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PubMed1992

Cytoprotection by 16,16-dimethylprostaglandin E2. Role of gastric juice and mucus gel layer.

A mechanism of cytoprotection by 16,16-dimethylprostaglandin E2 (16,16-dimethyl-PGE2) was investigated in rats with respect to possible roles of the gastric juice and the mucus gel layer. 16,16-Dimethyl-PGE2 significantly increased the volume of gastric juice and mucus thickness. In a gastric juice-emptied stomach, 16,16-dimethyl-PGE2 protected the gastric mucosa against 30% ethanol, but not against 40% ethanol. Moreover, this agent did not show any cytoprotective action even against 30% ethanol when both gastric juice and mucus gel were removed. In this situation there was no histological change in the depth of injury, whether 16,16-dimethyl-PGE2 was given as pretreatment or not. These results suggest that there are two mechanisms that may play major roles in the cytoprotection of the gastric mucosa by 16,16-dimethyl-PGE2: (a) dilution of necrotizing agents by increased gastric juice and (b) thickening of the mucus gel layer.

Animals↗

PubMed1990

[Cytoprotection by 16,16-dimethyl prostaglandin E2--role of gastric content and mucus gel layer].

The mechanism of cytoprotection by prostaglandins (PGs) is still unknown, although many hypotheses have been proposed. We postulated a hypothesis that increased gastric content and thickened mucus gel layer by PGs may protect the gastric mucosa against damage from necrotizing agents. Two series of experiments were performed on Wistar male rats, weighing 250-300 g. (1) 16,16-dimethyl prostaglandin E2 (dmPGE2) in doses of 20 micrograms/kg was given orogastrically. Fifteen minutes later, the stomachs were emptied and/or the mucus gel layer removed, and several concentration of ethanol applied. After ten minutes, the stomachs were removed and lesions of the gastric mucosae were evaluated macroscopically and histologically. (2) Volume and pH of the gastric content and mucus thickness were measured 15 minutes after dmPGE2 administration. DmPGE2 did not protect the gastric mucosa against 40% ethanol in the emptied stomach. This agent had no cytoprotective action on the emptied and mucus gel-removed stomach in 30% ethanol application. These results had no significant difference with control group (saline 1 ml p.o.) about the extent of erosion. In histological study of the erosive region by scanning and light microscopy, we also found no differences in the depth of erosion between dmPGE2 group and control. In addition, dmPGE2 increased the gastric volume and mucus thickness significantly. These data suggest that following two effects by PGs play major role in cytoprotection of the gastric mucosa; (1) dilution of necrotizing agents by increased gastric content, and (2) thickening of the mucus gel layer.

16,16-Dimethylprostaglandin E2↗

PubMed1990

Adaptive cytoprotection of gastric surface epithelial cells against injury by physiologic concentrations of bile acid.

The purpose of this study was to determine whether adaptive cytoprotection of gastric mucosa could be demonstrated with concentrations of bile acid, which is normally found in the human stomach, and whether cyclooxygenase inhibition, in turn, could blunt the response. Surface epithelial cell exfoliation and ion fluxes were used as end points. A transduodenal gastric cannula was placed, and the pylorus/gastroesophageal junction was ligated in adult male Sprague-Dawley rats that had been anesthetized. In experiment 1 (N = 30), rat stomachs were exposed for 15 minutes to 5 ml of either a neutral test solution (160 mmol/L NaCl, pH 7) or 1 mmol/L acidified taurocholate (ATC) (100 mmol/L HCl, 60 mmol/L NaCl, 1 mmol/L taurocholic acid; pH 1.2). All rats were subsequently exposed for 15 minutes to 5 mmol/L ATC during which time mucosal injury was assessed by measuring net flux of H+, Na+, and K+, volume, and DNA efflux. In experiment 2 (N = 35), all stomachs were pretreated for 15 minutes with 1 mmol/L ATC before mucosal injury with 5 mmol/L ATC (15 minutes). Eighteen rats were pretreated with indomethacin (5 mg/kg) subcutaneously 75 minutes before the experiment was begun, and the same parameters were measured. Pretreatment of rat gastric mucosa with 1 mmol/L ATC significantly attenuated the mucosal injury that was seen with subsequent exposure to 5 mmol/L ATC, resulting in significantly (p less than 0.05) less luminal H+ loss (-16 +/- 4 vs -32 +/- 4 mEq/15 min) and DNA efflux (181 +/- 21 vs 270 +/- 25 micrograms/15 min) than the nonadapted group. Indomethacin pretreatment significantly attenuated the adaptive protective response, resulting in greater loss of H+ (-29 +/- 4 vs -18 +/- 3) and DNA efflux (190 +/- 35 vs 110 +/- 18, both p less than 0.05) after exposure to 5 mmol/L ATC. These studies demonstrate that adaptive cytoprotection of gastric mucosa occurs with physiologic concentrations of an irritant that is normally present in the stomach. Indomethacin blunts this effect, which suggests that adaptive cytoprotection in this setting may be mediated by production of endogenous prostaglandins.

Acids↗

PubMed1989

The cytoprotective effect of the desamino-D-Trp 7-10 fragment of somatostatin on ethanol-induced erosions in the rat stomach.

The concept of cytoprotection was established by Robert. It means that several materials of different structure and in doses which are not antisecretoric ones, can protect the gastric mucosa against exogenous noxous agents. Absolute ethanol causes haemorrhagic erosions on the rat gastric mucosa. Somatostatin (SRIF) and its 7-10 fragment, which is the active centre of the hormone were cytoprotective in the ethanol-induced cytoprotective model. The desamino-D-Trp fragment (a suspected enzyme resistant variant of the active centre of SRIF) is also protective. It decreases significantly the extension of the lesions. Its dose-response curve shows two peaks, which may correspond to the existence of two SRIF receptor types, described in the rat gastric mucosa.

Animals↗

PubMed1989

The free radical mechanisms in beta-carotene induced gastric cytoprotection in HCl model.

The aims of our experiments were to clear up the possible correlations between the free radical mechanisms and the gastric cytoprotection of beta-carotene on HCl-induced gastric mucosal lesions. The beta-carotene was intragastrically given in doses of 1 and 10 mg/kg and 30 min. later 1 ml 0.6 N HCl was given to provoke the mucosal damage. After 1, 5, 15, 30 and 60 min. the animals were sacrificed. The number and severity of gastric mucosal lesions were calculated. The superoxide dismutase (SOD), glutathion peroxidase (GPX), catalase (CAT) activity and the malondialdehyde (MDA) and reduced glutathion (GSH) contents were determined from the gastric mucosa of rats. It was found that 1. beta-carotene was able to reduce the number and severity of ulcers only after 30 min.; 2. the CAT activity was decreased at 60 min. by carotene; 3. the GPX activity became dissimilar in the different groups after 15 min; 4. the changes of GSH were found to be similar ones; 5. the SOD activity was lower during the cyto-protection; 6. the MDA level remained practically unchanged. It has been concluded that 1. the free radicals are the consequences of the development of gastric ulcer and cytoprotection; 2. the scavenger character of beta-carotene is involved in its cytoprotective effect.

Animals↗

PubMed1985

Can acid inhibitors be "true" cytoprotective agents?

Cytoprotection is a biological process occurring independently of gastric acid inhibition. Evaluation of the possible cytoprotective activities of antisecretory drugs is therefore difficult, unless appropriate experimental models are employed. The results of cytoprotection studies with gastric acid inhibitors are reported and reviewed herein.

Animals↗

PubMed1988

Cytoprotective drugs: a new perspective in the treatment of adverse reactions to foods.

Food allergy (FA) and food intolerance (FI) are complex syndromes caused by adverse reactions to foods. Since mucosal permeability of the digestive tract is often increased during this pathology, we evaluated the clinical efficacy of two different cytoprotective drugs in patients with urticaria-angioedema due to FA and FI. These drugs were pirenzepine, an anti-muscarinic (anti-MI) receptor antagonist, and rosaprostol, a synthetic prostaglandin. Further, the results obtained by these schedules of treatment were compared with those achieved by the previously described polyantihistaminic treatment (ie, the association of anti-H1 plus anti-H2 receptor blockers). The present investigation suggests that the cytoprotective drugs are more effective than the antisecretive ones (ie, the anti-H2). Recently, anti-H2 drugs and ketotifen were shown to be in vitro inhibitors of the immune response and cromolyn was demonstrated capable of exerting an enhancing effect on T cell proliferation. In the present study we tested the effect of pirenzepine on several immunologic parameters, such as lymphocyte proliferation (through different activation pathways) and lymphokine (interleukin-2 and interferon-gamma) production. Since we found that pirenzepine does not affect the immune response and in consideration of its clinical efficacy, we consider this cytoprotective drug a valuable tool in the treatment of adverse reactions to foods.

Adult↗

PubMed1986

Evidence of the gastric cytoprotective effects of vitamin A, atropine and cimetidine on the development of gastric mucosal damage produced by administration of indomethacin in healthy subjects.

Certain compounds such as prostaglandins, atropine, cimetidine and carotenes are able to prevent the development of gastric mucosal damage produced in experimental animals or in man by intragastric administration of necrotizing agents such as indomethacin without significantly inhibiting gastric acid secretion. The clinical background of this gastric cytoprotection and its importance for man is not yet known, although the beneficial effects of these compounds have been demonstrated in human therapy. In the present study, carried out in 66 healthy human subjects, it was found that vitamin A at a dose of 100,000 IU i.m., atropine at 0.125 mg i.m., and cimetidine at 12.5 mg i.m., which doses do not inhibit the gastric basal secretion nor the maximal secretory response to pentagastrin stimulation, each prevented the gastric microbleeding produced by the oral application of indomethacin. It is concluded that this gastric cytoprotection, characteristic of prostaglandins but extending to atropine, cimetidine and vitamin A, holds good in man as well as experimental animals. Thus the potential clinical significance of gastric cytoprotection induced by these compounds may be considerable.

Atropine↗

PubMed1984

Cytoprotection by somatostatin of normal and malignant clonogenic cells against the in vitro cytotoxicity of bischloroethylnitrosourea (BCNU).

The various pharmacological effects of somatostatin may be explained by the hypothesis that the paracrine peptide, by "stabilizing" cell membranes, inhibits the secretion of hormones as well as protects other cells (vascular endothelium, parenchyma) from different lesions (vasculo-, organo-, cytoprotection). This hypothesis was tested in vitro, using bischloroethyl-nitrosourea (BCNU)-intoxicated stem cells of normal mouse granulopoiesis and of the L 1210 leukemia. Clonogenic mouse bone marrow and L 1210 cells were grown in agar-containing glass capillaries. Using these colony assays and a ID90 of BCNU, cyclic somatostatin influenced the BCNU-cytotoxicity neither at simultaneous nor at subsequent application. However, when given 2 h prior to BCNU, the inhibition of colony growth was almost totally abolished. This cytoprotective effect was seen with normal granulopoietic as well as with leukemic cells. The effect did not show up, if the inactive linear somatostatin was used. N-acetyl-cysteine, a SH-compound applied as a chemoprotective adjunct, did not reveal a cytoprotective effect under identical experimental conditions, either. The results were discussed in view of common efforts to reduce the toxicity of cancer chemotherapy.

Acetylcysteine↗

PubMed1982

Gastric cytoprotection by antacids and papaverine in rats.

Prostaglandin E2 (PGE2) prevented hemorrhagic ulceration of rat stomach mucosa induced by various procedures when given orally at a non-antisecretory dose. This effect of PGE2 is called gastric cytoprotection. We used absolute ethanol, 0.6 N hydrochloric acid and 0.2 N sodium hydroxide as damaging agents. Ranitidine at an antisecretory dose did not exhibit any cytoprotective effect. However, the poorly absorbable antacids, magnesium hydroxide plus aluminium hydroxide and aluminium phosphate inhibited the development of hemorrhagic lesions significantly. A similar protective effect was seen after intragastric administration of papaverine, which is known to stimulate endogenous prostaglandin synthesis. However, the question as to whether or not stimulation of endogenous prostaglandin synthesis is the mode of action of the cytoprotective effect of papaverine and poorly absorbable antacids, cannot yet be answered.

Aluminum Compounds↗

PubMed1984

The effect of gastric cytoprotective drugs (atropine, cimetidine, vitamin-A) on the indomethacin induced intestinal ulcers in rats.

The effect of various gastric cytoprotective drugs was studied on the development of indomethacin induced intestinal ulcers. CFY strain rats weighing 200-250 g were used. Indomethacin in a single dose of 20 mg/kg was given intragastrically in 1.5 ml. The animals received atropine (0.025-0.2-1.0 mg/kg), cimetidine (2.5-10-50 mg/kg) or vitamin-A(0.1-1.0-10 mg/kg) intraperitoneally in a single dose 15 min before the administration of indomethacin. In another study the animals received the same doses of atropine twice a day for 3 days. The small intestine was examined for lesions consisting of: (a) palpable nodules on the mesenteric attachement: (b) ulcers in the jejunum and ileum: (c) adhesions as a consequence of ulcer perforation. Neither histamin H2 receptor antagonists, anticholinergics, nor vitamin-A affected the number and the severity of the indomethacin induced intestinal ulcers. These results suggest that, whereas atropine, cimetidine and vitamin-A have a cytoprotecting effect in the stomach, it appears that they have no role in intestinal cytoprotection.

Animals↗

PubMed1984

Gastrointestinal cytoprotection by indomethacin + sodium salicylate combination in rat.

Non-steroidal antiinflammatory agents are well known to cause gastrointestinal damage in many species including the rat and human. Pelsonin a combination of indomethacin and sodium salicylate (1:10 ratio) has a cytoprotective effect against acidic-alcohol induced gastric necrosis, and it does not induce intestinal ulceration. Pelsonin is capable of blocking the formation of intestinal ulcers induced by oral indomethacin 10 mg/kg (curative cytoprotection). The cytoprotective potency of Pelsonin is due to sodium salicylate.

Animals↗

PubMed1984

Effects of a gastric antisecretory-cytoprotectant 2-methyl-8-(phenylmethoxy)imidazo[1,2-a]pyridine-3-acetonitrile (Sch 28 080) on cysteamine, reserpine and stress ulcers in rats.

Prostaglandin E2 and carbenoxolone, putative cytoprotective agents, were tested in cysteamine, reserpine and stress ulcers in rats. In cysteamine-induced duodenal ulcer, PGE2 was inactive at 0.1 and 0.5 mg/kg p.o.; carbenoxolone at 100 mg/kg p.o. decreased the incidence but not the severity of the ulcer. PGE2 at 5.0 mg/kg p.o. and carbenoxolone at 300 mg/kg p.o. showed moderate effects, but the dosage also inhibited cysteamine-stimulated acid secretion. PGE2 (0.1 and 0.3 mg/kg p.o.) was inactive and carbenoxolone (100 and 300 mg/kg p.o.) further aggravated the gastric ulceration caused by reserpine or cold-restraint stress. In contrast, atropine (3 and 10 mg/kg p.o.) and cimetidine (30, 100 and 300 mg/kg p.o.) were active in all three ulcer models. But the results with cimetidine in stress ulcer were somewhat variable. 2-methyl-8-(phenylmethoxy) imidazo [1,2-a] pyridine-3-acetonitrile (Sch 28 080), a novel structure with both cytoprotective and antisecretory activity, was highly efficacious in cysteamine, reserpine and stress ulcers (1-30 mg/kg p.o.), which was presumably adequately accounted for by its potent antisecretory activity. It is concluded that cysteamine, reserpine and stress ulcers may not be appropriate models for testing the potential antiulcer effect of primarily cytoprotective compounds.

Animals↗

PubMed1982

Gastric cytoprotection by pirenzepine. Role of endogenous prostaglandins.

This study compared the effects of pirenzepine, a novel selective antimuscarinic agent, and PGE2 applied topically on the gastric mucosa or parenterally on gastric secretion and formation of ASA and ethanol-induced gastric ulcerations in rats. Pirenzepine given topically in nonantisecretory dose prevented the formation of gastric ulcerations induced by ASA + 0.15 M HCl and absolute ethanol. These cytoprotective effects were comparable to those observed after PGE2 administered intragastrically or subcutaneously. Pirenzepine did not affect ulcer formation by ASA combined with 0.30 M HCl, whereas PGE2 was fully effective under these conditions. The cytoprotective action of pirenzepine was not accompanied by any change in the mucosal generation of PGs, indicating that endogenous PGs do not contribute to the cytoprotective property of this agent.

Animals↗

PubMed1982

Prostacyclin-mediated gastric cytoprotection is dependent on mucosal blood flow.

Although prostacyclin (PGI2) causes an increase in resting gastric mucosal blood flow, this effect is not thought to be correlated with its cytoprotective action. This study questions that hypothesis by assessing whether PGI2 cytoprotection occurs in the presence of decreased gastric mucosal blood flow. Twenty-four miniature swine were anesthetized with chloralose, ventilated, and catheterized to measure cardiac output and arterial pressure and to inject microspheres. An orogastric tube was placed for infusion of 2.5% autogenous bile in isotonic HCl (2 ml/kg/hr). Four experimental groups were used: I, control (no drugs); II, vasopressin (0.25 U/min intravenously); III, PGI2 (0.1 micrograms/kg/min intravenously); and IV, vasopressin and PGI2 combined. Gastric mucosal blood flow was documented at baseline and at 1, 2, and 3 hours of drug infusion by radiolabeled-microsphere technique. Stomachs were harvested and photographed, and lesions were scored (0 to 3) by blinded observers. Gastric mucosal blood flow was decreased (50%) in both groups that received vasopressin, increased (300%) in animals that received PGI2 alone, and unchanged in controls. All animals that received vasopressin, whether alone or with PGI2, developed mucosal injury (mean score 2.5 versus (2.2). Group I and group III animals did not develop lesions. The results of this study demonstrate that PGI2 failed to elevate gastric mucosal blood flow, which was already depressed to vasopressin, and that PGI2 failed to protect the gastric mucosa from injury in the presence of reduced blood flow. This suggests that PGI2 cytoprotection is linked to its effect on gastric mucosal blood flow.

Animals↗

PubMed1982

Do cytoprotective prostaglandins act as mild irritants?

Of the various mechanisms proposed to explain the cytoprotective properties of prostaglandins, mucus discharge seems the most probable. Mild irritants capable of eliciting mucus release have also been shown to exert cytoprotection. It is suggested that prostaglandins act as mild irritants of the mucosa and that cytoprotection is a mucosal reaction to mild irritation, through stimulation of mucus discharge.

Adenylyl Cyclases↗

PubMed1980

[Clinical aspects of cytoprotection with prostaglandin analogs].

Various prostaglandins posses antisecretory and cytoprotective actions on gastric mucosa. Cytoprotection by prostaglandins is unrelated to the inhibition of gastric acid secretion and can also be detected in small intestinal mucosa of the rat. Prostaglandins protect gastric mucosa against ulcerogenic compounds such as nonsteriod anti-inflammatory agents (NOSAC) as well as against the necrotizing affect produced by alcohol, 25% sodium chloride, 0.2 N solium hydroxide and 0.6 N hydrochloride acid. Prostaglandins protect in doses that are far too small to inhibit gastric acid secretion. At these doses no side-effects have been noted so far. This cytoprotective effect of prostaglandins might be beneficial in the treatment of a variety of diseases in which gastric mucosal injury in present.

Animals↗

PubMed1995

The cytoprotective effect of the immunomodulator AS101 against hydrochloride induced gastric lesions.

AS101 as a new immunomodulator has been shown to induce production of a variety of cytokines such as interleukin-1, interleukin-2, colony-stimulating factor, interferon-gamma and tumor necrosis factor, and demonstrate a potential chemo-protection from chemotherapy induced immunosuppression and hematopoietic toxicity in tumor bearing mice and cancer patients on phase I and II clinical trials. This study was designed to verify whether AS101 exerts a cytoprotective effect in rats and mice with gastric lesions induced by intragastric (i.g.) instilling of 0.6N hydrochloride (HCl). AS101 given intraperitoniously (i.p) 2h before a HCl administration markedly prevented HCl-induced gastric lesions both in rats and mice. It also accelerated the ulcer repair when given i.p. 1h after a HCl treatment. Indomethacin (IND), a cyclo-oxygenase inhibitor, given i.p. at a non-ulcerogenic dose of 5mg/kg 1h before AS101 administration, abolished its protective effect. Mechanistic analysis showed that the gastric cytoprotective property of AS101 appears to be mediated through the induction of prostaglandin E2 (PGE2) and epidermal growth factor (EGF), of which, both prevent the gastric mucosa from HCl ulceration while EGF also contributes to the promotion of ulcer repair. This study adds another cytoprotective property to the known immunomodulating role of AS101.

Adjuvants, Immunologic↗