implicated in the pathogenesis of cold stress- and ischemia-reperfusion-induced gastric lesions. The new functional components of RAS, such as Ang-(1-7), Ang IV, Ang-(1-12) and novel pathways ACE2 have been recently proposed to maintain physiological functions in the gastrointestinal (GI) tract. In this review, we describe the contribution of the Ang II metabolite, Ang-(1-7), to gastroprotection against stress-induced gastric lesions. First, Ang-(1-7) is produced in excessive amounts in the gastric mucosa of rodents, suggesting that this metabolite could be involved in the mechanism of gastric mucosal defense. Second, pretreatment with Ang(1-7) attenuated the gastric lesions induced by cold-restraint stress and raised the gastric blood flow, suggesting that this vasoactive metabolite of Ang II could be involved in the mechanism of gastric integrity and gastroprotection. This protective response can be demonstrated in experimental damage induced by acid-dependent (stress, ischemia-reperfusion) and acid-independent (ethanol) injury. We conclude that full understanding of the metabolic pathways of Ang I and Ang II conversion into vasoactive metabolites such as Ang-(1-7) in the stomach and the efficacy of Ang-(1-7) to attenuate gastric lesions induced by damaging agents may be useful in the treatment of upper Cl disorders including the mechanism of protection against mucosal damage induced by various ulcerogens and in the process of ulcer healing. Copyright (C) 2012 S. Karger AG, Basel

Melatonin is a major biosynthetic product of pineal gland exerting a potent antioxidant and the reactive oxygen metabolites scavenging activities but the mechanism of formation of this indole at extrapineal sources has not been fully elucidated. It is known that the gastrointestinal (GI)-tract plays an important role as a source of melatonin synthesis but the conversion of L-tryptophan into melatonin in the GI-tract of experimental animals and humans should be further examined. In this study, the conversion of L-tryptophan to melatonin was determined in the serum collected from rats administered intragastrically with this amino acid acting as melatonin precursor. For this purpose, a simple, sensitive and reliable method was developed for simultaneous determination of six L-tryptophan metabolites in rat serum, namely, 5-hydroxytryptamnie (5-HT), 5-hydroksytryptophan (5-HTR), kynurenin (KYN), antranilic acid (AA), indole-3-acetic acid (IAA) and melatonin that were analyzed in one chromatographic run by high-performance liquid chromatography (HPLC) with UV and native fluorimetric detection with multiple wavelengths. We used nucleosil Supelco C18 5 μm 4.6 mm x 250 nm column with the standard mobile phase consisting of solvent A (water/0.1% trifluoroacetic acid (TFA) and solvent B (methanol/0.1% TFA) in gradient elution. Fifty five rats received vehicle (saline) of L-tryptophan (50 mg/kg) or melatonin (50 mg/kg) by means of intragastric gavage and they were anesthetized and sacrificed at 0, 10, 20, 30, 60, 120 or 240 min upon L-tryptophan or melatonin administration for the venous blood withdrawal. The serum collected samples were kept on ice for the HPLC determination. The average recovery of 5-HT, 5-HRT, KYN, AA, TRP, IAA, and melatonin were 99±3%, 97±1.5%, 94±2.5%, 99±2.46, 98±1.5 and 98±2%, respectively. We conclude that 1) L-tryptophan is converted to melatonin in the GI-tract during the day when the pineal gland synthesis is inhibited, and 2) the reverse phase high performance liquid chromatography (RP-HPLC) is a new sensitive and reliable method that could be successfully applied to the study of kinetics and metabolism of L-tryptophan in GI-tract.

The pathogenesis of reflux esophagitis results from an imbalance between aggressive factors damaging the esophagus and the natural antireflux barriers. The local renin-angiotensin system (RAS) exists in esophageal mucosa, however, its contribution to the mechanism of esophageal integrity has not been clarified. Angiotensin-(1-7) (Ang-(1-7)) which is an important component of the RAS, was recently implicated in gastroprotection but its effect on damage induced by reflux esophagitis (RE) has not been explored. We evaluated the possible protective effect of Ang-(1-7) against mucosal lesions induced by the acute RE induced in anesthetized rats by ligating of the pylorus and the limiting ridge (transitional region between the forestomach and the corpus of stomach). Rats were pretreated 30 min before induction of RE either with 1) vehicle (saline), 2) Ang-(1-7) (5 75 μg/kg i.p.), 3) Ang-(1-7) (50 μg/ kg i.p.) without and with A 779 (2.5 mg/kg i.p.), a selective antagonist of Ang-(1-7) Mas receptor, 4) Ang 1-7 (50 μg/kg i.p.) without and with capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves, and 5) antisecretory treatment with PPI inhibitor, pantoprazole (10 mg/kg i.g.). Four hrs after induction of esophagitis, the damage was graded with mucosal lesion index (LI) from 0-6, the esophageal blood flow (EBF) was determined by H2-gas clearance technique and the RT-PCR expression and plasma levels of proinflammatory cytokines IL-1β and TNF-α was determined by ELISA. The esophageal LI and wet weight in esophagitis were significantly higher and the EBF was decreased by 35% as compared with the intact mucosa Pretreatment with Ang-(1-7) which in intact rats increased the EBF by 25% without any damage and alteration in plasma IL-1β and TNF-α levels, almost completely prevented, similarly as pantoprazole, the esophageal mucosal injury and significantly increased EBF by about 18% as compared to that in vehicle-controls with RE. The esophagoprotective effects and the rise in EBF induced by Ang-(1-7) were completely abolished by A779. Capsaicin denervation which by itself failed to affect the esophageal lesions, also reduced the esophagoprotective and hyperemic effects of Ang-(1-7) and both protection and hyperemia were restored by co-treatment with CGRP (10 μg/kg s.c.). Ang(1-7) significantly decreased the RE-induced increase in mRNA expression and plasma IL1β and TNF-α levels and these effects were also abolished by pretreatment with A779 and capsaicin-sensory denervation. We conclude that Ang-(1-7), a potent vasodilatatory member of angiotensin family peptides, exhibits esophagoprotection against the esophageal damage induced by reflux esophagitis via mechanism involving activation of Mas receptor, the stimulation of sensory nerves releasing of vasodilatatory CGRP and the suppression of expression and release of IL-1β and TNF-α.

Previous studies revealed that prostaglandins contribute to the mechanism of maintenance of gastrointestinal integrity and mediate various physiological aspects of mucosal defense. The suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after administration of various NSAID including aspirin (ASA). A worldwide use of ASA is now accepted due to its remarkable analgesic, antipyretic and anti-thrombotic prophylactics against myocardial infarct and coronary disorders despite the fact that the use of NSAIDs is associated with the risk of gastrointestinal bleedings, haemorrhagic lesions and ulcerations. It has become clear that other mediators besides prostaglandins can similarly act to protect the gastrointestinal mucosa of experimental animals and humans from injury induced by ASA. For instance, nitric oxide (NO) released from vascular epithelium, epithelial cells of gastrointestinal tract and sensory nerves can influence many of the same components of mucosal defense as do prostaglandins. This review was designed to provide an updated overview based on the experimental and clinical evidence on the involvement COX-2 derived products, lipoxins in the mechanism of gastric defense, gastroprotection and gastric adaptation to ASA. Lipoxins were recently considered as another group of lipid mediators that can protect the stomach similarly as NO-donors known to exert protective influence on the stomach from the injury under condition where the mucosal prostaglandin levels are suppressed. The new class of NO-releasing NSAIDs, including NO-aspirin or NO-naproxen, represent a very promising approach to reducing the toxicity of their parent NSAIDs. Aspirin-triggered lipoxin (ATL) synthesis, via COX-2, acts to reduce the severity of damage induced by this NSAID. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Evidence presented in this review documents that ATL also play in important role in gastric adaptation during chronic ASA administration. Suppression of COX-2 activity by selective COX-2 inhibitors such as rofecoxib or celecoxib was shown to abolish the production of ATL and to diminish the gastric tolerability of ASA and gastric adaptation developed in response to repetitive administration of this NSAID. Synthetic analogues of lipoxins as well as newer class of NSAIDs releasing NO may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAIDs ingestion.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for their anti-inflammatory, analgesic and antipyretic effects, however their use is associated with the broad spectrum of side effects observed in human as well as the experimental animals. Despite damaging activity of NSAIDs in upper gastrointestinal (GI) tract, these drugs exert deleterious influence in lower GI tract, including colon. The role of GI microflora in the pathogenesis of NSAIDs-induced experimental colonic damage is not completely understood. The aim of this study was 1) to evaluate the relative importance of the GI microflora on the experimental colonic damage in the presence of caused by NSAID, and 2) to assess the efficacy of antibiotic treatment with ampicillin on the process of healing of colitis. We compared the effect of vehicle, ASA applied 40 mg/kg intragastrically (i.g.) or the selective cyclooxygenase (COX)-2 inhibitor, celecoxib (25 mg/kg i.g.) without or with ampicillin treatment (800 mg/kg i.g.) administered throughout the period of 10 days, on the intensity of TNBS-induced colitis in rats. The severity of colonic damage, the alterations in the colonic blood flow (CBF) and myeloperoxidase (MPO) activity, the mucosal expression of TNF-α, IL-1β, COX-2, VEGF and iNOS and the plasma concentration of TNF-α and IL-1β were assessed. In all rats, the faeces samples as well as those from the colonic mucosa, blood, liver and spleen underwent microbiological evaluation for intestinal bacterial species including Escherichia coli and Enterococcus spp. The administration of TNBS resulted in macroscopic and microscopic lesions accompanied by the significant fall in the CBF, an increase in tissue weight and 4-5-fold rise in the MPO activity and a significant increase in the plasma IL-1β and TNF-α levels. ASA or celecoxib significantly increased the area of colonic lesions, enhanced MPO activity and caused the marked increase in colonic tissue weight and plasma IL-1β and TNF-α levels, as well as an overexpression of mRNA for IL-1β and TNF-α, COX-2, VEGF and iNOS in the colonic tissue. ASA and coxib also resulted also in a significant increase of E. coli counts in the stool at day 3 and day 10 day of the observation compared with the intact rats. Moreover, E. coli translocation from the colon to the blood and extraintestinal organs such as liver and spleen in the group of rats treated without or with ASA and coxib. E. coli was the most common bacteria isolated from these organs. Treatment with ampicillin significantly attenuated the ASA- or celecoxib-induced increase in plasma levels of IL-1β and TNF-α and suppressed the mucosal mRNA expression for IL-1β and TNF-β, COX-2, iNOS and VEGF in the colonic mucosa. Ampicillin administration caused a significant fall in the number of E. coli in the faeces at day 3 and day 10 of observation in ASA- and coxib-treated rats with colitis. Antibiotic therapy markedly reduced bacterial translocation to the colonic tissue and the extraintestinal organs such as the liver and spleen. We conclude that administration of ASA and to lesser extent of celecoxib, delays the healing of experimental colitis and enhances the alterations in colonic blood flow, proinflammatory markers such as IL-1β, TNF-α, COX-2, iNOS and VEGF and increased intestinal mucosal permeability resulting in the intestinal bacterial translocation to the blood, spleen and liver. Antibiotic treatment with ampicillin is effective in the diminishing of the severity of colonic damage, counteracts both the NSAID-induced fall in colonic microcirculation and bacterial E.coli translocation to the extraintestinal organs.

Introduction: Development of gastroesophageal reflux disease (GERD) takes place when the balance between irritant and protecting mucous membrane mechanisms is impaired. The chronic inflammation of the oesophagus results in serious complications including Barrett's metaplasia progression into esophageal adenocarcinoma. In the last few years the incidence of chronic gastroesophageal reflux disease has been increasing, especially in highly developed countries, and this chronic disease may result in the development of oesophageal adenocarcinoma, which is also observed with increased frequency.Aim: Creation and comparison of chronic gastroesophageal reflux disease models, as well as estimation of their suitability for the investigation of the process of natural carcinogenesis in the oesophagus.Material and methods: Ninety Wistar rats were used for the study on development of chronic oesophageal inflammation. Three major groups, A side to side anastomosis, B side to end anastomosis and C side to end anastomosis with total gastrectomy, were selected. In each group a different operation technique was performed to induce chronic oesophageal reflux. Groups A and B were characterized by mixed gastroduodenal reflux while group C included animals with only alkaline reflux.Results: In all three experimental models of GERD the morphological changes of the oesophageal mucosa were observed by gross inspection starting 1 month after the surgery. Under microscopic investigation chronic inflammation of the oesophageal mucosa progressing to Barrett's metaplasia and in some cases to cancer was also confirmed. Conclusions: All experimental animal models developed due to GERD are highly reproducible and exhibit low mortality. Macroscopic and microscopic assessment of oesophageal inflammation that developed in response to experimental reflux confirmed that these models are suitable and useful for determination of the pathogenesis of Barrett's related oesophageal cancer.