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PubMed1992

Role of mucosal prostaglandins in vagally-mediated adaptive cytoprotection in the rat.

This study was designed to investigate whether vagal innervation and mucosal prostaglandins (PGs) participate in gastric adaptive cytoprotection. Rats were divided into three groups; sham operation (control), truncal vagotomy or splanchnicotomy. In the first experiment, 100% ethanol (EtOH) was orally administered 15 min after pretreatment with 20% EtOH to all 3 groups. One hour later, the gastric mucosa was examined macroscopically. In a second experiment, the mucosal PG contents 15 min after administration of either 20% EtOH or saline were measured by high performance liquid chromatography. In truncal vagotomized rats, the adaptive cytoprotection caused by exposure to 20% EtOH in control and splanchnicotomized rats was not observed and an increase in hemorrhagic lesion severity was seen. In the control and splanchnicotomized rats, PGE2 contents were elevated following 20% EtHO treatment, as compared to those in the saline-treated rats. However, PGE2 contents in vagotomized rats were not altered by EtOH exposure, and were significantly lower than in the control and splanchnicotomized groups, whereas PGF2 alpha and PGD2 contents were significantly higher after EtOH administration as compared to those in saline-treated rats. These results suggest that vagal innervation is essential for adaptive cytoprotection and that the vagotomy-induced decrease in PGE2 and increases in PGF2 alpha and PGD2 following 20% EtOH administration, may be caused by a disturbance in adaptive cytoprotection.

Animals↗
PubMed1999

[Experiences with sodium selenite in treatment of acute and late adverse effects of radiochemotherapy of head-neck carcinomas. Cytoprotection Working Group in AK Supportive Measures in Oncology Within the scope of MASCC and DKG].

BACKGROUND: The principle of cytoprotection became a new supportive strategy in oncology during the last decade. Two principal ways of cytoprotection are well known in practice: the addition of external free thiols (for example amifostine) or the activation of internal detoxification-pathways (for example the activation of glutathione peroxidase) by administration of additional selenium. OWN EXPERIENCES: We report about our experiences in both fields: At first we could show the significant possibilities of cytoprotection to reduce the acute hematological and non hematological toxicities of a simultaneous radiochemotherapy (2 cycles Carboplatin, 2 Gy single dose, 60 Gy total dose) of head and neck cancer patients. After 1 year the survival of amifostine-protected patients was better compared to the control, the rate of severe late complications (xerostomia Grade 3/4) was decreased from 57% to 14%. At second we report about the usage of selenium in the treatment of paravasats (10 patients) and interstitial lymph edema (20 patients). In the acute intervention group 9/10 patients resolved from the paravasats without any necrosis. In the late intervention group 12/20 patients showed reduced edema. Nine of 15 patients with a supraglottic edema and subsequent dyspnoea resolved under treatment without any tracheostomy. CONCLUSION: On the base of these data we have planned a phase-I/II study to investigate the chances of both cytoprotectants alone and in combination in order to get the most favorable supportive regimen for our basic type of radiochemotherapy.

Adult↗
PubMed1989

Effect of sialoadenectomy on adaptive cytoprotection in the rat.

In the present study we have investigated the effect of sialoadenectomy in the rat on adaptive cytoprotection induced by intragastric instillation of an irritant concentration of ethanol (10% wt/vol). Gastric mucosae were examined 1 h after oral administration of 100% ethanol. In animals with intact salivary glands, pretreatment with saline was followed 15 min later by 100% ethanol. This treatment was associated with a significant degree of mucosal damage. However, prior administration of 10% ethanol in place of saline reduced the area of ulceration. In sialoadenectomized rats, the irritant concentration of ethanol did not protect the gastric mucosa from the damaging actions of absolute ethanol. The effect was partially restored if sialoadenectomized rats were treated for 3 days with an aqueous extract of rat salivary gland tissue. Histologic examination revealed no differences in the extent of epithelial damage or adherent mucus between rats with intact salivary glands and sialoadenectomized rats following pretreatment with either saline or 10% ethanol. Although adaptive cytoprotection in animals with intact salivary glands was not associated with increases in mucosal capacities for prostaglandin E2 or 6-keto prostaglandin F1 alpha biosynthesis, sialoadenectomy resulted in a reduction in the mucosal biosynthetic capacities for both prostanoids. Salivary gland extract administration to sialoadenectomized rats did not significantly alter mucosal prostaglandin biosynthesis levels. These data suggest that salivary gland factors affected adaptive cytoprotection induced by an irritant dose of ethanol. Although endogenous prostaglandin biosynthesis capabilities do not appear to be altered in adaptive cytoprotection, salivary factors appear to influence mucosal generation of prostaglandins.

Animals↗
PubMed1992

Glycine cytoprotection during lethal hepatocellular injury from adenosine triphosphate depletion.

Glycine protects renal tubule cells from cell death during adenosine triphosphate (ATP) depletion. Although the liver plays a key role in glycine metabolism, information is lacking regarding the effects of glycine on lethal hepatocellular injury. Thus, the aim of this study was to determine the potential cytoprotective role of glycine during ATP depletion of rat hepatocytes. Metabolic inhibition with 2.5 mmol/L potassium cyanide (KCN) was used to produce ATP depletion. Hepatocyte suspensions treated with KCN had a 2-hour viability of 5.9% +/- 2.0%, whereas cells treated with KCN in the presence of 2.0 mmol/L glycine had a viability of 80.2% +/- 1.5%, which was virtually identical to controls (81.5% +/- 1.9%). Glycine cytoprotection was dose dependent and amino acid specific. The cytoprotective effect of glycine was not mediated by protein synthesis, glycine mitochondrial metabolism, cytosolic acidosis, or preservation of either intracellular cellular glutathione or ATP. However, glycine did decrease total cellular proteolysis by 18% +/- 2%, 25% +/- 3%, and 33% +/- 1% after 1, 2, and 3 hours of KCN treatment, respectively (P less than 0.01). Inhibition of proteolysis by glycine was dose dependent over the same range as its cytoprotection. The results suggest that glycine protects against hepatocellular injury by inhibiting degradative proteolytic activity. It was concluded that proteolysis may be an important mechanism contributing to lethal injury of hepatocytes during ATP depletion.

Adenosine Triphosphate↗
PubMed1993

Cytoprotection by inhibition of chloride channels: the mechanism of action of glycine and strychnine.

Previous studies have demonstrated that strychnine mimics the cytoprotective effects of glycine (1) and that strychnine binds specifically to renal proximal tubules (RPT) at cytoprotective concentrations (2). The goal of this study was to determine a mechanism by which strychnine and glycine are cytoprotective. Antimycin A (0.1 microM) caused chloride influx subsequent to mitochondrial inhibition and prior to the release of lactate dehydrogenase (LDH) activity (a marker of cell death/lysis). The addition of strychnine or glycine prevented the chloride influx and LDH release. The chloride channel inhibitors ethacrynic acid, furosemide, anthracene-9-carboxylic acid, DIDS, and SITS decreased LDH release in RPT exposed to antimycin A with a rank order of potency of DIDS > ethacrynic acid = furosemide = anthracene-9-carboxylic acid > SITS. These data, in conjunction with the preceeding paper, indicate a critical role for chloride influx in cell death/lysis; support the existence of a novel strychnine binding site on the plasma membrane of RPT that is coupled to a chloride channel; and suggest that glycine and strychnine are cytoprotective through their inhibition of chloride influx.

Animals↗
PubMed1985

Cytoprotective and antisecretory properties of a non-diarrheogenic and non-uterotonic prostacyclin analog: U-68,215.

U-68,215 [15-Cyclohexyl-9-deoxo-13,14-dihydro-2',9 alpha-methano-4,5,6,16,17,18,19,20-octanor-3-oxa-3,7-(1', 3'-interphenylene)-PGE1] is a stable prostacyclin analog. When given orally to rats, it is cytoprotective for the stomach (ED50: 0.8 micrograms/kg) and the intestine (ED50: 22 micrograms/kg), is gastric antisecretory (ED50: 35 micrograms/kg) and antiulcer (aspirin) (ED50: 5 micrograms/kg). The oral antisecretory ED50 in dogs is 50 micrograms/kg. It has a long duration of gastric cytoprotection: 8-10 hours compared to 3 hours for 16,16-dimethyl PGE2. Unlike most prostaglandins of the E type, it is not diarrheogenic (not enteropooling), it does not induce cellular proliferation of the gastrointestinal mucosa, when given twice a day for eight days, it is not uterotonic (in monkeys), and it does not prevent embryo implantation in hamsters. It inhibits ex vivo platelet aggregation (ED50: 300 micrograms/kg), but does not promote bleeding from cut vessels nor from gastric ulcers. U-68,215 lowers blood pressure at an oral dose corresponding to 1-5 times the antisecretory ED50 in rats and dogs, and to 150 times the cytoprotective ED50 in rats. It may be of therapeutic value in the treatment of conditions where inhibition of gastric acid secretion is desirable, e.g., gastric and duodenal ulcer, and in conditions responding to cytoprotection, e.g., stress ulcers, hemorrhagic gastritis and gastric erosions associated with nonsteroidal antiinflammatory drugs.

Alprostadil↗
PubMed2003

Interleukin-11-induced heat shock protein 25 confers intestinal epithelial-specific cytoprotection from oxidant stress.

BACKGROUND & AIMS: The mechanisms of interleukin-11 (IL-11) cytoprotection in intestinal epithelial injury are largely unknown. IL-11 protects barrier integrity during oxidant stress, a common endpoint of numerous types of intestinal injury including ischemia and immune-mediated inflammation. Because heat shock proteins (hsp) are cytoprotective in intestinal epithelia, we hypothesized that IL-11-conferred cytoprotection is mediated by inducible hsps. METHODS: IL-11 receptor (IL-11R) activation was determined using phospho-specific antibodies to STAT3. IL-11 induction of hsp72 and hsp25 was determined by immunoblot in IEC-18 crypt and young adult mouse colon colonic epithelial cells. Epithelial resistance to oxidant injury by monochloramine was determined by (51)Cr release. Stable hsp anti-sense IEC-18 cell clones were obtained by electroporation and hygromycin B selection. The IL-11 effect on hsp25 distribution was characterized by analysis of Triton x-100 insoluble fractions, 2-D isoelectric focusing gels, and confocal microscopy. RESULTS: IL-11R signaling was detected in all cells under study. IL-11 induces hsp25 in an intestinal epithelial-specific manner that significantly preserves cellular viability in the presence of monochloramine. This effect was significantly reversed in intestinal epithelia stably expressing anti-sense to hsp25. IL-11 induced a shift of hsp25 to Triton x-100 insoluble fractions containing cytoskeletal elements, which was not associated with altered hsp25 phosphorylation. The shift was not paralleled by increased hsp25 co-localization with F-actin by confocal microscopy. CONCLUSIONS: The induction of hsp25 by IL-11 confers epithelial-specific cytoprotection that is independent of phosphorylation-dependent co-localization of hsp25 to F-actin, thereby contributing to the protective effects of IL-11 in models of intestinal epithelial injury.

3T3 Cells↗
PubMedDate not supplied

Expression of cyclooxygenase (COX)-1 and COX-2 in adaptive cytoprotection induced by mild stress.

Prostaglandins (PG) derived from COX-1 play an important role in the maintenance of mucosal integrity but the role of COX-2-derived products in mucosal defence mechanism has not been fully explained. Mild stress is known to prevent gastric mucosal lesions induced by severe stress via the phenomenon of adaptive cytoprotection but it remains unknown which COX is involved in this adaptation. In this study, the mucosal expression of COX-1 and COX-2 was examined and the inhibitors of these enzymes were used to determine the contribution of these enzymes in adaptive cytoprotection induced by mild stress. Male Wistar rats were exposed to mild water immersion and restraint stress (WRS) at various time intervals ranging from 5 min up to 2 h followed 1 h later by exposure to severe 3.5 h WRS with or without pretreatment with: 1) NS-398 (10 mg x kg(-1) i.g.), a selective COX-2 inhibitor; 2) resveratrol (5 mg x kg(-1) i.g.), a selective COX-1 inhibitor; 3) meloxicam (2 mg x kg(-1) i.g.), preferential COX-2 inhibitor; and 4) indomethacin (5 mg x kg(-1) i.p), non-selective inhibitor of COX. The number of WRS lesions was counted, gastric blood flow (GBF) was measured by H2-gas clearance technique, mucosal biopsy samples were taken for the assessment of PGE2 by radioimmunoassay, and the expression of COX-1 and COX-2 mRNA by RT-PCR. WRS for 3.5 h produced numerous gastric lesions, decreased GBF by 48% and inhibited formation of PGE2 by 68% as compared to intact mucosa. Exposure to mild WRS during 5-30 min by itself failed to affect mucosal integrity but significantly attenuated gastric lesions induced by exposure to severe 3.5 h stress; the maximal protective effect being achieved with mild WRS during 15 min. This protective effect was accompanied by the rise in GBF and the generation of PGE2 in the gastric mucosa. After extension of mild WRS from 15 min up to 1 or 2 h before more severe 3.5 h WRS, the loss of cytoprotective effect of mild WRS against severe stress accompanied by significant fall in the GBF were observed. Pretreatment with NS-398 (10 mg x kg(-1) i.g.) that failed to affect mucosal PGE2 generation, reduced significantly the protection and accompanying rise in GBF produced by mild WRS whereas resveratrol partly reduced the protection and the rise in GBF induced by mild WRS. Meloxicam or indomethacin significantly inhibited PGE2 generation and completely abolished the hyperemia and protection induced by mild WRS against more severe stress. The protective and hyperemic effects of mild WRS were completely restored by the addition of 16,16 dm PGE2 (5 microg x kg(-1) i.g.) to NS-398 or resveratrol, while the deleterious effects of meloxicam and indomethacin were significantly attenuated by the concomitant treatment with this PGE2 analogue. We conclude that PG derived from both, COX-1 and COX-2 appear to be involved in adaptive cytoprotection developed in response to mild stressors.

Adaptation, Physiological↗
PubMed1999

Long-lasting cytoprotection after pentadecapeptide BPC 157, ranitidine, sucralfate or cholestyramine application in reflux oesophagitis in rats.

Recently, the effectiveness of pentadecapeptide BPC 157 and other anti-ulcer agents, called 'direct cytoprotection', was evidenced in totally gastrectomized rats duodenum challenged with cysteamine 24 h after surgery, and sacrificed 24 h after ulcerogen application. The further focus was on the possibility that this effect could be seen over a more prolonged period (1, 2, 4 weeks), and in other parts of the gastrointestinal tract (i.e. oesophagus). After the removal of the stomach, the oesophagus and jejunum were joined by a termino-lateral anastomosis. The animals were euthanized 7, 14 or 28 d after surgery, when oesophagitis was blindly assessed both macroscopically (percentage of ulcerations areas) and microscopically (percentage of areas of ulcers, regeneration and hyperplasia; number of inflammatory cells - polymorphonuclear and mononuclear). Starting 24 h after surgery, the medication was continuously given in the drinking water, in a volume of 12.5 mL/rat daily, until euthanasia at the end of the observation period, i.e. 7, 14, 28 d following surgery. Based on previous experiments, the doses of agents were daily calculated per kg b.w. as follows: BPC 157 125 mg or 125 ng, cholestyramine 2.5 mg, ranitidine 125 mg, sucralfate 725 mg, whereas controls received 72.5 mL x kg(-1) water. In support of these initial findings, and considering gastrectomized acid-free rats as an ideal model for long-term cytoprotective studies as well, pentadecapeptide BPC 157 markedly attenuated termino-lateral oesophagojejunal anastomosis-reflux oesophagitis also over a quite prolonged period. This efficacy was only partly shared by other anti-ulcer agents. After 1-week-old oesophagitis (microscopical assessment), but not after 2 or 4 weeks, less damaged mucosa was noted in rats drinking ranitidine or sucralfate compared to controls. Similar effectiveness was noted for cholestyramine. The obtained results were supported also by inflammatory cell assessment. Compared with control values, BPC 157-treated groups consistently presented less polymorphonuclears and less mononuclears in all assessed periods. Interestingly, the values obtained in other treated groups showed no difference compared with control values. Thus, despite limitations, a generalization supporting a direct importance of a common cytoprotective approach, could be clearly provided. A useful, long-lasting cytoprotective activity (apparently more prominent in BPC 157 rats, than in reference agents, ranitidine, sucralfate, as well as cholestyramine) may be a likely suitable therapy in otherwise resistant reflux oesophagitis conditions.

Animals↗
PubMed1997

Induction of a 72-kDa heat shock protein and cytoprotection against thioacetamide-induced liver injury in rats.

Heat shock proteins are ubiquitous intracellular proteins induced by various physiological stress-related events. A 72-kDa heat shock protein (HSP72) has been reported to be an endogenous cytoprotectant in variety of cells in vitro. In order to study the cytoprotective function of HSP72 in the liver, the effect of preinduction of HSP72 in rat liver by systemic hyperthermia on thioacetamide-induced hepatic injury was investigated in this study. Expression of HSP72 in the liver was investigated by immunoblot and densitometric analysis. Rats were injected with thioacetamide (100 mg/kg, subcutaneously) with or without preinduction of HSP72 by hyperthermia. Serum AST and ALT concentrations were measured before and after thioacetamide injection in both group. Histologic alteration of the liver was evaluated also. Systemic hyperthermia (42.5 degrees C, 20 min) significantly induced HSP72 in the liver. Thioacetamide-induced hepatic injury was clearly prevented by preinduction of HSP72 by hyperthermia. Prevention of hepatocyte damage was more clear in the area around central veins where HSP72 induction was apparent. Our findings might suggest that HSP72 has an important function in the liver with respect to cytoprotection. These results might be important for understanding the mechanism of "adaptive cytoprotection" in the liver mediated by the function of heat shock proteins as "molecular chaperons" as reported in vitro.

Alanine Transaminase↗
PubMed1996

Differential cytoprotection by glycine against oxidant damage to proximal tubule cells.

Tert-butyl hydroperoxide (tBHP) injured freshly isolated proximal tubules in an Fe-dependent fashion that was ameliorated by a lipophilic antioxidant, diphenyl-p-phenylenediamine (DPPD), but was only minimally affected by glycine. Menadione-induced injury was Fe-independent and was unaffected by DPPD, but was strongly blocked by glycine. Fe was highly toxic when intracellular loading was facilitated by concomitant treatment with hydroxyquinoline (HQ). This toxicity was blocked by DPPD or chelating the Fe, but not by glycine. All of the lesions were characterized by severe depletion of glutathione and other soluble thiols. Menadione induced large increases in protein associated with the Triton-insoluble cytoskeleton and decreases in protein thiol content, consistent with extensive cross linking, but did not increase thiobarbituric acid reactive substances (TBARS). tBHP and HQ + Fe had either no effect or only moderate, delayed effects on cytoskeletal proteins, but induced substantial increases of TBARS. Glycine did not the alter changes in cytoskeletal proteins, thiols, or TBARS produced by any of the agents. Protection against tBHP toxicity by deferoxamine and DPPD was accompanied by substantial suppression of TBARS accumulation. Superimposition of hypoxia during tBHP exposure reduced TBARS accumulation and restored cytoprotective activity to glycine. Thus, in contrast to its consistently strong cytoprotection against a number of other insults, glycine is only variably cytoprotective against oxidant lesions in freshly isolated proximal tubules. Extensive oxidative crosslinking of proteins is compatible with maintenance of glycine cytoprotection against lethal membrane damage. Fe-induced injury to proximal tubules associated with lipid peroxidation as manifested by TBARS formation is a relatively glycine-insensitive insult.

Animals↗
PubMed2004

Indole-based analogs of melatonin: in vitro antioxidant and cytoprotective activities.

The known neuroprotective actions of melatonin could be due to its antioxidant or radical scavenging activity, or they could be due to specific interactions of the indole with its receptors. A study of structure-activity relationships may provide useful information when a validated macromolecular target has not been (or is not) identified. A set of indole derivatives, with changes in the 5-methoxy and acylamino groups, the side chain position and the lipophilic/hydrophilic balance, were selected and tested for their in vitro antioxidant potency in the ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid disodium salt) and thiobarbituric acid reactive substances (TBARS) assays and for their cytoprotective activity against kainate excitotoxicity on cerebellar cell cultures. No quantitative model was able to relate the potencies obtained in the two antioxidant assays, probably because they are related to different physico-chemical properties. However, the lipophilicity of the compounds and the antioxidant potency in the TBARS assay were linearly correlated. This may be due to improved access to the lipidic substrate, where the antioxidant action occurs. In the cytoprotection assay, most compounds showed potencies comparable with or lower than melatonin. An exception was N-[2-(5-methoxy-1H-indol-2-yl)ethyl]acetamide (12), yielding, at 50 microM, percentages of cell vitality higher than 75%, while melatonin EC50 was 333 microM. No correlation was observed between cytoprotective and antioxidant potencies, nor with MT1 or MT(2) receptor affinity. Compound 12 is a low-affinity antagonist at melatonin membrane receptors, and one of the most potent compounds in the antioxidant assays; its cytoprotective potency and the absence of agonist activity at melatonin membrane receptors make it a valid candidate for further investigations.

Animals↗
PubMed1998

Conditional expression of mitogen-activated protein kinase phosphatase-1, MKP-1, is cytoprotective against UV-induced apoptosis.

UV irradiation induces apoptosis in U937 human leukemic cells that is accompanied by the activation of both the stress-activated protein kinase (SAPK) and p38 mitogen-activated protein kinase (MAPK) signal transduction pathways. The MAPK phosphatase, MKP-1, is capable of inactivating both SAPK and p38 MAPK in vivo. To determine whether MKP-1-mediated inhibition of SAPK and/or p38 MAPK activity provided cytoprotection against UV-induced apoptosis, a U937 cell line conditionally expressing MKP-1 from the human metallothionein IIa promoter was established. Conditional expression of MKP-1 was found to abolish UV-induced SAPK and p38 MAPK activity, and inhibit UV-induced apoptosis as judged by both morphological criteria and DNA fragmentation. MKP-1 was also found to inhibit other biochemical events associated with apoptosis, including activation of caspase-3 and the proteolytic cleavage of the caspase-3 substrate, poly(ADP ribose) polymerase. These findings demonstrate that MKP-1 acts at a site upstream of caspase activation within the apoptotic program. The cytoprotective properties of MKP-1 do not appear to be mediated by its ability to inhibit p38 MAPK because the p38 MAPK specific inhibitor SB203580 had no effect on UV-induced apoptosis in U937 cells. Furthermore, by titrating the level of MKP-1 expression it was found that MKP-1 inhibited UV-induced SAPK activity, DNA fragmentation, and caspase-3 activation in a similar dose-dependent manner. The dual-specificity phosphatase, PAC1, which does not inhibit UV-induced activation of SAPK, did not provide a similar cytoprotection against UV-induced apoptosis. These results are consistent with a model whereby MKP-1 provides cytoprotection against UV-induced apoptosis by inhibiting UV-induced SAPK activity.

Apoptosis↗
PubMed2001

The cytoprotective effects of the glycoprotein 130 receptor-coupled cytokine, cardiotrophin-1, require activation of NF-kappa B.

Many cell types mount elaborate, compensatory responses to stress that enhance survival; however, the intracellular signals that govern these responses are poorly understood. Cardiotrophin-1 (CT-1), a stress-induced cytokine, belongs to the interleukin-6/glycoprotein 130 receptor-coupled cytokine family. CT-1 is released from the heart in response to hypoxic stress, and it protects cardiac myocytes from hypoxia-induced apoptosis, thus establishing a central role for this cytokine in the cardiac stress response. In the present study, CT-1 activated p38 and ERK MAPKs as well as Akt in cultured cardiac myocytes; these three pathways were activated in a parallel manner. CT-1 also induced the degradation of the NF-kappa B cytosolic anchor, I kappa B, as well as the translocation of the p65 subunit of NF-kappa B to the nucleus and increased expression of an NF-kappa B-dependent reporter gene. Inhibitors of the p38, ERK, or Akt pathways each partially reduced CT-1-mediated NF-kappa B activation, as well as the cytoprotective effects of CT-1 against hypoxic stress. Together, the inhibitors completely blocked CT-1-dependent NF-kappa B activation and cytoprotection. A cell-permeable peptide that selectively disrupted NF-kappa B activation also completely inhibited the cytoprotective effects of CT-1. These results indicate that CT-1 signals through p38, ERK, and Akt in a parallel manner to activate NF-kappa B and that NF-kappa B is required for CT-1 to mediate its full cytoprotective effects in cardiac myocytes.

Animals↗
PubMed1999

Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron.

It is often postulated that the cytoprotective nature of heme oxygenase (HO-1) explains the inducible nature of this enzyme. However, the mechanisms by which protection occurs are not verified by systematic evaluation of the physiological effects of HO. To explain how induction of HO-1 results in protection against oxygen toxicity, hamster fibroblasts (HA-1) were stably transfected with a tetracycline response plasmid containing the full-length rat HO-1 cDNA construct to allow for regulation of gene expression by varying concentrations of doxycycline (Dox). Transfected cells were exposed to hyperoxia (95% O(2)/5% CO2) for 24 h and several markers of oxidative injury were measured. With varying concentrations of Dox, HO activity was regulated between 3- and 17-fold. Despite cytoprotection with low (less than fivefold) HO activity, high levels of HO-1 expression (greater than 15-fold) were associated with significant oxygen cytotoxicity. Levels of non-heme reactive iron correlated with cellular injury in hyperoxia whereas lower levels of heme were associated with cytoprotection. Cellular levels of cyclic GMP and bilirubin were not significantly altered by modification of HO activity, precluding a substantial role for activation of guanylate cyclase by carbon monoxide or for accumulation of bile pigments in the physiological consequences of HO-1 overexpression. Inhibition of HO activity or chelation of cellular iron prior to hyperoxic exposure decreased reactive iron levels in the samples and significantly reduced oxygen toxicity. We conclude that there is a beneficial threshold of HO-1 overexpression related to the accumulation of reactive iron released in the degradation of heme. Therefore, despite the ready induction of HO-1 in oxidant stress, accumulation of reactive iron formed makes it unlikely that exaggerated expression of HO-1 is a cytoprotective response.

Animals↗
PubMed1993

Central action of TRH to induce vagally mediated gastric cytoprotection and ulcer formation in rats.

The vagus nerve plays an important role in gastric cytoprotection and gastric lesion formation, but the central and peripheral mechanisms by which the vagus mediates these dual effects on the gastric mucosa are still not well established. Recent evidence indicates that the tri-amino acid peptide thyrotropin-releasing factor (TRH) acts in the brain, most likely in the dorsal vagal complex, and stimulates gastric vagal efferent discharges. Such increased vagal activity results in cholinergic stimulation of the gastric secretory and motor functions that influence the resistance of the gastric mucosa to injury. Low doses of TRH or its stable analogue, RX 77368 (0.5-1.5 ng), injected into the cisterna magna, confer cytoprotection against ethanol-induced gastric lesions through the vagal cholinergic stimulation of gastric prostaglandin release. After higher doses of RX 77368 (3-300 ng), cytoprotection is observed only when the associated increase in acid secretion is prevented by omeprazole. Intracisternal injection of RX 77368 at doses of 1-3 micrograms induces the development of acute gastric lesions within 4 h which are further enhanced by indomethacin in fasted rats. Gastric lesions are related to the vagally mediated sustained increase in gastric acid and pepsin secretion, motility, and vascular changes. These data, added to the neuroanatomic evidence of high concentrations of TRH fibers and receptors in the dorsal vagal complex, indicate that medullary TRH may play an important role in the central vagal regulation of gastric mucosal resistance. This mucosal resistance is influenced by the interaction between vagal-cholinergic activation of cytoprotective mechanisms (prostaglandin, increased gastric mucosal blood flow) and ulcerogenic factors (histamine, acid, pepsin, motility).

Animals↗
PubMed2002

Allelic variants of the human glutathione S-transferase P1 gene confer differential cytoprotection against anticancer agents in Escherichia coli.

The polymorphic human GSTP1 gene locus encodes proteins that differentially metabolize electrophilic substrates, including, many chemotherapeutic agents used in clinical cancer therapy. In this study, we used XL1-Blue MRF strain, transformed with phagemid expression vectors carrying cDNAs of three GSTP1 alleles, to investigate the cytoprotective abilities of the different GSTP1 alleles against four clinically active anticancer agents, namely, carboplatin, cisplatin, thiotepa, and 4-hydroperoxyifosfamide. Following induction of protein expression with isopropyl-beta-d-thiogalactoside, the cells were treated with each drug for 3 h (1 h for 4-hydroperoxyifosfamide). Surviving fractions were determined and used to compute a cytoprotective factor for each allele against each drug. The results showed all the GSTP1 alleles to be cytoprotective, albeit, to different degrees. For cisplatin and carboplatin, the allele was most protective, with CPs of 5.58 and 3.76, respectively, compared with 1.21 and 1.61 for and 2.50 and 2.79 for. In contrast, protection against thiotepa was highest for the allele, with a cytoprotective factor of 1.56, compared to 1.32 for and 1.1 for. For 4-hydroperoxyifosfamide, the CP for and was the same, 1.45, compared with 1.18 for. These data demonstrate significant differences in the ability of the different GSTP1 alleles to protect against the cytotoxicity of electrophilic anticancer agents. The level of protection differs significantly between different GSTP1 alleles, and between different anticancer agents. The optimized prokaryotic system described provides a useful and rapid tool for pharmacogenetic analysis of the effects of genes on drug sensitivity.

Antineoplastic Agents↗
PubMed1995

The mechanistic pathway of gastric adaptive cytoprotection: a study on different components of the autonomic nervous system.

1. The involvement of different components of the autonomic nervous system in the pathogenesis of ethanol-induced damage and the adaptive cytoprotection of mild irritants were studied in the gastric mucosa of male rats. 2. Capsaicin, yohimbine, and domperidone aggravated the 100% ethanol-induced gastric mucosal damage and attenuated the cytoprotective action of 20% ethanol, but not of 5% NaCl and 0.3 M HCl. Butoxamine and prazosin blocked the adverse actions of yohimbine and domperidone respectively. 3. Atropine, pirenzepine, and lidocaine lessened the severity of 100% ethanol-induced mucosal injury and further increased the cytoprotective action of 5% NaCl and 0.3 M HCl, but not of 20% ethanol. 4. Our results demonstrated that sensory afferent neurones, alpha 2-adrenoceptors and D2-dopaminergic receptors all play a significant role in the defensive mechanism of the gastric mucosa and the adaptive cytoprotection of 20% ethanol, while the M1- and M2-muscarinic receptors and sensory chemoreceptors on the gastric mucosa contribute only to the former action. The adverse effect of yohimbine and domperidone on lesion formation is probably mediated through the release of catecholamines, which subsequently act on the beta 2- and alpha 1-adrenoceptors respectively.

Adaptation, Physiological↗