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PubMed2004

Cytoprotective effects of heme oxygenase-1 induction by 3-O-caffeoyl-1-methylquinic acid.

The novel antioxidant 3-O-caffeoyl-one-methylquinic acid (MCGA3) is a methyl chlorogenic acid derivative isolated from bamboo leaves. MCGA3 scavenges reactive oxygen species (ROS) and inhibits lipid peroxidation and xanthine oxidase in vitro. In this study, we evaluated the cytoprotective effect of MCGA3, which occurs via heme oxygenase-1 (HO-1) induction in bovine vascular endothelial cells exposed to tert-butylhydroperoxide (tBHP). Cells treated with 1 mM tBHP (6-18 h) generated substantial ROS and concomitantly lost most intracellular lactate dehydrogenase (LDH), which then caused necrotic cell death. Of the several MCGA antioxidants and structurally related phenolic acids examined in this study, MCGA3 (0.01-0.15 mM) was found to completely block this necrosis and generation of ROS by tBHP. Surprisingly, MCGA3 by itself was found to be a potent inducer of HO-1. We observed the time- and dose-dependent induction of HO-1 mRNA and protein, which was closely associated with decreased intracellular ROS and necrosis against tBHP. Deesterified or Al-chelated MCGA3 or co-treatment with MCGA3 and actinomycin D abolished HO-1 induction and the antinecrotic effect of MCGA3. Zinc protoporphyrin IX and cycloheximide attenuated the cytoprotection afforded by MCGA3, but did not reduce HO-1 mRNA. Interestingly, N-acetylcysteine (1 mM) enhanced the HO-1 induction of MCGA3, but N-acetylcysteine itself did not induce HO-1. These results suggested that not only ortho-dihydroxyl groups but also aromatic ester and methoxyl ester moieties are necessary for full HO-1 induction and cytoprotection against toxic tBHP-derived ROS. Ferritin mRNA was also upregulated during all HO-1 induction by MCGA3, which might decrease iron and lower ROS levels. Consequently, the combined action of HO-1 and ferritin may protect cells from toxic tBHP-mediated necrosis.

Acetylcysteine↗
PubMed1997

Role of cellular thiol status in tocopheryl hemisuccinate cytoprotection against ethyl methanesulfonate-induced toxicity.

Suspensions of rat hepatocytes treated with the alkylating agent ethyl methanesulfonate (EMS) exhibited extensive lipid peroxidation as well as rapid and near complete depletion of cellular reduced glutathione (GSH) levels prior to cell death. Pretreatment of hepatocytes with medium deficient in sulfur amino acids accelerated cell death induced by EMS, confirming the previously reported cytoprotective role for GSH in this toxic event. Nearly all of the cellular GSH lost following 50 mM EMS treatment was accounted for as S-ethyl glutathione (GS-Et). No significant formation of glutathione disulfide was observed. The GS-Et formed was not exported from the cell but remained at high intracellular concentrations throughout the course of the experiment. In addition, EMS treatment inhibited the efflux of intracellular GSH and inhibited the cellular accumulation of glutamate (Glu). Supplementation of hepatocytes with 25 microM d-alpha-tocopheryl hemisuccinate (TS) protected these cells against EMS-induced lipid peroxidation and cell death. Cytoprotection with TS had no effect on EMS-induced depletion of intracellular GSH or intracellular levels of GS-Et or Glu. However, TS supplementation did prevent EMS-induced depletion of cellular protein thiols. Interestingly, the pretreatment of hepatocytes with 1 mM dithiothreitol promoted EMS toxicity. The results of this study suggest that the cytoprotective abilities of TS are related to the prevention of both EMS-induced lipid peroxidation and protein thiol depletion. Thus, the onset of lipid peroxidation and the loss of protein thiols in hepatocytes appear to be critical cellular events leading to EMS-induced cell death.

Animals↗
PubMed1984

Further evidences on gastric cytoprotection exerted by pirenzepine.

Pirenzepine (P) exerts cytoprotective action through a mechanism so far poorly understood. The aim of the present work was to evaluate the protective effect of P and by comparison PGE2, in different cytoprotective models: NaOH 0.2 N; antral ulcer induced by indomethacin; and in an "in vivo" model using ethanol (50% 1ml/rat p.o.) as mucosal barrier damaging agent. In this last group of experiments gastric mucosal potential difference (DP), Na+ concentrations and pH were measured. These parameters provided a clear measure of the mucosal barrier recovery from damaging agents. P., like PGs, significantly protect mucosa against NaOH 0.2 N induced ulcers with an ED50 = 21.94 mg/kg os, a similar activity was found for the antral ulcers induced by indomethacin (ED50 22.06 mg/kg os). Moreover P. significantly antagonized the PD reduction induced by ethanol in rat. PGE2 was strikingly active in this model. P. and PGE2 significantly decreased also Na+ ion concentration altered by ethanol. Although this paper shows a positive effect of P on the gastric mucosal barrier, further studies are necessary to clarify the mechanism of gastric cytoprotection of P.

Animals↗
PubMed1999

Cytoprotective effects of trimetazidine in carmustine cholestasis.

Carmustine [1 ,3-bis(2-chloroethyl)-1-nitrosurea (BCNU)] is an antitumour agent, however, its usefulness has been limited by a side effect; which involves pericholangitis and intrahepatic cholestasis. The primary effects of cholestasis is well known; bile flow retention, intracellular Ca++ accumulation and acidosis although it may lead to hepatotoxicity by dose-dependent manner. Recent studies provide evidence that lipoperoxidation (LPO) and alterations in the antioxidant system may significantly contribute to BCNU induced hepatotoxicity. Trimetazidine, (1-[2,3,4-Trimethoxy-benzyl] piperazine HCl; TMZ) introduced as an antianginal compound, is found to exhibit various cytoprotective features by preserving cellular ATP levels, limiting intracellular acidosis and inorganic phosphate as well as Na+ and Ca++ accumulation in ischemic cardiac injury. No study was undertaken to investigate the cytoprotective role of TMZ in cholestatic injury till today; therefore we initiated this study to investigate if its cytoprotective features also exhibit in the liver and to characterize further the cholestatic response to BCNU administration. Male rats were randomly seperated to control (CONT) (n = 15), BCNU administered (BCNU) (n = 16) and BCNU+TMZ administered (BCNU+TMZ) (n = 12) groups. The control rats received a single dosage of 2 ml/kg of corn oil (i.p.) while the BCNU group received a single dosage of BCNU (20 mg/kg, i.p.) in corn oil. In the BCNU + TMZ group 2,5 mg/kg/day (i.p.) of TMZ was administered for three days. This group also received BCNU (20 mg/kg, i.p.) in corn oil, 12 hours after the initial dose of TMZ. The cholestatic effect of BCNU was monitored by stasis markers such as ALP, GGT and total bilirubin levels. Hepatic TBARS analysis was determined with the modified method of OKHAWA et al. based on the reaction of lipid peroxides with thiobarbituric acid. Oxidized (GSSG) and reduced (GSH) glutathione levels were measured by the modified enzymatic recycling method of TEARE et al. Statistical tests were performed using Kruskal Wallis one-way Anova test and posthoc analysis by Newman-Keuls test. The BCNU group and the BCNU + TMZ group showed significant increases (p = 0.029) in hepatic TBARS levels compared to the CONT group; however the difference between the BCNU and BCNU + TMZ groups in regard to TBARS was not significant. BCNU and BCNU + TMZ groups manifested a significant decrease (p = 0.0005) in GSH levels as compared to controls. GSH/GSSG ratios in the BCNU and BCNU + TMZ group also manifested a significant decrease (p = 0.0013) as compared to the CONT group. TMZ administration caused a significant increase in total GSH levels (p = 0.0026) in BCNU + TMZ group when compared to the BCNU group. Our results support the hypothesis that BCNU induced cholestasis partly involves LPO revealed by the distinct increase in the content of TBARS in the liver after BCNU administration. BCNU is a potent inhibitor of GSSG reductase altering the preservation of the thiol redox balance in the system. As a result, supranormal concentrations of intracellular GSSG would accumulate in the hepatocyte and the extrusion of this oxidized compound would require active transport leading to ATP hydrolysis. This would deplete the energy stores of the cell which would accelerate further the possible prooxidant status. Although administration of TMZ did not provoke any significant alterations in LPO, it preserved the total GSH levels of the cell probably by improving the energy status of the cell by protection of ATP-producing processes at the mitochondrial level and provision of the necessary substrates for GSH synthesis. This protective role in the antioxidant system normalizes the altered GSH levels by BCNU and hence proposes TMZ to be a promising agent in the cholestatic injury.

Animals↗
PubMed2001

The relationship between UVB screening and cytoprotection by microcorpuscular ZnO or ascorbate against DNA photodamage and membrane injuries in keratinocytes by oxidative stress.

Decreased cell viability and increased formation of cyclobutane-type pyrimidine dimers (CPDs) in DNA of UVB-irradiated keratinocytes were shown to be appreciably restored by the addition of w/o emulsion of microcorpuscular zinc oxide (mcZnO) with a corpuscle diameter of 0.15 microm. The cytoprotection was exerted only by 20 wt/wt% mcZnO at levels equivalent to 40- to 100-microm-thick emulsion layers, which screened 90-92% of the incident UVB. However, protection was not seen by mcZnO below 20-microm thickness, which, unexpectedly, screened 79% of the incident radiation. This suggests that thorough UVB screening is necessary for cytoprotection. This may be attributable to involvement of intracellular reactive oxygen species (ROS) secondarily generated from UVB-irradiated mcZnO. Intracellular ROS was increased in mcZnO-added cells in a time-dependent manner even after UVB irradiation, contrasting with reduction of intracellular ROS in ascorbic acid-added cells. UVB-induced disruption of cell membrane integrity was reduced by mcZnO at 100-microm thickness, equivalent to the addition of ascorbic acid of 50 microM. Thus, mcZnO was thought to be cytoprotective through reductions of intracellular ROS generation, CPD formation and cell membrane disintegration when added so abundantly so as to achieve UVB-screening more than 90%.

Animals↗
PubMed2002

Comparative cytotoxic and cytoprotective effects of taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA) in HepG2 cell line.

This study was performed to compare the effects of two hydrophilic bile acids, taurohyodeoxycholic acid (THDCA) and tauroursodeoxycholic acid (TUDCA), on HepG2 cells. Cytotoxicity was evaluated at different times of exposure by incubating cells with increasing concentrations (50-800 micromol/l) of either bile acid, while their cytoprotective effect was tested in comparison with deoxycholic acid (DCA) (350 micromol/l and 750 micromol/l)-induced cytotoxicity. Culture media, harvested at the end of each incubation period, were analyzed to evaluate aspartate transaminase (AST), alanine transaminase and gamma-glutamyltranspeptidase release. In addition, the hemolytic effect of THDCA and TUDCA on human red blood cells was also determined. At 24 h of incubation neither THDCA nor TUDCA was cytotoxic at concentrations up to 200 and 400 micromol/l. At 800 micromol/l both THDCA and TUDCA induced a slight increase in AST release. At this concentration and with time of exposure prolonged up to 72 h, THDCA and TUDCA induced a progressive increase of AST release significantly (P<0.05) higher than that of controls being AST values for THDCA (2.97+/-0.88 time control value (tcv) at 48 h and 4.50+/-1.13 tcv at 72 h) significantly greater than those of TUDCA (1.50+/-0.20 tcv at 48 h and 1.80+/-0.43 tcv at 72 h) (P<0.01). In cytoprotection experiments, the addition of 50 micromol/l THDCA decreased only slightly (-5%) AST release induced by 350 micromol/l DCA, while the addition of 50 micromol/l TUDCA was significantly effective (-23%; P<0.05). Higher doses of THDCA or TUDCA did not reduce toxicity induced by 350 micromol/l DCA, but were much less toxic than an equimolar dose of DCA alone. At the concentration used in this experimental model neither THDCA nor TUDCA was hemolytic; however at a very high concentration (6 mmol/l) both bile acids induced 5-8% hemolysis. We conclude that bile acid molecules with a similar degree of hydrophilicity may show different cytotoxic and cytoprotective properties.

Alanine Transaminase↗
PubMed1992

Structure-activity relationship in the gastric cytoprotective effect of several sesquiterpene lactones.

The structural requirements for the gastric cytoprotective activity of several sesquiterpene lactones are reported. A theoretical-experimental study on the potentially active centers is carried out. The biological evaluation of reduced analogues and the simulation of the molecular interactions between these compounds and an endogenous cysteine residue suggest that the presence of a non sterically hindered Michael acceptor seems to be an essential structural requirement for the cytoprotective activity in this family of compounds. This observation suggests that cytoprotection is mediated through a Michael reaction between the sulfhydryl-containing peptides of the mucosa and Michael acceptors present in the molecules under study. This mechanism of action is in addition to and distinct from the one proposed in our previous paper, namely, that these sesquiterpenes stimulate endogenous synthesis of prostaglandins.

Lactones↗
PubMed1997

Structure-cytoprotective activity relationship of simple molecules containing an alpha,beta-unsaturated carbonyl system.

In previous reports we attributed the cytoprotective activity of several sesquiterpene lactones to the presence of a nonhindered electrophilic acceptor in their structure. We suggested that the mechanism of protection would be, at least in part, mediated through a reaction between the electrophilic acceptor and the sulfhydryl-containing groups of the mucosa. We report here the gastric cytoprotective effect of simple molecules containing an alpha, beta-unsaturated carbonyl group. In the present paper, we undertake the study of molecular accessibility and molecular shape, in addition to conformational, electronic, and steric factors. Our results helped to establish two important facts connecting chemical structure with cytoprotective effect. Firstly, an adequate molecular accessibility appears to be necessary to produce the biological response, and secondly, the alpha,beta-unsaturated carbonyl system has to be included in a cyclic structure or, at least, in the proximity of a cyclic system.

4-Butyrolactone↗
PubMedDate not supplied

The gastric cytoprotective effect of several sesquiterpene lactones.

The aerial part of Artemisia douglasiana, used in folk medicine as a cytoprotective agent against the development of peptic ulcer, was studied, its active principle dehydroleucodine [1] isolated, and its pharmacological properties analyzed. In order to establish whether or not the reported activity is particular to sesquiterpene lactones, the study of the cytoprotective activity of several related guaianolides and pseudoguaianolides from plants was undertaken. Ludartin [3], 8-angeloyloxy-3-hydroxyguaia-3(15),10(14),11(13)-trien-6,12- olide [4], hymenin [5], mexicanin I [6], helenanin [7], and 9-O-desacetylsparthulin-2-O-angelate [8] were found to exhibit protection. Desacetoxymatricarin [2] did not show cytoprotective activity. The results obtained from the different sesquiterpene lactones studied suggest that the presence of the alpha-methylene-gamma-lactone moiety is, in principle, a requirement for the observed antiulcerogenic activity.

Animals↗
PubMed1994

Mucus synthesis and sulfhydryl groups in cytoprotection mediated by dehydroleucodine, a sesquiterpene lactone.

The aerial parts of Artemisia douglasiana have been used in folk medicine as a cytoprotective agent against the development of peptic ulcer. Dehydroleucodine [1], its active principle, significantly prevents the formation of gastric lesions induced by the exposure of the rats to absolute ErOH. It was found in this study that (a) pretreatment of rats with 1 (40 mg/kg, po) caused a significant increase in glycoprotein synthetic activity, approximately sevenfold as large as that of the control; and (b) pretreatment of the rats with the thiol reagent N-methylmaleimide (NEM) significantly diminished the cytoprotection provided by 1. However, the protective effect of 1 was not totally abolished by pretreatment with a combination of indomethacin and NEM, indicating additional mechanisms are involved in the cytoprotective action of 1.

Animals↗
PubMed1999

Partial characterization of mechanisms of cytoprotective action of hydrophilic bile salts against hydrophobic bile salts in rats: relation to canalicular membrane fluidity and packing density.

Bile salts regulate the subselection of phosphatidylcholine species secreted into bile and thereby modulate bile metastability. The aim of this study was to determine whether bile salts alter phosphatidylcholine species of the canalicular membrane, and if they do, to clarify whether the cytoprotective action of hydrophilic bile salts is associated with modulation of phosphatidylcholine composition in cell membrane bilayers. Bile salt-pool-depleted rats were infused intravenously with sodium taurocholate at a constant rate (200 nmol/min/100 g body wt) for 2 hr, followed by infusion of either sodium tauroursodeoxycholate, sodium tauroalphamuricholate, or sodium taurobetamuricholate (200 nmol/min/100 g) for 2 hr. Biliary outputs of cholesterol and phosphatidylcholine and phosphatidylcholine hydrophobicity in bile and subcellular fractions were determined. The cytoprotective action of hydrophilic bile salts was determined by the release of canalicular membrane-localizing enzymes (alkaline phosphatase, leucine aminopeptidase) into bile. Tauroursodeoxycholate, taurobetamuricholate, and tauroalphamuricholate decreased the release of these enzymes when compared to values under taurocholate infusion. Bile phosphatidylcholine hydrophobicity was also decreased by the bile salts, whereas the cholesterol/phosphatidylcholine ratio was increased. In contrast, phosphatidylcholine hydrophobicity in the canalicular membrane was increased by these three bile salts. In conclusion, hydrophilic bile salts promote biliary secretion of relatively hydrophilic phosphatidylcholine secretion into bile, and consequently phosphatidylcholine hydrophobicity in canalicular membranes increased. Such an alteration in phosphatidylcholine species within canalicular membrane enhances its lateral packing density with less fluidity, and this may account, in part, for the cytoprotective action of hydrophilic bile salts against hydrophobic bile salts.

Animals↗
PubMed2005

Pulmonary toxicity associated with the treatment of non-small cell lung cancer and the effects of cytoprotective strategies.

Concurrent chemoradiation regimens for the treatment of non-small cell lung cancer have resulted in improved treatment outcomes. However, they are also more toxic. Acute esophagitis and pneumonitis are experienced by a large number of treated patients. Cytoprotective agents are used to reduce treatment-related toxicity. The cytoprotectant amifostine has been shown to reduce some of the toxicity associated with concurrent chemoradiation. Clinical studies of its role in reducing esophagitis and radiation pneumonitis are discussed. Lung irradiation also leads to a reduction in lung diffusion capacity (DLCO). The magnitude of this reduction is related to the volume of lung irradiated as well as to the use and timing of chemotherapy. Concurrent chemoradiation regimens result in a larger reduction in DLCO than radiation alone. Small changes in DLCO can be detected with sensitive pulmonary function tests, but are subclinical. Larger reductions in DLCO correlate with significant clinical symptoms. Preliminary data show that amifostine can significantly decrease the treatment-related reduction in DLCO associated with concurrent chemoradiation (42% v 24%; P = .004). Additional studies are being designed to verify these results and to further define the evolving role of cytoprotection in cancer care.

Amifostine↗
PubMed2001

Cytoprotection against mechanical forces delivered through beta 1 integrins requires induction of filamin A.

Cells in mechanically active environments can activate cytoprotective mechanisms to maintain membrane integrity in the face of potentially lethal applied forces. Cytoprotection may be mediated by expression of membrane-associated cytoskeletal proteins including filamin A, an actin-binding protein that increases the rigidity of the subcortical actin cytoskeleton. In this study, we tested the hypotheses that applied forces induce the expression of filamin A specifically and that this putative protective response inhibits cell death. Magnetically generated forces were applied to protein-coated magnetite beads bound to human gingival fibroblasts, cells with constitutively low basal levels of filamin A mRNA and protein. Forces applied through collagen or fibronectin, but not bovine serum albumin or poly-l-lysine-coated beads, increased mRNA and protein content of filamin A by 3-7-fold. Forces had no effect on the expression of other filamin isotypes or other cytoskeletal proteins. This effect was dependent on the duration of force and was blocked by anti-beta(1) integrin antibodies. Force also stimulated a 60% increase in expression of luciferase under the control of a filamin A promoter in transiently transfected Rat2 fibroblasts and was dependent on Sp1 transcription factor binding sites located immediately upstream of the transcription start site. Experiments with actinomycin D-treated cells showed that the increased filamin A expression after force application was due in part to prolongation of mRNA half-life. Antisense filamin oligonucleotides blocked force-induced filamin A expression and increased cell death by >2-fold above controls. The force-induced regulation of filamin A was dependent on intact actin filaments. We conclude that cells from mechanically active environments can couple diverse signals from forces applied through beta-integrins to up-regulate the production of cytoprotective cytoskeletal proteins, typified by filamin A.

Animals↗
PubMed1996

In-vitro and in-vivo antibacterial activity of plaunotol, a cytoprotective antiulcer agent, against Helicobacter pylori.

Recently, some antiulcer agents have been reported to have antibacterial activity against Helicobacter pylori, which is highly associated with gastritis and peptic ulcers. In-vitro and in-vivo activity of plaunotol, a cytoprotective antiulcer agent, against H. pylori was investigated. Antibacterial activity of plaunotol against a standard strain (NCTC 11637) and 14 clinical isolates was compared with those of other cytoprotective antiulcer agents: benexate, sofalcone, teprenone, cetraxate, and gefarnate, by an agar dilution method. The MIC50 and MIC90 of plaunotol against 15 strains were 6.25 and 12.5 mg/L, respectively, making it the most potent of the cytoprotective antiulcer agents. The bactericidal effect of plaunotol was investigated using an in-vitro killing assay. Plaunotol at concentrations of more than 6 mg/L induced a rapid reduction of culture turbidity, with an extensive loss of viability, within 30 min. Observation by scanning electron microscopy revealed that plaunotol caused autolysis and treated cells were deformed. In-vivo activity of plaunotol against H. pylori was examined in a nude mouse gastritis model. Plaunotol significantly decreased the number of H. pylori in the stomach of nude mice. In addition, the antiulcer agent enhanced the antibacterial activity of amoxycillin or clarithromycin in the infection model.

Amoxicillin↗
PubMed1993

Effects of intracerebroventricular injection of indomethacin on adaptive gastric cytoprotection in the conscious rat.

We investigated the role of prostaglandins in the central nervous system for the adaptive gastric cytoprotection in male Wistar rats with chronic intracerebroventricular cannulas. Three, 50, 200, or 500 micrograms of indomethacin or vehicle alone was injected via the intracerebroventricular (central) or intraperitoneal route 1 h before oral administration of 20% ethanol. The animals were then given 1 ml of absolute ethanol 15 min later. One hour later, gastric mucosal damage and plasma indomethacin concentrations were measured. Pretreatment with 50-500 micrograms of indomethacin abolished adaptive gastric cytoprotection induced by 20% ethanol in a dose-dependent fashion, regardless of the route of administration. Central administration of 3 micrograms indomethacin resulted in a more than twofold increase in mucosal damage compared with intraperitoneal administration. Plasma indomethacin concentrations were increased dose-dependently. However, plasma levels were lower in rats administered centrally than those peripherally at a dose of 50 micrograms indomethacin or more. On the other hand, plasma indomethacin concentrations did not differ between central and intraperitoneal administration of 3 micrograms indomethacin. Measurement of gastric mucosal blood flow revealed that central administration of 3 micrograms indomethacin reduced gastric mucosal blood flow, whereas intraperitoneal administration of an identical dose had no effect. These results suggest that central prostaglandins may contribute to adaptive gastric cytoprotection, possibly by altered gastric mucosal blood flow.

Animals↗
PubMed1993

Pentagastrin cytoprotection in ethanol-induced gastric mucosal lesions in rats.

To establish pentagastrin cytoprotection, the effectiveness of various doses of pentagastrin on ethanol induced gastric mucosal lesions was investigated in Wistar rats. Significant protection was obtained only after parenteral pretreatment with the exception of the lowest dose (1 microgram/kg b.w.). Pentagastrin cytoprotection is not mediated either by a dopamine, muscarinic or gastrin/CCK receptor or by prostaglandin synthesis. However, the protective effect of pentagastrin is abolished by prior vagotomy, although this procedure alone or sham operation is ineffective to influencing control-ethanol lesions. In secretory studies pentagastrin increased both the volume of gastric juice and total acid output. Unlike cytoprotection, these were reversed by vagotomy, but also with atropine and problumide, whereas domperidone and indomethacin were ineffective.

Animals↗
PubMedDate not supplied

Gastric cytoprotection: morphological perspectives.

In 1979, a new mechanism of gastric defense named cytoprotection was followed by numerous reports elucidating this interesting and important phenomenon. During this decade, however, the concept and definition of gastric cytoprotection have been modified from the morphological and ultrastructural viewpoints. This review attempts to describe the concept and mechanisms of cytoprotection as well as its pathophysiological features. Specifically, in vitro studies using isolated cells or monolayer cultured cells as well as molecular investigations of signal transduction system have been documented.

Adaptation, Physiological↗
PubMed1985

Cytoprotective effect of prostaglandins on isolated rat liver cells.

In vitro studies were carried out on isolated rat hepatocytes to examine further the proposed cytoprotective actions of prostaglandins (PG) using carbon tetrachloride (CCl4) as the toxic agent. Isolated hepatocytes, prepared by collagenase, were cultured in Leibowitz-15 medium. Following preincubation, CCl4 (300 or 150 micrograms/ml) was added to the hepatocytes. Treatment with Indomethacin (INDO), 16, 16-dimethyl-PGE2(PGE2) and prostacyclin (PGI2) was assayed in the cultures. Cell damage was measured by lactic dehydrogenase (LDH) release. 6-keto-PGF1 alpha was measured in the supernatant by direct radioimmunoassay. The results showed PGI2 (30.0 ng/ml) treatment 30 min after CCl4 (300 micrograms/ml) addition to be highly protective (p less than 0.001 versus CCl4 control). PGE2 (3 ng/ml) showed similar protection (p less than 0.001). INDO (2 micrograms/ml) following CCl4 (150 micrograms/ml) demonstrated increased cell death (p less than 0.001). INDO (0.5 micrograms/ml) reduced 6-keto-PGF1 alpha production (p less than 0.05). Low dose ethanol (1.5 micrograms/ml) increased 6-keto-PGF1 alpha production (p less than 0.05). Ethanol (1.5 micrograms/ml), added to stimulate endogenous PG production, was cytoprotective when added prior to CCl4 (p less than 0.01). This protection was suppressed by INDO. Ethanol added after CCl4 was not protective. We conclude that exogenously added PGI2 and PGE2 are cytoprotective in this in vitro model and that endogenous PG production may play a protective role in the initial stages of cellular damage.

Animals↗