Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Cytoprotection”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1998

Gastric cytoprotection is secondary to increased mucosal fluid secretion: a study of six cytoprotective agents in the rat.

We tested the hypothesis that rapidly developing gastric cytoprotection produced by topical application of exogenous compounds is a result of increased gastric mucosal fluid secretion. Ex vivo gastric chambers were prepared in rats which were subsequently exposed topically to one of the prostaglandin (PG) E1 analogues misoprostol or rioprostil, PGE2, nicotine, N-ethylmaleimide (NEM), 0.25 M HCl, or to their respective vehicles. All agents were added to empty chambers to avoid complications resulting from dilution by gastric contents. Effects of these agents on intraluminal volume changes, blood flow, juxtamucosal pH, histology, and on the mucosal damage resulting from necrotizing agents were studied. All six agents were cytoprotective and each increased net secretion of fluid by the chambered mucosae. Gastric blood flow was not significantly increased by NEM, by 0.25 M HCl, or by nicotine compared to controls, and the juxtamucosal pH was not significantly increased by any of the three agents for which this was studied. Vacuole formation in surface epithelial cells and subepithelial edema were seen after exposure to some agents, but none of the agents led to formation of a thick barrier of exfoliated cells and mucus. Ablation of primary afferent nerves with capsaicin abolished both protection by 0.25 M HCl and the net increase in fluid secretion by the mucosae. Capsaicin ablation did not alter either the protection afforded by NEM or the increase in volume of secretion. We conclude that increased mucosal fluid secretion is the common factor present with all six cytoprotective agents and hence may be the predominant mechanism of cytoprotection against topically applied necrotizing agents.

Animals↗
PubMed1985

Cytoprotective agents and ulcer relapse.

This study establishes that real differences between relapse rates exist, and confirmed previous observations by Pounder et al. that relapse rates influence clinical outcomes in ulcer populations. The results make it clear that the way in which a drug influences relapse is an important determinant of therapeutic efficiency, additional to the requirement for healing efficiency. Cytoprotective agents as a group appear to be associated with lower relapse rates than cimetidine. It is not known whether the differences are peculiar to cimetidine, specific to the blockade of H2-histamine receptors, or whether they relate to the process of inhibition of secretory processes generally. Clearly, further comparisons are needed; however, conventional clinical trials are not designed to provide the necessary information. For the healing of peptic ulcers, lower relapse rates appear to provide therapeutic advantage to members of the cytoprotective group when compared with agents acting via anti-secretory mechanisms, in addition to that associated with the local (non-systemic) mode of action where applicable.

Aluminum↗
PubMed1985

Gastric cytoprotection by pirenzepine in rats: evaluating method for cytoprotective activity by antisecretory agents.

The effects of antisecretory agents, pirenzepine, atropine and cimetidine, on gastric mucosal lesions induced in rats by ethanol, HCI (0.6 N), HCI-acidified 50% ethanol and HCI-acidified 50 mM sodium taurocholate (TCA) were comparatively studied with PGE2. The involvement of gastric acid in the formation of ethanol-induced necrosis was also studied. PGE2 and pirenzepine inhibited necrosis induced by all necrotizing agents at the non-antisecretory doses, and the cytoprotective effect of pirenzepine was not abolished by indomethacin. Atropine and cimetidine did not inhibit HCI-induced necrosis even at the antisecretory dose. Atropine and cimetidine at the antisecretory dose inhibited necrosis induced by ethanol, but did not inhibit the red streaks. The ethanol-induced necrosis was also inhibited by neutralizing intragastric H+ with Tris buffer. In gastric fistula rats, alkalinization of the lumen was observed by exposure to ethanol, but necrosis was not produced. There is a close relationship between the necrosis and intragastric acid. Thus it is assumed that gastric acid is involved in the formation of ethanol-induced necrosis. It was suggested that pirenzepine possesses cytoprotective action which is not related to endogenous PGs. On the other hand, the antiulcer actions of atropine and cimetidine may be due, in a part, to antisecretory effects.

Animals↗
PubMed1988

Adaptive cytoprotection by 0.25 M HCl is truly "cytoprotective" and may not depend upon elevated levels of prostaglandin synthesis.

The ability of a mild irritant to reduce ethanol-induced damage to the rat gastric mucosa was investigated using an ex vivo gastric chamber preparation. Exposure to 0.25 M hydrochloric acid (HCl) did not cause significant damage to the surface epithelium, but did reduce both the lesion area and the extent of superficial epithelial damage caused by subsequent exposure to 40% ethanol (EtOH). "Adaptive cytoprotection" was also demonstrated by the reduction of ethanol-induced changes in transmural potential difference and net K+ efflux, and by rapid recovery of these physiological parameters following the removal of ethanol from the chamber. Pretreatment of rats with indomethacin at a dose that has been shown to significantly inhibit gastric cyclooxygenase activity did not significantly affect the ability of 0.25 M HCl to reduce the effects of ethanol on lesion area, epithelial damage, potential difference, and net K+ efflux.

Animals↗
PubMed1987

Cytoprotective action of histamine against 0.6 N HCl-induced gastric mucosal injury in rats; comparative study with adaptive cytoprotection induced by exogenous acid.

We examined the effects of histamine 2HCl (a stimulator of endogenous acid production) and exogenous acid on transmucosal potential difference (PD) and pH of anesthetized rat stomachs, in order to investigate the mechanism underlying the protective action of histamine against 0.6 N HCl-induced gastric mucosal injury in conscious rats. Subcutaneously administered histamine (3-20 mg/kg) dose-dependently produced a decrease in the PD and pH, and it reduced the severity of gastric mucosal injury caused by 0.6 N HCl. Both indomethacin (5 mg/kg, s.c.) and cimetidine (100 mg/kg, s.c.) completely reversed the protection afforded by histamine (20 mg/kg), although the decreased PD and pH responses were unaffected or inhibited, respectively, by indomethacin or cimetidine. Protective action of histamine was also partially mitigated by omeprazole (30 mg/kg, s.c.) which completely abolished histamine-induced acid secretion. On the other hand, exposure of the stomach for 10 min to exogenous acid (0.1-0.35 N HCl) caused a PD reduction and an increase of pH, in a concentration-related manner. The injury caused by 0.6 N HCl was prevented by prior exposure to these low concentrations of HCl, and the degrees of inhibition were associated with the concentration of HCl and the magnitude of PD reduction caused by HCl. The pretreatment with indomethacin, but not cimetidine or omeprazole, significantly antagonized the increased pH and mucosal protection induced by 0.35 N HCl. These results suggest that histamine protected the gastric mucosa against 0.6 N HCl-induced injury by two different ways, mediated with endogenous prostaglandins, (a) mainly through stimulation of H2-receptors and (b) partly through adaptive cytoprotection induced by acid.

Adaptation, Physiological↗
PubMed1999

New model of cytoprotection/adaptive cytoprotection in rats: endogenous small irritants, antiulcer agents and indomethacin.

Adaptive cytoprotection in the stomach was originally defined by applying the exogenous irritants only. The contribution of endogenous irritants as inductors of initial lesions was not specially evaluated. No attempt was made to either focus antiulcer agent activity on adaptive cytoprotection, or split their 'cytoprotection' into complex adaptive cytoprotective activity and simple cytoprotective effects. Agents had so far not been applied simultaneously with the second challenge with ethanol (or irritant), when differences between cytoprotection and adaptive cytoprotection appear. Gastrojejunal anastomosis for 24 h in rats was introduced as new model for analyzing cytoprotection/adaptive cytoprotection. The contribution of the up-normal level of endogenous irritants and the endogenous small irritant-induced minor lesions during the adaptive cytoprotection were studied. The effect of late challenge with 96% ethanol in the presence of an up-normal level of endogenous irritants and endogenous small irritant-induced minor lesions was compared with results of classic studies of ethanol-induced gastric lesions in normal rats (1 ml/rat i.g.). Antiulcer agents or a prostaglandins-synthesis inhibitor, indomethacin, given once only in classic studies, were given at several points during injury induction: (i) surgery, (ii) mild ethanol, (iii) strong ethanol, (iv) strong ethanol applied after a suitable period following either mild ethanol or surgery). Their effects were compared in rats treated as follows: exogenous irritant studies (96% or 20% ethanol), exogenous/exogenous irritant studies (20% ethanol 1 h before 96% ethanol), endogenous irritant studies (gastrojejunal anastomosis for 24 h), and endogenous/exogenous irritant studies (gastrojejunal anastomosis for 24 h before 96% ethanol). Characteristic of the various irritants differed: the (preceding) small irritants (exogenous (i.e., mild ethanol in healthy intact rats) (exogenous irritant studies) vs. endogenous (e.g., (increased) gastric acid secretion, duodenal reflux in gastric content in rats with termino-lateral gastrojejunal anastomosis) (endogenous irritant studies)). These factors caused modifications of agents' activities not, as initially thought, giving simple 'cytoprotection', but being only cytoprotective, or adaptive cytoprotective, or both cytoprotective and adaptive cytoprotective. Atropine (10 mg/kg i.p.) and ranitidine (10 mg) had only cytoprotective activity (exogenous irritant-studies), whereas pentadecapeptide BPC157 (10 microg or 10 ng), and omeprazole (10 mg) had mainly adaptive cytoprotective activity (endogenous/exogenous irritant studies) or both cytoprotective and adaptive cytoprotective activities (exogenous/exogenous irritant studies). Augmentation of the lesions by indomethacin (5 mg/kg s.c.), showed that only events preceding the late challenge with ethanol may be prostaglandin-dependent in both models. The second, adaptive cytoprotective part, seen after late ethanol challenge, may be either prostaglandin-dependent (exogenous/exogenous irritant studies) or non-dependent (endogenous/exogenous irritant studies). Both spontaneous lesion reduction, as an essential mechanism of adaptive cytoprotection, and the further lesion reduction by agents, such as pentadecapeptide BPC 157 and omeprazole, suggests that these agents function as an essential link between the various reactions in cytoprotection/adaptive cytoprotection.

Amino Acid Sequence↗
PubMed1997

PGE2-mediated cytoprotection in renal epithelial cells: evidence for a pharmacologically distinct receptor.

Although the exact mechanism of prostaglandin E2 (PGE2)-mediated cytoprotection has not been elucidated, its ability to induce cytoprotection in cell culture suggests this action occurs at the cellular level. The present studies were conducted to determine whether PGE2 induces protection against 2,3,5-(trisglutathion-S-yl)-hydroquinone [2,3,5-(trisglutathion-S-yl)-HQ]-mediated cytotoxicity in a renal proximal tubule epithelial cell line (LLC-PK1) and to delineate the cellular and molecular mechanisms associated with this response. Pretreatment of LLC-PK1 cells with 0.01-40 microM PGE2 for 24 h fully protects against a moderately toxic concentration of 2,3,5-(trisglutathion-S-yl)-HQ. PGE2-mediated cytoprotection is observed in cells pretreated at pH 7.4 but not at pH 7.8. However, cytoprotection is observed in LLC-PK1 cells pretreated with the PGE2 analog, 11-deoxy-16,16-dimethyl PGE2 (DDM-PGE2) but not with the PGE2 receptor [E-prostanoid (EP)] agonists 17-phenyltrinor PGE2 (EP1), 11-deoxy PGE1 (EP2/EP4), sulprostone (EP1/EP3), PGE1, or PGA2. 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent activator of protein kinase C (PKC), also induces cytoprotection, supporting a role for this pathway in the cytoprotective response. PGE2, DDM-PGE2, and TPA all induce the binding of nuclear proteins to a TPA responsive element (TRE), whereas analogs that did not induce cytoprotection (PGE1, 17-phenyltrinor PGE2, sulprostone) were without effect. DDM-PGE2- and TPA-mediated cytoprotection and TRE binding activity are inhibited by N-(2[[3-(4-bromophenyl)-2-propenyl]-amino]-ethyl)-5-isoquinolinesulfonam ide (H-89), a PKC inhibitor. These data suggest that cytoprotection by PGE2 and DDM-PGE2 in LLC-PK1 cells is mediated by a PKC-coupled receptor, which is pharmacologically distinct from the presently classified EP receptor subtypes.

16,16-Dimethylprostaglandin E2↗
PubMed2000

DDM-PGE(2)-mediated cytoprotection in renal epithelial cells by a thromboxane A(2) receptor coupled to NF-kappaB.

The present studies were conducted to determine the pharmacological nature of a cytoprotective 11-deoxy-16,16-dimethyl-PGE(2) (DDM-PGE(2)) receptor in LLC-PK(1) cells. DDM-PGE(2)-mediated cytoprotection against 2,3,5-(trisglutathion-S-yl)hydroquinone (TGHQ)-mediated cytotoxicity can be reproduced using thromboxane A(2) (TXA(2)) receptor (TP) agonists (U46619 and IBOP), and the cytoprotective response to DDM-PGE(2) and TP agonists is inhibited by TP antagonists (SQ-29,548 and ISAP). Western blot analysis using an antipeptide antibody against the human platelet TP receptor (55 kDa) identified a particulate associated 54-kDa protein. DDM-PGE(2)-mediated 12-O-tetradecanoyl phorbol-13-acetate (TPA) responsive element (TRE) binding activity is not inhibited by cyclooxygenase inhibitors (aspirin and indomethacin) or a TXA(2) synthase inhibitor (sulfasalazine), suggesting that the biological response to DDM-PGE(2) is not dependent on de novo TXA(2) biosynthesis. Peak DDM-PGE(2)- and U46619-mediated TRE binding activity and nuclear factor-kappaB (NF-kappaB) binding activity are inhibited by SQ-29,548. The full cytoprotective response to DDM-PGE(2) requires an 8-h pulse with agonist. DDM-PGE(2)-mediated TRE and NF-kappaB binding activity remain elevated in the presence of agonist and rapidly decay following agonist washout, suggesting a direct correlation between DDM-PGE(2)-mediated cytoprotection and persistent DNA binding activities. TPA, a protein kinase C activator, induces cytoprotection and a persistent increase of NF-kappaB binding activity. DDM-PGE(2)-mediated cytoprotection and NF-kappaB binding activity but not TRE binding activity are inhibited by sulfasalazine. We conclude that the DDM-PGE(2) receptor is a TP receptor and that the cytoprotective response may be mediated in part by NF-kappaB.

Animals↗
PubMed1989

A pharmacological approach to cellular mechanisms of PGI2-induced gastric cytoprotection on ethanol-induced gastric mucosal damage in rats.

The aims of this study were as follows: 1. to analyse the effects of drugs with different subcellular mechanisms on the PGI2-induced gastric cytoprotection in a non acid dependent (ethanol-induced) gastric ulcer model; 2. to identify the affinity and intrinsic activity curves on the PGI2-induced gastric cytoprotection; 3. to evaluate the main cellular mechanisms of PGI2-induced gastric mucosal defence. The observations were carried out on both sexes of CFY-strain rats, weighing 180 to 210 g. The gastric mucosal damage was produced by intragastric administration of 96% ethanol. The animals were killed at 1 hr after administration of ethanol, and the number and severity of gastric mucosal lesions (ulcers) was noted. Atropine, actinomycin D, cimetidine, mannomustine, dinitrophenol, epinephrine, pentagastrin, histamine, ouabain, tetracycline were given intraperitoneally (in different doses) at 30 min before administration of ethanol. The effects of these drugs were tested on the PGI2-induced (5 micrograms/kg was given intragastrically) gastric cytoprotection. It has been found that: 1. atropine, actinomycin D, cimetidine, epinephrine, ouabain, tetracycline and mannomustine inhibited the PGI2-induced gastric cytoprotection; 2. histamine, pentagastrin and 2,4-dinitrophenol enhanced the PGI2-induced gastric cytoprotection; 3. the molar concentrations of these drugs modifying the PGI2-induced gastric cytoprotection differed significantly. It has been concluded that: 1. the drugs stimulating or inhibiting the cell functions are capable to modify the extent of PGI2-induced gastric cytoprotection; 2. different subcellular mechanisms (oxidative phosphorylation, increased synthesis of proteins, ribonucleic and deoxyribonucleic acids, modifications of membrane-bound ATP-dependent energy systems) are involved in the development of PGI2-induced gastric cytoprotection.

Animals↗
PubMed1998

Histological study of mechanisms of adaptive cytoprotection on ethanol-induced mucosal damage in rat stomachs.

Adaptive cytoprotection in the gastric mucosa could be induced by exposure to low concentrations of noxious agents. However, experimental results reported so far were based on macroscopic studies. We aimed to investigate the phenomenon of gastric adaptive cytoprotection of mild irritants and its correlation with intramucosal mucus at the histological level. It was found that histological damage induced by ethanol had a negative correlation with the length of the mucus-secreting layer in the gastric mucosa. Mild irritants such as 20% ethanol and 5% NaCl preserved the 100% ethanol-induced intramucosal mucus depletion, but only the former agent demonstrated a cytoprotective effect against the histological damage, indicating that preservation of intramucosal mucus may not necessarily play a permissive role in adaptive cytoprotection. The capsaicin-sensitive sensory afferent neurons, sensory chemoreceptors, muscarinic receptors, alpha2-adrenoceptors and peripheral dopamine D2-receptors were found to be the components of the autonomic nervous system involved in the cytoprotective processes of 20% ethanol. Endogenous mediators including nitric oxide, prostaglandins, and possibly nonprotein sulfhydryl compounds also seemed to participate in such protection. Nevertheless, 0.3 M HCl did not show any effect either on mucosal damage or depletion of intramucosal mucus induced by absolute ethanol. These findings suggest that only 20% ethanol shows histological cytoprotection, which would involve various components of the autonomic nervous system and endogenous mediators. Furthermore, this investigation also implies a new perspective: that in order to study a true adaptive cytoprotection, histological examination of the gastric mucosa should be performed.

Adaptation, Physiological↗
PubMed1995

Adaptive cytoprotection in cultured rat gastric mucus-producing cells. Role of mucus and prostaglandin synthesis.

In cultured gastric mucosal cells, we investigated whether: (1) adaptive cytoprotection was associated with stimulation of endogenous prostaglandin synthesis; (2) prostaglandins given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage; and (3) a relationship existed between cytoprotection and mucus release. Cytolysis was quantified by measuring 51Cr release from prelabeled cells. Mucus release was determined by measurement of [3H]glucosamine release. Concentrations of ethanol > 12% caused cell damage and increased 51Cr release dose dependently. Pretreatment with low concentrations of ethanol (0.5-1.5%) decreased ethanol-induced 51Cr release, but also decreased prostaglandin E2 synthesis. Prostaglandin E2 and 16,16-dimethyl prostaglandin E2 given exogenously were cytoprotective against ethanol-induced gastric mucosal cell damage. Treatment with low concentrations of ethanol (1.5%) increased mucus release from cultured gastric mucosal cells. However, prostaglandin E2 and 16,16-dimethyl prostaglandin E2 did not affect mucus release. We conclude that in cultured gastric mucus-producing cells: (1) adaptive cytoprotection occurs without stimulation of endogenous prostaglandin synthesis but with increase in mucus release; and (2) exogenous prostaglandins are cytoprotective against ethanol-induced gastric mucosal cell damage without stimulating mucus release in vitro. We postulate that adaptive cytoprotection in cultured gastric mucus-producing cells is not mediated by prostaglandin, but by mucus released in response to a mild irritant.

16,16-Dimethylprostaglandin E2↗
PubMedDate not supplied

Examination of the mechanisms of action of diverse cytoprotectants in renal cell death.

Glycine, strychnine, muscimol, allopregnanolone, and pregnenolone sulfate act in the late phase of renal cell injury, block Cl- influx and cell lysis induced by the mitochondrial inhibitor antimycin A, and promote the recovery of respiration and ion transport following hypoxia/reoxygenation. However, the mechanism of action of these compounds has not been completely elucidated. Recently, we have shown that calpains are critical mediators of renal cell death produced by diverse toxicants and that antimycin A exposure results in calpain translocation from the cytosol to the membrane fraction that is temporally associated with Cl- influx and precedes cell death/lysis. The current study examined the effects of a group of diverse cytoprotectants on calpain activity and determined if calpain inhibition plays a role in the cytoprotection produced by these compounds. The cytoprotection produced by glycine, strychnine, muscimol, allopregnanolone, and pregnenolone sulfate in rabbit renal proximal tubules exposed to antimycin A was associated with the inhibition of antimycin A-induced calpain translocation. None of the cytoprotectants had a direct effect on calpain activity. All of the cytoprotectants decreased calcium-ionophore-induced cell death. Glycine, strychnine, and muscimol also blocked antimycin A mediated extracellular Ca2+ influx. These data suggest that the cytoprotective mechanism of action of glycine, strychnine, and muscimol involves the inhibition of antimycin A mediated extracellular Ca2+ influx as well as calpain translocation and associated Cl- influx. In contrast, the mechanism of action of the neurosteroids results only from the blockade of calpain translocation and associated Cl- influx.

Animals↗