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Central venous catheters (CVC) are used in many clinical settings for a variety of indications. We performed a systematic literature review concerning case reports of retained calcified fibrin sheaths after dialysis CVC removal. The aim of our study was to systematize the knowledge regarding clinical management of this phenomenon, placing special emphasis on diagnostic radiological features in different imaging modalities, including chest radiography, echocardiography, computed tomography, and magnetic resonance imaging. We discuss the most common risk factors associated with this CVC complication. In our review, we found eight cases of hemodialysis patients. The most common risk factors associated with calcified fibrin sheath formation in the analyzed cases were pro-thrombotic and pro-calcification factors related to patient comorbidities, and prolonged catheter dwell time. Differentiating between a calcified fibrin sheath (present in about 6% of patients with long-term indwelling CVC as diagnosed by computed tomography) and a retained catheter tip can be challenging. The initial diagnosis based on imaging methods was incorrect in most of the analyzed cases. This suggests that some cases of retained fibrin sheaths may remain undetected or misinterpreted. This is important in patients with known pro-thrombotic and pro-calcification risk factors and prolonged catheter dwell time. Therefore, implementation of preventive strategies, familiarity with radiological findings of this phenomenon, comparison with previous imaging studies, and an overall comprehensive assessment with clinical data is imperative.

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.

Some recent studies indicate that cannabis may induce acute pancreatitis in humans and administration of anandamide increases the severity of acute pancreatitis; whereas another study exhibits some therapeutic effects in acute pancreatitis. Aim of the present study was to discover what is the reason for these opposite confusing results and to determine the role of sensory nerves in this effect. Acute pancreatitis was induced in rats by cerulein. Anandamide, an endogenous cannabinoid, was administered i.p. (1.5 micromol/kg) before or 2 h after cerulein administration. Stimulation of sensory nerves was performed by capsaicin (0.5 mg/kg s.c.). In rats treated with combination of anandamide plus capsaicin, capsaicin was given 10 min after each dose of anandamide. After the last injection of cerulein or 4 h later, the study was terminated. In our study we observed that stimulation of sensory nerves by capsaicin, before administration of cerulein, reduced the severity of acute pancreatitis. Anandamide, administered alone before cerulein, increased pancreatic damage in acute pancreatitis. Anandamide administered in combination with capsaicin, before cerulein, abolished the capsaicin-induced protective effect on the pancreas. Opposite effects were observed when capsaicin and anandamide were administered after injection of cerulein. Capsaicin increased the severity of acute pancreatitis, whereas anandamide reduced pancreatic damage and reversed the deleterious effect of capsaicin. We conclude that the effect of anandamide on the severity of acute pancreatitis depends on the phase of this disease. Administration of anandamide, before induction of pancreatitis, aggravates pancreatic damage; whereas anandamide administered after induction of pancreatitis, reduces the severity of acute pancreatitis. Sensory nerves are involved in the mechanism of this biphasic effect of anandamide.

Orexin-A, identified in the neurons and endocrine cells in the gut, has been implicated in control of food intake and sleep behavior but little is known about its influence on gastric secretion and mucosal integrity. The effects of orexin-A on gastric secretion and gastric lesions induced in rats by 3.5 h of water immersion and restraint stress (WRS) or 75% ethanol were determined. Orexin-A (5-80 microg/kg i.p.) increased gastric acid secretion and attenuated gastric lesions induced by WRS and this was accompanied by the significant rise in plasma orexin-A, CGRP and gastrin levels, the gastric mucosal blood flow (GBF), luminal NO concentration and an increase in mRNA for CGRP and overexpression of COX-2 protein and the generation of PGE(2) in the gastric mucosa. Orexin-A-induced protection was abolished by selective OX-1 receptor antagonist, vagotomy and attenuated by suppression of COX-1 and COX-2, deactivation of afferent nerves with neurotoxic dose of capsaicin, pretreatment with CCK(2)/gastrin antagonist, CGRP(8-37) or capsazepine and by inhibition of NOS with L-NNA. This study shows for the first time that orexin-A exerts a potent protective action on the stomach of rats exposed to non-topical ulcerogens such as WRS or topical noxious agents such as ethanol and these effects depend upon hyperemia mediated by COX-PG and NOS-NO systems, activation of vagal nerves and sensory neuropeptides such as CGRP released from sensory nerves probably triggered by an increase in gastric acid secretion induced by this peptide.

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.

Ghrelin, a 28-amino-acid peptide produced predominantly by oxyntic mucosa has been reported to affect the pancreatic exocrine function but the mechanism of its secretory action is not clear. The effects of intraduodenal (i.d.) infusion of ghrelin on pancreatic amylase outputs under basal conditions and following the stimulation of pancreatic secretion with diversion of pancreato-biliary juice (DPBJ) as well as the role of vagal nerve, sensory fibers and CCK in this process were determined. Ghrelin given into the duodenum of healthy rats at doses of 1.0 or 10.0 microg/kg increased pancreatic amylase outputs under basal conditions or following the stimulation of pancreatic secretion with DPBJ. Bilateral vagotomy as well as capsaicin deactivation of sensory fibers completely abolished all stimulatory effects of luminal ghrelin on pancreatic exocrine function. Pretreatment with lorglumide, a CCK(1) receptor blocker, reversed the stimulation of amylase release produced by intraduodenal application of ghrelin. Intraduodenal ghrelin at doses of 1.0 or 10.0 microg/kg increased plasma concentrations of CCK and ghrelin. In conclusion, ghrelin given into the duodenum stimulates pancreatic enzyme secretion. Activation of vagal reflexes and CCK release as well as central mechanisms could be implicated in the stimulatory effect of luminal ghrelin on the pancreatic exocrine functions.

Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, has been shown to exhibit gastroprotective properties. The aim of present study was to determine whether ghrelin administration protects the pancreas against ischemia/reperfusion-induced pancreatitis and, if so, what is the role of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in this effect. In sham-operated or hypophysectomized rats, acute pancreatitis was induced by pancreatic ischemia followed by reperfusion. Ghrelin (4, 8 or 16 nmol/kg/dose) or IGF-1 (20 nmol/kg/dose) were administered intraperitoneally twice before and during induction of acute pancreatitis. In pituitary-intact rats, treatment with ghrelin attenuated the development of ischemia/reperfusion-induced pancreatitis and this effect was associated with partial reversion of the pancreatitis-evoked decrease in serum concentration of GH and IGF-1. Hypophysectomy eliminated GH from the serum, reduced serum IGF-1 concentration by 90% and increased in the severity of ischemia/reperfusion-induced pancreatitis. Administration of ghrelin was without any beneficial effect in this group of rats. In contrast, administration of IGF-1 in hypophysectomized rats reduced the severity of ischemia/reperfusion-induced pancreatitis in hypophysectomized rats. We conclude that administration of ghrelin inhibits the development of ischemia/reperfusion-induced pancreatitis and this effect is mediated by its influence on the release of GH and IGF-1.

Ghrelin is involved in the control of food intake, but its role in gastroprotection against the formation of gastric mucosal injury has been little elucidated. We studied the effects of peripheral (i.p.) and central (i.c.v.) administration of ghrelin on gastric secretion and gastric mucosal lesions induced by 3 h of ischemia/reperfusion (I/R) with or without inhibition of ghrelin growth hormone secretagogue type 1a receptor (GHS-R1a) by using ghrelin antagonist, d-Lys(3)-GHRP-6; blockade of cyclooxygenase (COX)-1 (indomethacin, SC560 [5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-trifluoromethylpyrazole]) and COX-2 (rofecoxib); and bilateral vagotomy or capsaicin denervation. I/R produced typical gastric erosions, a significant fall in the gastric blood flow (GBF), an increase in gastric myeloperoxidase (MPO) activity and malonyldialdehyde (MDA) content, and the up-regulation of mucosal ghrelin mRNA. Ghrelin dose-dependently increased gastric acid secretion and significantly reduced I/R-induced gastric erosions, while producing a significant rise in the GBF and mucosal PGE(2) generation and a significant fall in MPO activity and MDA content. The protective and hyperemic activities of ghrelin were significantly attenuated in rats pretreated with d-Lys(3)-GHRP-6 and capsaicin denervation and completely abolished by vagotomy. Indomethacin, SC560, and rofecoxib, selective COX-1 and COX-2 inhibitors, attenuated ghrelin-induced protection that was restored by supplying the methyl analog of prostaglandin (PG) E(2). The expression of mRNA for COX-1 was unaffected by ghrelin, but COX-2 mRNA and COX-2 protein were detectable in I/R injured mucosa and further up-regulated by exogenous ghrelin. We conclude that ghrelin exhibits gastroprotective and hyperemic activities against I/R-induced erosions, the effects that are mediated by hormone activation of GHS-R1a receptors, COX-PG system, and vagal-sensory nerves.

Ghrelin, identified in the gastric mucosa, has been involved in the control of food intake and growth hormone (GH) release, but whether this hormone influences the gastric secretion and gastric mucosal integrity has been little elucidated. We compared the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of ghrelin on gastric secretion and gastric lesions induced in rats by 75% ethanol or 3.5 h of water immersion and restraint stress (WRS) with or without suppression of nitric oxide (NO)-synthase or functional ablation of afferent sensory nerves by capsaicin. The number and the area of gastric lesions was measured by planimetry, the GBF was assessed by the H2-gas clearance method and blood was withdrawn for the determination of the plasma ghrelin and gastrin levels. In addition, the gastric mucosal expression of mRNA for CGRP, the most potent neuropeptide released from the sensory afferent nerves, was analyzed in rats exposed to WRS with or without ghrelin pre-treatment. Ghrelin (5-80 microg/kg i.p. or 0.6-5 microg/kg i.c.v.) increased gastric acid secretion and attenuated gastric lesions induced by ethanol and WRS. This protective effect was accompanied by a significant rise in the gastric mucosal blood flow (GBF), luminal NO concentration and plasma ghrelin and gastrin levels. Ghrelin-induced protection was abolished by vagotomy and significantly attenuated by L-NNA and deactivation of afferent nerves with neurotoxic dose of capsaicin. The signal for CGRP mRNA was significantly increased in gastric mucosa exposed to WRS as compared to that in the intact gastric mucosa and this was further enhanced in animals treated with ghrelin. We conclude that central and peripheral ghrelin exerts a potent protective action on the stomach of rats exposed to ethanol or WRS, and these effects depend upon vagal activity and hyperemia mediated by the NOS-NO system and CGRP released from sensory afferent nerves.

Candida albicans frequently inhabits the gastrointestinal tract of humans leading to gastrointestinal candidiasis, especially following suppression of gastric acidity, but studies on the relation between this fungal infection and gastric pathology are limited due to lack of convenient animal models resembling Candida infection in humans. MATERIAL AND METHODS. We compared the effects of C. albicans and vehicle inoculation on gastric secretion and healing of gastric ulcers induced by acetic acid in rats treated with 1) ranitidine (30 mg kg(-1) day(-1) s.c.) and 2) aspirin (ASA) (60 mg kg(-1) day(-1) i.g.) with or without probiotic bacteria Lactobacillus acidophillus. At day 0 and at 4, 15 and 25 days after ulcer induction, the ulcer area, the gastric blood flow (GBF), the quantitative gastric cultures of Candida and the expression of mRNAs for pro-inflammatory cytokines IL-1beta and TNF-alpha and growth factors EGF and TGFalpha were assessed in the gastric mucosa.Gastric acid output was reduced by over 40% soon after Candida inoculation and this effect persisted during all time intervals tested. The area of ulcers in control rats significantly decreased at day 15 and the ulcers disappeared almost completely after 25 days of their induction. In contrast, the ulcers were present until day 25 in Candida-inoculated rats followed by a fall in GBF and a rise in plasma gastrin levels, these effects being significantly attenuated by the co-treatment with Lactobacillus. Candidiasis was accompanied by up-regulation of mRNA for IL-1beta, TNF-alpha, EGF and TGFalpha and a significant increment in plasma IL-1beta and TNF-alpha levels.1) Persistent colonization with Candida could be achieved in rats treated with antisecretory agents or non-steroidal anti-inflammatory drugs (NSAIDs) such as ASA; 2) candidiasis reduces gastric acid secretion, while delaying ulcer healing possibly due to the impairment in GBF in the ulcer area and enhanced expression and release of IL-1beta and TNFalpha and 3) probiotic therapy could be useful in the treatment against the deleterious action of fungal infection on the healing of pre-existing gastric ulcers.

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.

Melatonin, an antioxidant, protects the pancreas against acute inflammation but, although this indole is released mainly at night, no study has been undertaken to determine circadian changes of plasma melatonin levels and the severity of acute pancreatitis. The aims of this study were: (a) to compare the severity of caerulein-induced pancreatitis (CIP) produced in the rat during the day and at the night, and (b) to assess the changes of plasma melatonin level and the activity of an antioxidative enzyme; superoxide dismutase (SOD), in the pancreas subjected to CIP during the day time and at night without or with administration of exogenous melatonin or its precursor; l-tryptophan. Rats were kept in 12 hr light/dark cycle. CIP was induced by subcutaneous infusion of caerulein (5 μg/kg/hr for 5 hr). Melatonin (5 or 25 mg/kg) or l-tryptophan (50 or 250 mg/kg) was given intraperitoneally 30 min prior to the start of CIP. CIP induced during the day time was confirmed by histological examination and manifested by pancreatic edema, and rises of amylase and lipase plasma activities (by 400 and 500%, respectively), whereas pancreatic SOD, pancreatic blood flow (PBF) and oxygen consumption by pancreatic tissue (VO2) were decreased by 70, 40 and 45%, respectively, as compared with the appropriate controls. All morphological and biochemical parameters of CIP induced at night were significantly less severe, compared with those recorded during the light phase. Plasma melatonin immunoreactivity was significantly higher during the night, than during the day, especially following administration of melatonin or its precursor, which reversed all manifestations of CIP. In conclusion, a circadian rhythm modulates the severity of CIP with a decrease of pancreatitis severity during the night compared with that at the day time and this may be due to the increased plasma level of melatonin and higher activity of SOD in the pancreas.

Melatonin, considered as a main pineal product, may be also synthetized in the gastrointestinal tract from L-tryptophan. Melatonin has been recently shown to affect insulin release and its receptors have been characterized in the pancreas however, the effects of melatonin on the pancreatic enzyme secretion have not been examined. The aim of this study was to investigate the effects of melatonin or L-tryptophan on amylase secretion in vivo in anaesthetized rats with pancreato-biliary fistulas, and in vitro using isolated pancreatic acini. Melatonin (1, 5 or 25 mg/kg) or L-tryptophan (10, 50 or 250 mg/kg) given to the rats as a intraperitoneal (i.p.) bolus injection produced significant and dose-dependent increases in pancreatic amylase secretion under basal conditions or following stimulation of enzyme secretion by diversion of bile-pancreatic juice. This was accompanied by a dose-dependent rise in melatonin plasma level. Stimulation of pancreatic enzyme secretion caused by melatonin or L-tryptophan was completely abolished by vagotomy, deactivation of sensory nerves with capsaicin or pretreatment with CCK 1 receptor antagonists (tarazepide or L-364,718). Pretreatment with luzindole, an antagonist of melatonin MT 2 receptor failed to affect melatonin- or L-tryptophan-induced amylase secretion. Administration of melatonin (1, 5 or 25 mg/kg i.p.) or L-tryptophan (10, 50 or 250 mg/kg i.p.) to the rats resulted in the dose-dependent increase of cholecystokinin (CCK) plasma immunoreactivity. Enzyme secretion from isolated pancreatic acini was not significantly affected by melatonin or L-tryptophan used at doses of 10 -8 -10 -5 M. We conclude that exogenous melatonin, as well as that produced endogenously from L-tryptophan, stimulates pancreatic enzyme secretion in vivo while increasing CCK release. Stimulatory effect of melatonin or L-tryptophan on the exocrine pancreas involves vagal sensory nerves and the CCK release by these substances.

Ghrelin is an important hormone involved in the control of the human appetite center. Recently, protective properties of this hormone have been recognized in various models of impairment of the gastric mucosa, including stress, ischemia and reperfusion (I/R). Ghrelin is predominantly secreted by the gastric mucosa of stomach, but there are other sources of ghrelin, for example in the hypothalamus and various parts of the central nervous system (CNS) that should be taken into consideration. This hormone exerts biological effects via the activation of growth hormone secretagogue receptor (GHSR), the presence of which was confirmed in different parts of the gastrointestinal (GI) tract and midbrain structures. Although substantial evidence of the divergent biological effects of ghrelin and the mechanism of its action has been emphasized, the precise mechanisms of ghrelin which affords GI protection is still unclear. Particularly, there is a sparse amount of evidence concerning its action on the GI system. The major aim of the present study was to evaluate the importance of peripherally and centrally administered ghrelin at different times of the ischemia and reperfusion (I/R period in the modulation of resistance of the intestinal mucosa to the injury induced by ischemia and subsequent reperfusion. Secondly, we wanted to evaluate the possible mechanism of the action of ghrelin with a particular focus on its influence on the intestinal blood flow. Male Wistar rats were divided into 4 series (A-D) of the experimental groups (n=7). In series A the importance of peripherally administered ghrelin at different time of I/R period was studied. In series B the importance of centrally administered ghrelin at different time of I/R period was evaluated. In series C and D, the mechanisms of peripherally and centrally administered hormone were examined, respectively. Two models of the I/R period were selected: short lasting (30/60 min) and long lasting (60/120 min). The following drugs were used: ghrelin (50 μg/kg i.p. or 1 nmol in 10 μl i.c.v.), 6 hydroxy dopamine (50 mg/kg i.p.), nadolol (0.5 mg/kg i.p.), calcitonin gene related peptide fragment (CGRP(8-37), 100 μg /kg i.p.), capsaicin (5-10 mg/100 ml solution s.c.). The mesenteric blood flow (MBF-ml/min), the intestinal microcirculatory blood flow (LDBF-PU), the arterio-venous oxygen difference (AVO(2)-ml/O(2)/100 ml blood), and the intestinal oxygen uptake (VO(2)) in ml O(2)/min were measured. Mucosal impairment was assessed planimetrically with the use of a digital photo analyzer (LA) and histologically with the use of the six-point Park/Chiu scale. Peripheral administration of ghrelin evoked marked increase of MBF and LDBF by 42% and 48%, respectively, with significant reduction of LA by 38%. When ghrelin was administered at the beginning of the reperfusion period during the short I/R period or prior to the long lasting I/R period, the vascular reactions and protective effects were reduced, but not completely abolished. The central administration of ghrelin before the short I/R period significantly increased the MBF and LDBF by about 32% and 35%, respectively, as well as LA reduction by about 20% in comparison to the control group. However, when ghrelin was administered prior to the long I/R period or after the onset of completed ischemia, neither vascular nor protective effects were noticed. Sensory denervation and the blockade of the CGRP1 receptors totally blocked the protective and hyperemic effects of the peripherally administered ghrelin. Selective blockade of the adrenergic system or blunting of the vagal nerves (vagotomy) significantly but not totally eliminated the effects of centrally applied ghrelin, which were abolished when both adrenergic and parasympathetic pathways were ablated. These results indicate that ghrelin applied centrally or peripherally markedly increases resistance of the intestinal tissue during the I/R period induced mucosal and hyperemic impairment evoked by I/R. Ghrelin is an important mediator of the increase in the intestinal microcirculation and elevation of the intestinal metabolism, which seems to be, at least in part, responsible for the observed protection of the intestine subjected to I/R. Impairment of this microvasculature response due to I/R seems to be responsible for a markedly observed weaker effect of ghrelin when this hormone was administered after the ischemic period. The lack of a protective effect observed after central administration of this peptide against a long lasting I/R period is probably due to damage of neural pathways caused by I/R. Finally, the peripheral activity of ghrelin in the intestine is mediated by the sensory neurons with a prominent role of CGRP released from their endings. However, this peripheral action of ghrelin depends upon the proper functioning of both the sympathetic and parasympathetic system.

Background and Aim: Lipopolysaccharide (LPS) has been proposed to act as one of numerous virulence factors in the Helicobacter pylori (HP)-infected stomach. However, little is known as to whether the gastric mucosa can withstand the repeated LPS insult, and how the possible adaptation to this endotoxin influences the damage induced by strong irritants. We determined the effect of a single or repeated parenteral administration of LPS obtained from HP on acute gastric lesions induced by intragastric application of 100% ethanol (1.5 ml) and by water immersion and restraint stress (WRS). Methods: The area of the gastric lesions was measured by planimetry, mucosal gastric blood flow (GBF) was determined by H2 gas clearance, and gastric luminal content was collected for the determination of luminal NO2–/NO3– levels by the Griess reaction. Biopsy samples were taken for the measurement of prostaglandin (PG) E2 by radioimmunoassay and mucosal expression of constitutive and inducible nitric oxide synthase (cNOS and iNOS), constitutive (COX-1) and inducible cyclooxygenase (COX-2), heat shock protein 70 (HSP 70) mRNA and protein were analyzed by RT-PCR and Western blot. Results:HP LPS (1 mg/kg i.p.) injected once or 5 times produced negligible macroscopic injury and failed to influence GBF significantly compared to the injuries recorded in vehicle-controlled rats. Single and repeated (5 times) administration of HP LPS significantly reduced ethanol- and WRS-induced lesions, these protective effects were accompanied by a rise in GBF and excessive luminal release of NO. The suppression of NOS activity by L-NAME (20 mg/kg i.p.), a nonspecific NOS inhibitor, or L- (30 mg/kg i.g.), a specific iNOS inhibitor, and of COX-2 activity by NS-398 reversed the protective and hyperemic effects of single or repeated LPS administrations against ethanol and WRS damage and the accompanying rise in NO and PGE2 production. These effects of L-NAME were significantly antagonized by the addition of L-arginine, a substrate for NO synthesis. The signals for cNOS, COX-1 and HSP 70 mRNA were detected by RT-PCR in the vehicle-treated gastric mucosa, whereas gene and protein expression of iNOS, COX-2 and HSP 70 mRNA were significantly increased only in rats treated with 1 or 5 applications of HP LPS. Conclusions: Repeated injections of HP LPS enhance gastric mucosal resistance to the mucosal damage induced by ethanol and WRS via a mechanism involving mucosal overexpression of iNOS, COX-2 and HSP 70 with subsequent excessive production of NO and PGE2.

Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.

Recent identification of specific leptin receptors in the pancreas suggests that this peptide may also play some role in this gland.To examine the effect of intraperitoneal (i.p.) or intracerebroventricular (i.c.v.) administration of leptin in rats on caerulein-induced pancreatitis (CIP), pancreatic gene expression of leptin and inflammatory cytokine production.Caerulein (25 micrograms/kg) was infused subcutaneously into conscious rats over 5 h to produce CIP. Leptin (1, 5, or 10 micrograms/kg) was injected i.p. or i.c.v. 30 min prior to the CIP induction. The plasma level of TNF alpha and IL-4 was determined by ELISA, while plasma leptin was measured by RIA and leptin gene expression in pancreas by RT-PCR.CIP was characterized by the usual pancreatic edema, reduction in pancreatic blood flow (PBF) and an increase in serum levels of amylase, TNF alpha and IL-4. Pretreatment with i.p. or i.c.v. leptin of the CIP rats partially reversed the harmful effects of CIP on the pancreas, and reduced pancreatic inflammation and the fall in PBF. This was accompanied by a dose-dependent reduction in serum levels of amylase and TNF alpha, while serum IL-4 in the CIP rats pretreated with leptin rose dose-dependently as compared to control rats with CIP alone. Pretreatment with leptin resulted in the dose-dependent rise in plasma leptin level over that observed in vehicle-treated controls. Leptin mRNA expression in the pancreas was dose-dependently increased after infusion of caerulein. Leptin content in isolated pancreatic acini was also increased dose-dependently by caerulein added to the incubation medium bathing these acini.(1) Exogenous leptin protects the pancreas against damage by CIP; (2) endogenous leptin seems to limit the extend of pancreatic damage, and (3) these protective effects of leptin could be attributed to the reduction in TNF alpha and to the increase in IL-4 production.

Gastroesophageal reflux disease (GERD) is a global disease rapidly increasing among world population. The pathogenesis of reflux esophagitis which is considered as the early stage of GERD is complex, resulting from an imbalance between aggressive factors damaging the esophagus and a number of the natural defense mechanisms. The esophageal mucosa is in a state of continuous exposure to potentially damaging endogenous and exogenous factors. Important aggressive components of gastric refluxate include acid and pepsin and also pancreatic enzymes and bile. Among aggressive factors of exogenous origin, cigarette smoking, non-steroidal anti-inflammatory drugs (NSAID), and steroids are of the utmost importance. The basic level of esophageal defense against acid-pepsin damage consists of the anti-reflux mechanisms such as the luminal acid clearance and removal of the esophageal contents and neutralization of luminal acidity. In addition the esophageal mucosal protection includes the presence of pre-epithelial, epithelial and post-epithelial cellular and functional components. Recently, the progress have been made in the understanding of role of the heptapeptide member of the renin-angiotensin system (RAS), angiotensin-(1-7) (Ang-(1-7)) in the control of gastrointestinal functions. It has been shown that all components of local RAS including Ang-(1-7) are detectable in the gastrointestinal wall including not only the stomach but also the esophagus. Previous studies revealed that Ang-(1-7), which is an important component of the RAS, exerts vasodilatory, anti-inflammatory and antioxidant activities in the stomach. Ang-(1-7) was recently implicated in gastroprotection, but its effects on esophageal mucosa in a rodent model of reflux esophagitis and in human subjects presenting GERD symptoms have not been explored. The present study was aimed to evaluate the possible protective effects of Ang-(1-7) and Mas-receptors upon esophageal mucosal damage in acute reflux esophagitis (RE) induced in anesthetized rats by ligating the pylorus and the limiting ridge (a transitional region between the forestomach and the corpus of stomach). Consequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Because Mas receptors are functionally linked to nitric oxide (NO) formation, we also studied involvement of endogenous NO in the mediation of protective and circulatory effects of exogenous Ang-(1-7). Moreover, an attempt was made to assess the possible role of sensory neurons in the modulation of the protective effects exerted by Ang-(1-7)/Mas receptor system. Six series of rats were pretreated 30 min before induction of RE with 1) vehicle (saline), 2) Ang-(1-7) (5-50 μg/kg i.p.), 3) A779 (50 μg/kg i.p.), the selective Mas receptor antagonist applied alone, 4) Ang-(1-7) (50 μg/kg i.p.) combined with A779, 5) L-NNA (20 mg/kg i.p.) administered alone, and 6) Ang-(1-7) (50 μg/kg i.p.) combined with L-NNA. In separate group of rats, capsaicin (total dosage of 125 mg/kg within three days) was administered s.c. 2 weeks before the induction of RE to induce functional ablation of sensory nerves. Rats with intact sensory nerves and those with capsaicin-induced sensory denervation received vehicle (saline) or Ang-(1-7) (50 μg/kg i.p.) to determine whether this vasoactive metabolite of angiotensin I could be also effective in rats with capsaicin-induced impairment of the synthesis and release of sensory neuropeptides such as CGRP. Four hours after induction of RE, the mucosal damage was graded with mucosal lesion index (LI) from 0 to 6, the esophageal microcirculatory blood flow (EBF) was determined by H2-gas clearance technique and plasma level of pro-inflammatory cytokines interleukin-1b (IL-1β), and tumor necrosis factor-α (TNF-α) was determined by ELISA. The expression of proinflammatory factors including COX-2, cytokine IL-1β and hypoxia inducible factor 1alpha (Hif1α) was analyzed in the esophageal mucosal biopsies. In rats with RE, the esophageal LI was significantly elevated comparing its value observed in intact rats, and the EBF was significantly decreased as compared with intact mucosa. Pretreatment with Ang-(1-7) of control rats without esophagitis induced increase in EBF by about 25% without any macroscopic changes in the esophageal mucosa or in the plasma level of cytokines. In animals with RE, pretreatment with Ang-(1-7) significantly reduced gross and histological esophageal mucosal injury and significantly increased EBF in comparison to vehicle-pretreated animals. The observed gross and histologic esophagoprotective effect of Ang-(1-7) was totally abolished by A779 so in rats with combined treatment of A779 with Ang-(1-7), the LI was identical with this observed in control RE and the EBF was decreased in these animals by about 39%. Inhibition of NO synthase by L-NNA significantly reduced the LI and the rise in EBF caused by Ang-(1-7). Similarly, the capsaicin denervation also significantly attenuated the vasodilatory and the esophagoprotective effects of Ang-(1-7). The expression of proinflammatory factors COX-2, Hif1α and IL-1β which was negligible in intact esophageal mucosa, was upregulated in esophageal mucosa of rats with RE. In contrast, the administration of Ang-(1-7) resulted in a downregulation of mRNA for COX-2, Hif1 and IL-1β in esophageal mucosa an this effect was abolished in A779-dependent manner. The Ang-(1-7) significantly decreased the RE-induced elevation of plasma levels of IL-1β and TNF-α, and this effect was also reversed by pretreatment with A779, and significantly attenuated by pretreatment with L-NNA and capsaicin-induced sensory denervation. The present study indicates that the protective effect of Ang-(1-7) observed in the esophageal mucosa during early acute stage of gastroesophageal reflux depends upon the enhancement of esophageal microcirculatory blood flow via the activation of Mas receptor possibly due to NO synthase/NO system activation, stimulation of sensory nerves, the inhibition of expression of pro-inflammatory factors including COX-2, Hif1α and IL-1β and release of proinflammatory cytokines IL-1β and TNF-α.

Acute gastric mucosal lesions represent an important clinical problem. The experimental model of acute gastritis such as water immersion restraint (WRS) stress is useful tool in examination of pathomechanism of acute gastric damage. Nitric oxide (NO) plays an important role in the maintenance of gastric barrier, however the role of reactive oxygen species (ROS) in the interaction between NO and gastric mucosa integrity has been little studied. The purpose of our present study was to explain the participation of ROS in healing of WRS-induced gastric lesions accelerated by NO. Experiments were carrying out on 120 male Wistar rats. To assess gastric blood flow (GBF) laser Doppler flowmeter was used. The number of gastric lesions was established by planimetry. The colorimetric assays were used to determine gastric tissue level of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), the products of lipid peroxidation by ROS, as well as superoxide dismutase (SOD) activity, the enzyme scavanger of ROS. We demonstrated that 3.5 h of WRS resulted in appearance of acute gastric mucosal lesions accompanied by a significant decrease of GBF. Biological effects of ROS were estimated by measuring tissue level of MDA and 4-HNE, as well as the SOD activity. It was demonstrated that 3.5 h of WRS led to significant increase of MDA and 4-HNE mucosal level, that was accompanied by a decrease of SOD activity. Pretreatment with NO-donors (SIN-1, SNAP, nitroglycerin, NO-ASA) resulted in reduction of gastric lesions number, increment of GBF, decrease of MDA and 4-HNE tissue level and increase of SOD activity. Suppression of ROS play an important role in NO-donors action in gastroprotection against gastric acute lesions induced by 3.5 h of WRS. NO-donors cause an attenuation of lipid peroxidation as documented by a decrease of MDA and 4-HNE levels and enhancement of antioxidative properties as evidenced by increase of SOD activity.

INTRODUCTION AND RESEARCH AIMS: The aim of the work was an evaluation of the impact of physical exertion on the regulating of food intake and digestive system hormone release as well as the partly connected phenomenon of evaluating the subjective sensation of hunger and the amount of food consumed at various time following physical exercise.The tests covered 12 young, healthy men, for whom the effects of physical exertion of a moderate and high intensity on the subjective sensation of hunger/satiety, evaluated by means of visual analogue scales, on food intake as well as on the metabolic and hormonal parameters were tested.Physical exertion resulted in a fall in the subjective sensation of hunger, but only following intensive exertion was this statistically significant. The intake of food was greater after exertion when compared to the control group. Moderate exertion resulted in a statistically significant but short-lived increase in the ghrelin level. This effect was not observed after intensive exertion, while in those tests during the post-meal period there occurred a fall in the concentration of ghrelin in the plasma. After exertion a physical fall was observed in the concentration of insulin in the plasma, for the intake of food resulted in a notable increase in its level.Physical highly intensive exertion, results in a temporary reduction in the subjective sensation of hunger but leads to an increased food intake. The current research suggests that moderate but not intensive physical exertion stimulates the secretion of ghrelin.

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.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) are members of the largest nuclear hormone receptor family of transcription factors (1). PPAR gamma (PPARgamma) plays an important role in adipogenesis, control of sensitivity to insulin, inflammation and atherosclerosis but recent studies also suggest that PPARgamma is involved in cell cycle withdrawal. PPARgamma can promote cell differentiation, exert an antiproliferative action and inhibit angiogenesis (2, 3). However, there are studies showing that activation of PPARgamma promotes the development of colon cancer (4). These data are in sharp contrast with studies that attribute anticancer effects to PPARgamma in gastrointestinal malignancies. Probably, the action of PPARgamma on cell cycle and proliferation depends on the cell type and presence of other stimuli that predispose cells to cancer development. Amidated and non-amidated gastrins may play an important role in the proliferation and carcinogenesis of GI cancers. It is known that gastrin peptides activate phosphorylation of Protein Kinase B (PKB/Akt) and anti-apoptotic signalling but there is little known about the link between gastrins and PPARgamma receptors in relation to apoptosis.

Ablation of sensory nerves impairs healing of gastric ulcers, but the role of free radicals in the healing process has been little studied. The aim of our present investigations was to determine the participation of reactive oxygen species (ROS) in sensory nerve activity during WRS. Experiments were carried out on male Wistar rats and the number of gastric lesions was measured by planimetry. Colorimetric assays were used to determine gastric mucosal levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), as well as superoxide dismutase (SOD) activity. We found that capsaicin-inactivation of sensory nerves resulted in magnification of gastric mucosal damage induced by the WRS. In this process, oxidative stress occurs, as reflected by an increase of MDA and 4-HNE tissue concentrations (an index of lipid peroxidation), and a decrease of SOD activity, could play an important role. Pentoxyfilline-induced gastroprotection and hyperemia depends upon attenuation of the oxidative stress. This protection and hyperemia were, at least in part, attenuated by ASA. Afferent sensory fibers participate in the pathogenesis of ulcers. Lipid peroxidation plays an important role in this process.

Reactive hyperemia (RH) is an abrupt blood flow increase following release from mechanical occlusion of an artery, with restoration of intra-arterial pressure. The mechanism of this postocclusion increase in blood flow in the gut is multifactorial. Relaxation of intestinal resistance vessels, observed during RH, may involve myogenic, metabolic, hormonal and neurogenic factors. Evidence exists that histamine is an important endogenous mediator of various functions of the gut, including blood flow. The vascular effects of histamine in the intestinal circulation are due its agonistic action on histamine H1, H2 and H3 receptors. In the present study the hypothesis was tested that peripheral histamine H3 receptors are involved in the mediation of RH in the intestinal circulation. In anesthetized rats, anterior mesenteric artery blood flow (MBF) was determined with ultrasonic Doppler flowmeter, and arterial pressure (AP) was determined with a transducer. The increase in the volume of blood accumulating during RH (RH-volume), the peak increase of arterial blood flow (RH-peak response) and the duration of the hyperemia (RH-duration) were used to quantify RH after occluding the anterior mesenteric artery for 30, 60 and 120 s. Hyperemia parameters were determined before and after administration of the selective histamine H3 receptor antagonist clobenpropit. Pretreatment with clobenpropit was without any effect on control MBF and AP but significantly reduced most of RH responses. These findings support the hypothesis that histamine H3 receptors do not play any role in the control of intestinal vasculature at basal conditions but these receptors participate in the intestinal hyperemic reaction in response to complete temporal intestinal ischemia.

Impairment of blood perfusion in gastric mucosa results in the formation of erosions and ulcers. Nitric oxide (NO), produced via activity of NO-synthase (NOS), appears to be a one of major factors, involved in the regulation of the gastric blood flow (GBF). Inhibition of this enzyme by N-nitro-L-arginine (L-NNA) results in local decrease of NO production, reduces GBF and impairs gastric mucosal integrity, the effects that can be reversed by the pretreatment with L-arginine, the NOS substrate. However, little information is available regarding the contribution of reactive oxygen species (ROS)-induced lipid peroxidation and NO to the mechanism of gastric mucosal integrity. Therefore, the aim of our present study was to determine the action of pentoxyfilline (PTX), an inhibitor of tumor necrosis factor alpha (TNFalpha) with or without NOS inhibition by L-NNA administration in rats with water immersion and restraint stress (WRS)-induced gastric lesions. Experiments were carried out on 100 male Wistar rats. The gastric blood flow (GBF) was measured using laser Doppler flowmeter. The area of gastric lesions was determined by planimetry and the levels of proinflammatory cytokines (IL-1beta and TNFalpha) were measured by ELISA. Colorimetric assays were employed to determine gastric mucosal levels of lipid peroxidation products, such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and antioxidant enzymes including superoxide dismutase (SOD) activity, as well as tissue concentration of reduced glutathione (GSH). Administration of PTX significantly attenuated the gastric lesions, induced by 3.5 h of WRS and this was accompanied by the rise in the GBF and a significant decrease in plasma proinflammatory cytokines (IL-1beta and TNFalpha) levels, as well as the reduction of lipid peroxidation. Exposure of rats to WRS suppressed the SOD and GSH activities and these effects were reversed by PTX. The protective and hyperemic effects of PTX, as well as an increase in mucosal SOD activity and GSH concentration were counteracted by pretreatment with L-NNA, but restored by the pretreatment with L-arginine, a NOS substrate. We conclude that PTX exerts beneficial, gastroprotective effect against WRS-induced gastric lesions due to enhancement in gastric microcirculation, possibly mediated by the enhanced NOS activity as well as local action of NO and by the attenuation of oxidative metabolism and generation proinflammatory cytokines.

Data concerning cardiovascular effects of peripherally and centrally located histamine H(3) receptor stimulation are contradictory, and despite excessive studies their role in the control of the cardiovascular function have not been cleared yet. Effect of histamine H(3) receptors activation have been attributed to modulation of sympathetic system activity but exact role of peripherally and centrally located histamine H(3) receptors stimulation in the modulation of vascular tone of the mesentery and intestinal metabolism remains unexplored. Aim of the present study was to evaluate the role of centrally and peripherally located histamine H(3) receptors in the modulation of vascular tone of the mesentery and metabolic activity of intestinal tissue. In anesthetized rats total mesenteric blood flow (MBF), mucosal intestinal blood flow (LDBF), intestinal oxygen uptake (VO(2)) and arterial pressure (AP) were determined. Intestinal arterial conductance (C) was also calculated. Administration of the selective histamine H(3) receptor agonist imetit (10 micromol/kg i.a) evoked marked changes in hemodynamic and metabolic parameters; MBF, LDBF, C and VO(2) were significantly increased, whereas AP was significantly decreased. Pretreatment with histamine H(3) receptor antagonist clobenpropit (4 micromol/kg i.a.) abolished imetit-induced circulatory and oxygen uptake responses. Clobenpropit (4 micromol/kg i.a.) alone failed to affect the MBF, LDBF, AP, C and VO(2) values. Central administration of imetit (0.1 micromol i.c.v.) markedly increased AP and decreased MBF, LDBF, C and VO(2). Pretreatment with histamine H(3) receptor antagonist clobenpropit (0,4 micromol i.c.v.) diminished circulatory and metabolic responses to centrally injected imetit. Central histamine H(3) receptors blockade by clobenpropit evoked no significant changes in the mesenteric arterial and mucosal microcirculatory blood flow, intestinal metabolism and mean arterial pressure. We conclude that, peripheral histamine H(3) receptors when stimulated decreases vasoconstrictory tone of the mesenteric artery and precapillary structures and evokes increase of intestinal oxygen uptake. This might be in part due to inhibition of sympathetic postganglionic fibers vasopressor activity. Central histamine H(3) receptor stimulation activates vasoconstrictory sympathetic adrenergic system with possible involvement of other, presumably non-histaminergic receptors system. At basal conditions neither central nor peripheral histamine H(3) receptors are involved in the control of mesenteric macro- and microcirculation and intestinal oxygen consumption.

Objective: High-dose Solu-Medrol (Upjohn, Kalamazoo, Mich) therapy has become standard care in the management of acute spinal cord injury (ASCI). This study attempts to define the adverse effects that Solu-Medrol therapy has on these patients. Design: Retrospective review with historical control. Material and Methods: From May 1990 to April 1994, all patients with ASCI admitted within 8 hours of injury received high-dose Solu-Medrol per the National Acute Spinal Injury Study (NASCIS-2) protocol. Their demographic and outcome parameters were compared with those of a group admitted from March 1986 to December 1993 with an associated ASCI who received no steroid therapy. Measurements and Main Results: Steroid therapy was associated with a 2.6-fold increase in the incidence of pneumonia and an increase in ventilated and intensive care days. However, it was associated with a decrease in duration of rehabilitation and had no significant impact on other outcome parameters, including mortality. Conclusions: Although the NASCIS-2 protocol may promote early infectious complications, it has no adverse impact on long-term outcome in patients with ASCIs.

Gastric microcirculation plays an important role in the maintenance of the gastric mucosal barrier and mucosal integrity. Sensory nerves are involved in the regulation of mucosal blood circulation and mucosal defense. Therefore, the ablation of these nerves by neurotoxic doses of capsaicin provides the possibility of determination of their role in gastric mucosal integrity. Stress ulceration represents a serious gastric lesions. Results of our previous experiments have indicated that water immersion and restraint stress (WRS) led to increased oxidative metabolism. Ablation of sensory nerves by high doses of capsaicin retards healing of gastric ulcers, but the role of reactive oxygen species (ROS) in the healing process has been little studied. Therefore, the aim of our present investigations was to determine the participation of ROS in sensory nerve activity during WRS. Experiments were carried out on 90 male Wistar rats and the area of gastric lesions was measured by planimetry. Colorimetric assays were used to determine gastric mucosal levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), as well as superoxide dismutase (SOD) activity. We demonstrated that inactivation of sensory nerves resulted in magnification of gastric mucosal damage induced by the WRS. In this process, oxidative stress, as reflected by an increase of MDA and 4-HNE tissue concentrations (an index of lipid peroxidation), as well as decrease of SOD activity, could play an important role. Aspirin, applied in a low dose, exerts a protective activity, possibly due to its metabolites, which possess the anti-oxidant and ROS scavanging properties. Pentoxyfilline-induced gastroprotection and hyperemia depends upon attenuation of the oxidative stress. This protection and hyperemia were, at least in part, attenuated by ASA.

Gastric microcirculation plays an important role in the maintenance of the mucosal gastric integrity and the mechanism of injury as well as providing protection to the gastric mucosa. Disturbances in the blood perfusion, through the microcapillaries within the gastric mucosa may result in the formation of mucosal damage. Acute gastric mucosal lesions constitute an important clinical problem. Originally, one of the essential component of maintaining the gastric mucosal integrity was the biosynthesis of prostaglandins (PGs), an issue that has captured the attention of numerous investigations. PGs form due to the activity of cyclooxygenase (COX), an enzyme which is divided into 2 isoforms: constitutive (COX-1) and inducible (COX-2) ones. The inhibition of COX-1 by SC-560, or COX-2 by rofecoxib, reduces gastric blood flow (GBF) and impairs gastric mucosal integrity. Another detrimental effect on the gastric mucosal barrier results from the ablation of sensory afferent nerves by neurotoxic doses of capsaicin. Functional ablation of the sensory afferent nerves by capsaicin attenuates GBF and also renders the gastric mucosa more susceptible to gastric mucosal damage induced by ethanol, aspirin and stress. However, the role of reactive oxygen species (ROS) in the interaction between COX specific inhibitors and afferent sensory nerves has not been extensively studied. The aim of our present study was to determine the participation of ROS in pathogenesis of stress-induced gastric lesions in rats administered with SC-560 or rofecoxib, with or without ablation of the sensory afferent nerves. ROS were estimated by measuring the gastric mucosal tissue level of MDA and 4-HNE, the products of lipid peroxidation by ROS as well as the SOD activity and reduced glutathione (GSH) levels, both considered to be scavengers of ROS. It was demonstrated that exposure to 3.5 h of WRS resulted in gastric lesions, causing a significant increase of MDA and 4-HNE in the gastric mucosa, accompanied by a decrease of SOD activity and mucosal GSH level. Pretreatment with COX-1 and COX-2 inhibitors (SC-560 and rofecoxib, respectively) aggravated the number of gastric lesions, decreased GBF, attenuated GSH level without further significant changes in MDA and 4-HNE tissue levels and SOD activity. Furthermore, the capsaicin--nactivation of sensory nerves resulted in exaggeration of gastric mucosal damage induced by WRS and this was further augmented by rofecoxib. We conclude that oxidative stress, as reflected by an increase of MDA and 4-HNE tissue concentrations (an index of lipid peroxidation), as well as decrease of SOD activity and the fall in GSH tissue level, may play an important role in the mechanism of interaction between the inhibition of COX activity and afferent sensory nerves releasing vasoactive neuropeptides. This is supported by the fact that the addition of specific COX-1 or COX-2 inhibitors to animals with capsaicin denervation led to exacerbation of gastric lesions, and further fall in the antioxidizing status of gastric mucosa exposed to stress.

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 w

Omentum was shown to exhibit angiogenic activity, but its role in healing of chronic gastric ulcers is unknown. This study was designed to compare the effects of omentum and basic fibroblast growth factor (bFGF), a potent angiogenic factor, on healing of chronic gastric ulcers in rats. Several series of rats with gastric ulcers were used: series A with intact omentum (control), series B with omentum resected, and series C with omentum placed on the serosal side of the ulcer. Series A-C were divided into four groups treated with vehicle (I); indomethacin (II), an inhibitor of prostaglandin formation, difluoromethylornithine (DFMO) (III); an inhibitor of polyamine biosynthesis or bFGF (IV). Seven days after ulcer induction, the animals were anesthetized, the gastric blood flow (GBF) was determined by laser Doppler flowmetry (LDF), and the ulcer area was measured by planimetry. Biopsy samples of the ulcer margin were taken for determination of the number of capillaries and myofibroblasts in the granulation tissue. Attachment of omentum significantly accelerated ulcer healing, whereas omentectomy delayed this process. LDF revealed the decrease in the GBF at the ulcer margin to 45% and at the ulcer bed to 18% of the value recorded in the intact adjacent mucosa. Attachment of the omentum significantly increased the blood flow at the ulcer margin and increased the number of capillaries and myofibroblasts in the granulation tissue. Indomethacin (1 mg/kg/day) that inhibited mucosal PGE2 by about 85% delayed significantly ulcer healing without affecting the blood flow in the ulcer area.(ABSTRACT TRUNCATED AT 250 WORDS)

Publisher Summary This chapter provides an outline of the antibacterial, antiviral, and antiparasitic activities of grapefruit seeds. Grapefruit seed extract (GSE) is a product of the grapefruit seed and pulps, and has been found to exert antibacterial, antiviral, and antiparasitic activities. Previous studies documented that grapefruit seeds are the major depositories for limonoids. Grapefruit also contains many flavonoid glycosides, naringenin, quercetin, kaempferol, hesperidin, and apigenin being the most abundant among their aglycones. Grapefruit seed extracts (GSEs), containing flavonoids, have been shown to possess antibacterial, antiviral, and antifungal properties. Furthermore, grapefruit-containing flavonoids such as naringenin were also recently implicated in cytoprotection against injury induced by algal toxins in isolated hepatocytes. The antimicrobiological properties of GSE against a wide range of gram-negative and gram-positive organisms were attributed to the disruption it caused to the bacterial membrane and the subsequent liberation by this extract of the bacterial cytoplasmic contents within a relatively short time. The underlying mechanism of the therapeutic efficacy of citrus seed extracts such as from grapefruits and red grapes seems to depend upon the presence of different classes of polyphenolic flavonoids, which were shown to inhibit platelet aggregation, thus decreasing the risk of coronary thrombosis and myocardial infarction. The mechanism of the gastroprotective activity of GSE appears to be dependent on endogenous PG and the functional activity of sensory nerves releasing CGRP. The major mechanism of protection against gastric mucosal damage involves enhancement of the gastric microcirculation mediated by increased generation of endogenous prostaglandins (PGs) and nitric oxide (NO) and activity of sensory neuropeptides such as CGRP. Interestingly, GSE in a formulation of Citricidal was demonstrated to be effective against more than 800 bacterial and viral strains, 100 strains of fungus, and a large number of single- or multi-celled parasites.

The purpose of this study was to develop an acute animal model of reflux esophagitis, which would be suitable to induce the esophageal damage caused by gastric acid reflux, thus mimicking the esophageal injury of human gastroesophageal reflux disease (GERD). Global research indicates that GERD is rapidly increasing among the world's population. NSAIDs are known to induce gastrointestinal damage and low doses of aspirin (ASA) have been shown to increase the incidences of GERD in humans. Gastric acid and pepsin secretion and enhanced COX-2 expression were implicated in the pathogenesis of reflux esophagitis, but the effect of selective COX-2 inhibitors against lesions induced by the reflux of gastric acid content into esophagus has not been thoroughly studied. Here, we compared the effect of aspirin (ASA) and so called "safe" nitric oxide (NO) derivative of ASA with those of non-selective and selective cyclooxygenase (COX)-1 and COX-2 in rat model of reflux esophagitis. Reflux esophagitis was induced in anesthetized rats by ligating the pylorus and limiting ridge transitional region between the forestomach and the corpus of stomach. Subsequently, the total gastric reservoir to store gastric juice was greatly diminished, resulting in the reflux of this juice into the esophagus. Rats with esophagitis received intragastric (i.g.) pretreatment either with: 1) vehicle (saline), 2) ASA or NO-ASA (100 mg/kg); 3) the non-selective COX inhibitor, indomethacin (5 mg/kg); 4) the selective COX-1 inhibitor, SC-560 (10 mg/kg), and 5) the selective COX-2 inhibitor, celecoxib (5 mg/kg). In a separate series of rats with reflux oesophagitis, the efficacy of ASA combined with a donor of NO, glyceryl trinitrate (GTN; 10 mg/kg i.g.) to prevent esophageal mucosal injury was investigated. Four hours after induction of esophagitis the gross mucosal damage was graded with a macroscopic lesion index (LI) from 0-6. The esophageal blood flow (EBF) was determined by H₂-gas clearance technique, the oesophageal mucosal and blood samples were collected for histology and analysis of the RT-PCR expression and release of proinflammatory cytokines IL-1β, TNF-α and IL-6 using specific ELISA. The exposure of the esophagus to reflux of gastric acid time-dependently increased the esophageal LI and morphologic damage, and decreased EBF with the most significant changes observed at 4 hrs after the ligation procedure. The pretreatment with native ASA in the dose that suppressed the generation of mucosal PGE₂, enhanced gross and histologic esophageal damage and produced a significant fall in EBF. NO-ASA or ASA coupled with GTN counteracted the aggravation of the damage and accompanying fall in EBF when compared with native ASA applied alone to rats with esophagitis. The proinflammatory cytokines IL-1β and TNF-α were overexpressed in rats with esophagitis and those pretreated with ASA but this effect was significantly attenuated by NO-ASA. Plasma IL-1β, TNF-α and IL-6 were negligible in the intact rats but significantly increased in those with esophagitis, with this effect being further enhanced by non-selective (indomethacin) and selective (SC-560, celecoxib) COX-1 and COX-2 inhibitors. We conclude that conventional NSAID such as aspirin augments esophagitis, while NO-ASA exerts the beneficial protective effect against reflux esophagitis via the enhancement of esophageal microcirculation due to NO release and an inhibitory effect on expression and release of pro-inflammatory cytokines.

There are few data concerning protective effects of leptin on gastric epithelium treated with necrotic factors: ethanol, bile salts and hiperosmotic solutions. Further investigations are needed to establish the role of hormone leptin in gastroprotection and in the process of chronic gastric ulcers healing in animals. Exogenous leptin administration plays protective effects against 75% ethanol damage in gastric epithelium. Nitric oxide is involved in gastroprotective effects of leptin and CCK.

Reactive hyperemia (RH) is a local, vascular response that occurs following release from mechanical occlusion of an artery, with restoration of intra-arterial pressure. The mechanism of this postocclusion hyperemia in the gut has not been identified, although metabolic, myogenic, and neurogenic mediators of this response have been proposed. The present study was conducted to evaluate a possible modulatory role for sensory innervation of the intestinal vasculature in RH, using acute and chronic treatment with capsaicin applied in different ways. In anesthetized rats, the velocity of flowing blood in the gut was determined continuously with a pulsed Doppler velocimeter, and arterial pressure was determined with a transducer. The increase in calculated intestinal vascular conductance at the height of RH (Ch), the excess volume of blood accumulating during RH, and the duration of the hyperemia were also used to quantify RH after occluding the anterior mesenteric artery for 30, 60, and 120 sec. In the initial control group of rats, the maximal increases in the velocity of flowing blood during RH were 61 +/- 4%, 90 +/- 7%, and 129 +/- 10% of control, conductances were increased to 192 +/- 5%, 222 +/- 12%, and 267 +/- 15% of control, volumes were 3.5 +/- 0.6 ml, 7.2 +/- 0.4 ml, and 16.2 +/- 1.8 ml, and durations of hyperemia were 78 +/- 5 sec, 93 +/- 6 sec, and 178 +/- 7 sec, respectively, after each elapsed period of occlusion. Acute treatment with periarterial capsaicin significantly decreased peak conductances in RH by 15-35% for all occlusions tested and reduced both volume and duration values. Rats treated with capsaicin in neonatal life exhibited reduced Ch values, as did adult rats treated chronically with capsaicin. Both periarterial and intrajejunal treatment with capsaicin decreased the duration of RH. Hexamethonium increased both Ch and the duration of RH and tended to reverse reductions in these parameters caused by capsaicin. These results suggest that sensory innervation of the intestinal vasculature exerts a modulatory influence in the regulation of intestinal RH.

Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.

This review summarizes the involvement of centrally and peripherally applied melatonin, a major hormone of pineal gland, in the mechanism of gastric mucosal integrity, gastroprotection and ulcer healing. Melatonin was originally shown to attenuate gastric mucosal lesions but the controversy exists in the literature as to whether melatonin derived from the pineal gland, considered as the major source of this indole or rather that locally generated from L-tryptophan within gastric mucosa, plays predominant role in the mechanism of gastrointestinal integrity. Both, intragastric (i.g.) and intracerebroventricular (i.c.v.) administration of melatonin and its precursor, L-tryptophan to rats without or with removed pineal gland by pinealectomy attenuates in the dose-dependent manner the formation of on gastric lesions induced by topical irritants and water immersion restraint stress (WRS). Melatonin accelerated the gastric ulcer healing and this was accompanied by the rise in gastric blood flow (GBF), the plasma melatonin and gastrin levels, the mucosal generation of PGE(2) and luminal NO content. Pinealectomy, which suppresses the plasma melatonin levels, markedly aggravated the gastric lesions induced by WRS. Concurrent supplementation of pinealectomized animals with melatonin or L-tryptophan, the melatonin precursor, attenuated the lesions induced by WRS. Treatment with luzindole, an antagonist of Mel(2) receptors, or with L-NNA, the NO-synthase inhibitor, significantly attenuated melatonin- and L-tryptophan-induced protection and the acceleration of ulcer healing and the accompanying increase in the GBF and luminal content of NO. We conclude that 1) exogenous melatonin and that released from the L-tryptophan attenuate lesions induced by topical irritant such as ethanol and WRS via interaction with MT(2) receptors and due to an enhancement of gastric microcirculation, probably mediated by NO and PG derived from cNOS, iNOS and COX-2 overexpression and activity, and 2) the pineal gland plays an important role in the limitation of WRS-induced gastric lesions and acceleration of ulcer healing via releasing melatonin predominately at night time, that exerts gastroprotective and ulcer healing actions.

Growth hormone (GH) has been shown to protect the intestinal barrier integrity and to stimulate the production of insulin-like growth factor 1 (IGF-1), which inhibits the development of acute pancreatitis. Sensory nerves are implicated in the protection of pancreatic tissue against acute inflammation. The aim of this study was to investigate the influence of exogenous GH on acute pancreatitis (AP) and to assess the involvement of sensory nerves and IGF-1 in above effect. Studies were performed on Wistar rats. AP was induced by subcutaneous administration of caerulein (25μg/kg) to the conscious animals. GH (1 or 2mg/kg) was administered to the rats as an intraperitoneal injection 30min prior to the start of AP. To deactivate sensory nerves capsaicin was given at total dose of 100mg/kg 10days before the experiments. AP was confirmed by histological examination and manifested by the significant rises of pancreatic weight, and serum activities of lipase, TNFα and IL-10 (by 550%, 300% and 50%, respectively), whereas IGF-1 blood concentration was markedly reduced. Administration of GH prior to the caerulein infusion significantly increased GH, IGF-1 and IL-10 blood levels, attenuated harmful effects of AP and reduced histological manifestations of pancreatitis in the rats with intact sensory nerves. This was accompanied by the reduction of serum lipase, and TNFα activities. In the AP rats with capsaicin-deactivated sensory nerves GH failed to protect the pancreas against acute damage and, as a consequence of above deactivation, IGF-1 was low. Conclusion GH modulates the development of acute pancreatitis in the presence of active sensory nerves probably via stimulation of IGF-1 release.

The aim of this study was to find out whether stimulated monocytes could trigger apoptosis of vascular endothelial cells. Human umbilical vein endothelial cells (HUVEC) (EC) were co-cultured for 24 h and 48 h with monocytes isolated from peripheral blood (peripheral blood monocytes) or MonoMac6 cell line activated previously with proinflammatory cytokines. Real-time PCR was conducted to investigate p53 up-regulated modulator of apoptosis (PUMA), heat shock protein HSP70 and HSP27 genes expression. Changes in the level of PUMA, HSP70, HSP27 and phospho-heat shock protein 27 (p-HSP27) proteins were analyzed by means of immunoprecipitation. Apoptosis was determined by TUNEL and poli-(ADP ribose) polymerase ( PARP ) cleavage assay. In HUVEC cells stimulated with monocytes hardly any increase of PUMA mRNA was observed, but the PUMA protein level was significantly up regulated especially after 24 h. Heat shock proteins (HSP70 and HSP27) mRNA expression was elevated after 24 h and 48h and confirmatory up regulation of these proteins was observed in HUVEC cells stimulated with peripheral blood monocytes but not with MonoMac6 cells. Interestingly, in nuclear compartment of HUVECs exposed to the monocytic line and native monocytes, a significant increase of p-HSP27 level has appeared. TUNEL and PARP cleavage assay did not show any apoptotic HUVEC cells after stimulation with monocytes. The main observations of this study indicate that monocytes do not trigger apoptosis of vascular endothelial cells. Proapoptotic activation mediated by PUMA that was observed seemed to be counterbalanced by significant increase of antiapoptotic HSP70, HSP27 and especially phospho-HSP27 proteins level.

The hypothesis was tested that peripheral, adrenergic nerves modulate reactive hyperemia (RH) in the intestinal circulation. In anesthetized rats, anterior mesenteric arterial occlusion for 30-120 s elicited subsequent RH responses, including 63-118% increases in the velocity of arterial blood flow, even greater increases in conductance, and durations of 64-139 s. The longer the period of arterial occlusion, the greater the magnitude of RH. Electrical stimulation of postganglionic, sympathetic nerves reduced RH responses in a frequency-dependent manner. RH responses were enhanced by pretreatment with hexamethonium and phenoxybenzamine and were diminished by pretreatment with propranolol. Propranolol also prevented the enhanced RH responses caused by hexamethonium and phenoxybenzamine. Reserpine prevented the enhanced RH responses to hexamethonium, but bilateral adrenalectomy did not. These findings support the hypothesis that peripheral sympathetic nerves modulate RH in rat gut, with alpha-adrenergic receptors restricting and beta-adrenergic receptors enhancing the hyperemia.

The influence of fungal colonization on the course of ulcerative colitis (UC) has not been thoroughly studied. We determined the activity of the disease using clinical, endoscopic and histological index (IACH) criteria in UC patients with fungal colonization and the healing process of UC induced by an intrarectal administration of trinitrobenzene sulfonic acid (TNBS) in rats infected with Candida, without and with antifungal (fluconazole) or probiotic (lacidofil) treatment. The intensity of the healing of the colonic lesions was assessed by macro- and microscopic criteria as well as functional alterations in colonic blood flow (CBF). Myeloperoxidase (MPO) content and plasma proinflammatory cytokines IL-1beta and TNF-alpha levels were evaluated. Candida more frequently colonized patients with a history of UC within a 5-year period, when compared with those of shorter duration of IBS. Among Candida strains colonizing intestinal mucosa, Candida albicans was identified in 91% of cases. Significant inhibition of the UC activity index as reflected by clinical, endoscopical and histological criteria was observed in the Candida group treated with fluconazole, when compared to that without antifungal treatment. In the animal model, Candida infection significantly delayed the healing of TNBS-induced UC, decreased the CBF and raised the plasma IL-1beta and TNF-alpha levels, with these effects reversed by fluconazole or lacidofil treatment. We conclude that 1) Candida delays healing of UC in both humans and that induced by TNBS in rats, and 2) antifungal therapy and probiotic treatment during Candida infection could be beneficial in the restoration and healing of colonic damage in UC.

In the present study on animal model of ulcerative colitis the influence of fungal colonization on the severity of inflammatory lesions in the colon and the course of their healing was evaluated. The results of our studies revealed, that significant fungal colonization (over 10(4) CFU/ml) delayed ulcer healing in the colon. It corresponded with the decrease of colonic blood flow (CBF) in the region of lesions and increase of interleukin (IL)-1beta, tumor necrosis factor(TNF)-alpha level in the serum. Introduction of antifungal therapy (fluconazole) or probiotic in rats inoculated with Candida accelerated the process of ulcer healing in the colon, expressed through the reduction of macro- and microscopic lesions in the colon and decrease of MPO, IL-beta TNF-alpha serum level.

Prostaglandins mediate various physiological aspects of mucosal defense and the suppression of prostaglandin synthesis in the stomach is a critical event in terms of the development of mucosal injury after NSAID administration. However, it has become clear that other mediators besides prostaglandins can similarly act to protect the stomach from injury. 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. Thus, administration of NO in a form of NO-donors exert protective influence on the stomach from the injury that usually occurs when mucosal prostaglandin levels are suppressed. The new class of NO releasing NSAIDs, including NO-aspirin, represent a very promising approach to reducing the toxicity of anti-inflammatory drugs. Lipoxins are another group of lipid mediators that can protect the stomach. Aspirin-triggered lipoxin synthesis, via COX-2, acts to reduce the severity of damage induced by this drug. Lipoxin analogues may prove to be useful for preventing mucosal injury and for modulating mucosal inflammation. Aspirin-triggered lipoxin also seems to play in important role in gastric adaptation during chronic aspirin administration. Suppression of COX-2 activity by selective COX-2 inhibitors abolishes the production of this endogenous gastroprotective substance and diminishes the gastric tolerability of NSAIDS and gastric adaptation to these drugs. This review was designed to give an updated overview on the physiological factors and experimental and clinical attempts that were used or may be used in the future as the therapeutic approach to counteract adverse effects in the stomach associated with NSAID ingestion.

The progress in basic and clinical gastrology indicates that gastric mucosal integrity represents a balance between offensive and defensive factors. The main offensive factors appear to be gastric acid and pepsin under health conditions, while the nonsteroidal anti-inflammatory drugs (NSAID) and Helicobacter pylori (H. pylori), infecting this mucosa, are currently considered the most important "aggressive" factors under pathological conditions. To the list of the aggressive factors, also stress, certain cytokines (TNF-alpha, IL-8, IL-11 and IL-18) and oxygen or nitrogen free radicals should be added. The aims of this review is the presentation of the involvement of aggressive and protective factors in the control of gastric acid secretion and appetite regulating hormones in maintaining gastric mucosal integrity and its protection against damaging factors.

The involvement of peroxisome proliferator-activated receptors (PPARs) in the cancer cell elimination through apoptosis is a generally accepted fact. However, some reports indicate that the activation of PPARgamma is directly responsible for carcinogenesis. Caco-2 cells, a human adenocarcinoma cells, were used as a model of colon cancer. Cell cultures (5 x 10(6) cell per dish) were pretreated for 24 h with PPAR gamma agonists ciglitazone (CI, 1 x 10(-6)M) and retinoic acid (RA, 1 x 10(-6)M) and part of the cultures were subsequently subjected to gamma-radiation (photons) with therapeutic dose of 2,5 Gy. Total cellular RNA and proteins (cytoplasmic and nuclear) were isolated 24h after cultures irradiation or 48 h after stimulation in the non irradiated part of experiment to preserve the equal growth time for all samples. gamma-Irradiation of the cells abolished nuclear translocation of PPARgamma under its agonists treatment and preserved PPARgamma in the cytoplasmic pool. But it did not affect the HSP 70 expression in response to ciglitazone and retinoic acid. Moreover, combined gamma-irradiation and CI/RA treatment of the cells changed the equilibrium between Bax and Bcl-2 mRNA to anti apoptotic state with increased expression of Bcl-2 and almost abolished expression of Bax. In conclusion, this paper provides an evidence for the anti-apoptotic action of PPARgamma agonists used along with the gamma-radiation. Moreover, it shows that the up-regulated HSP70, in response to PPARgamma agonists in gamma-irradiated cultures promotes cell survival.

Bacterial endotoxin (lipopolysaccharide, LPS), is the component of the cellular wall of Gram negative bacteria. Endotoxemia (sepsis) could produce multiorgan failure and could be particularly danger in the early period of life. The effects of endotoxemia induced in the neonatal period of life on the pancreatic secretory function and on pancreatic defense of adult organism have not been investigated yet. To induce endotoxemia suckling rats (30 g) have been injected intraperitoneally with LPS from E. coli (5, 10 or 15 mg/kg-day) during 5 consecutive days. Three months later in these animals (300 g) the studies on pancreatic secretion and acute pancreatitis were carried out. In the adult rats, which have been subjected in infancy to endotoxemia, basal pancreatic secretion was unaffected, whereas amylase secretions stimulated by caerulein or by diversion of pancreatic-biliary juice to the exterior were significantly, and dose-dependently reduced as compared to the untreated control. In the rats pretreated with LPS in the suckling period of life caerulein-induced amylase release from isolated pancreatic acini was significantly decreased, and dose-dependent reduction of mRNA signal for CCK1 receptor on pancreatic acini have been observed. Caerulein infusion (25 microg/kg) produced caerulein induced pancreatitis (AP) in all animals tested, that was confirmed by histological examination. In the rats, which have been subjected in the neonatal period of life to LPS (10 or 15 mg/kg-day x 5 days) all manifestations of AP have been reduced. In these animals acute inflammatory changes of pancreatic tissue have been significantly diminished. Pancreatic weight and plasma lipase activity, have been markedly decreased in these animals as compared to the control rats, subjected in the infancy to saline injection instead of LPS. Caerulein-induced fall in an antioxidative enzyme; SOD concentration was reversed and accompanied by significant reduction of lipid peroxidation products; MDA+ 4 HNE in the pancreatic tissue.1/ neonatal endotoxemia reduces gene expression for CCK1 receptor and could produce impairment of the exocrine pancreatic function at adult age; 2/ Prolonged exposition of suckling rats to bacterial endotoxin attenuated acute pancreatitis induced in these animals at adult age and this effect could be related to the increased concentration of antioxidative enzyme SOD in the pancreatic tissue.