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PubMed1981

Prevention of sepsis-induced gastric lesions in dogs by cimetidine via inhibition of gastric secretion and by prostaglandin via cytoprotection.

The cytoprotective and acid-inhibitory effects of cimetidine and 16,16-dimethyl PGE2 were evaluated in a septic canine erosive gastritis model. In 21 dogs, total gastric fistulas were created, and after a 3-wk recovery period, basal, food-, and pentagastrin-stimulated acid output were measured. Then bacterial peritonitis was created by the intraperitoneal instillation of Pseudomonas, Bacteroides, Streptococcus Fecalis, Klebsiella and canine gallbladder bile. In 5 dogs no drug were given throughout the septic period while in 16 dogs either cimetidine, 6 or 12 mg/kg i.m. every 6 h, or 16,16-dimethyl PGE2, 0.2 or 0.4 microgram/kg i.m. every 6 h, was given 24 h before the induction of peritonitis and continued for 3 days. All 21 dogs had positive blood cultures on the 1st septic day. In the control animals, basal, food-, and pentagastrin-stimulated acid output significantly increased during the first 2 septic days, and gastroscopy demonstrated bleeding acute fundic erosions. Cimetidine decreased basal, food-, and pentagastrin-stimulated acid output in a dose-related manner, and only with the higher dose did it prevent gastric mucosal damage. 16,16-Dimethyl PGE2, 0.4 microgram/kg, significantly decreased acid output and prevented gastric mucosal damage. 16,16-Dimethyl PGE2 0.2 microgram/kg, although having no apparent effect on basal, food-, and pentagastrin-stimulated acid output, prevented the development of acute gastric erosions. Thus, in the canine septic model, acid output significantly increases during sepsis. Cimetidine prevents the development of sepsis-induced gastric erosions by inhibition of acid secretion and 16,16-dimethyl PGE2 by cytoprotection.

Animals↗

PubMed1994

Gastric cytoprotective activity of endogenous 5-HT.

The role of endogenous serotinin in the formation of gastric damage was studied in rats. Stress ulcers were induced by ultrasounds, immobilization and immobilization plus cold. The damage of gastric mucosa was estimated (arbitrary scale) and serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations in this tissue measured. In all examined groups of animals with gastric mucosal damages the lower levels of 5-HT and 5-HIAA in gastric mucosa were observed. In some experimental groups animals were treated with serotonergic receptor antagonists 30 min. before stress. The administration of ICS 205-930 (80 micrograms/kg), 5-HT3 receptor antagonist, and DAU-62855 (80 micrograms/kg), 5-HT4/5-HT3 receptors antagonist, reduced the intensity of stress gastric injuries. In contrast the administration of methysergide (8 mg/kg), 5-HT1/5-HT2 receptors antagonist, enhanced the stress gastric mucosa damage. 16, 16 dimethyl PGE2 (10 micrograms/kg) protected stomach against stress stimuli and accompanied increase of serotonin and 5-HIAA concentration in gastric mucosa was observed. Both 5-HT3/5-HT4 receptor antagonist had an additive cytoprotective effect when given in combination with PGE2 analog. In the presence of methysergide gastroprotective effect of PGE2 was abolished. The present studies demonstrate that cytoprotective effect of endogenous serotonin depends on 5-HT1 and 5-HT2 receptors stimulation in the gastric mucosa and the protective effect of prostaglandins depends partly on the regulation of serotonin metabolism.

Acoustic Stimulation↗

PubMed1994

Verapamil used in lung transplantation: could it have a cytoprotective effect during the ischemic phase of pulmonary preservation? Study on alveolar type II cells.

It has been shown that Verapamil (V) improves lung preservation, but it is not clear whether the effect is due to vasodilation, with a more homogeneous cooling effect during hypothermic preservation, or a direct cytoprotection. Attempting to verify this, we studied the cellular viability of rats' pneumocytes type II primary cultures separately incubated in the first experiment for 6 hours in Ringer Lactate (RL) +/- V (10 mg/l) at 25 degrees C and at 4 degrees C, and in the second experiment for the same period in RL, EuroCollins (EC) and Collins (CL) solution +/- V (10 mg/l) at 4 degrees C. We analyzed the influence of the drug using two methods: the total protein content in each culture and the metabolic function of the cells using the rate of protein synthesis by means of 35 S methionine uptake assay. All data showed that there were no significant statistical difference (Student t-test, p > 0.05) in the use of verapamil during alveolar type II cells either in normothermic or hypothermic preservation. Thus we conclude that the protection of this calcium channel blocker during lung preservation is probably due to the effect on pulmonary vessels rather than to a direct cytoprotective effect on the lung cells.

Animals↗

PubMed1995

Ursodeoxycholate (UDCA) inhibits the mitochondrial membrane permeability transition induced by glycochenodeoxycholate: a mechanism of UDCA cytoprotection.

Ursodeoxycholate (UDCA), a hydrophilic bile salt, ameliorates hepatocellular injury by toxic bile salts and is used to treat cholestatic liver disease. However, the mechanisms of bile salt-mediated hepatocyte necrosis and UDCA cytoprotection remain unclear. Hepatocyte necrosis is thought to be caused by the mitochondrial membrane permeability transition (MMPT). Thus, the aims of our study were to determine if a toxic bile salt, glycochenodeoxycholate (GCDC) induces the MMPT and if so, whether UDCA prevents the bile salt-induced MMPT. The MMPT was assessed in isolated rat liver mitochondria. Cell viability was measured in isolated rat hepatocytes. GCDC induced the MMPT in a dose-dependent manner. The GCDC-induced MMPT was partially blocked by cyclosporin A plus trifluoperazine, known inhibitors of the MMPT. UDCA also inhibited the GCDC-induced MMPT, and partially blocked the MMPT by phenylarsene oxide, an established mediator of the MMPT. UDCA or cyclosporin A plus trifluoperazine protected against loss of hepatocyte viability during treatment with GCDC. In conclusion, GCDC induces a MMPT; a finding providing a physicochemical explanation for the bioenergetic form of cell necrosis caused by toxic bile salts. UDCA cytoprotection may, in part, be due to inhibition of the bile salt-induced MMPT.

Animals↗

PubMed1994

Cytoprotective effect of prostaglandin E2 and I2 in experimental liver damage.

Cytoprotective effect of prostaglandin E2 and prostacyclin on carbon tetrachloride-induced liver damage was studied in rats. The role of endogenous prostaglandins in hepatic cytoprotection was also evaluated. The study population consisted of 275 rats. The study was carried out in two stages because of using two compounds: PGE2 and PGI2. The activity of the following enzymes in blood and hepatic tissue was measured as a criterion of liver damage: 1. ALAT, 2. AspAT, 3. AP, 4. ChE. The results of the present study show that exogenous prostaglandins protect the liver against toxic effects of CC14. Exogenous prostaglandins play also a therapeutic role in the damaged organ. It is also possible that endogenous prostaglandins perform protective functions. In an experiment in male white Wistar rats protective effect of prostaglandin PGE2 and PGI2 on carbon tetrachloride-induced liver damage was studied. The study was carried out in two stages because of using two different prostaglandins. The present results confirm protective effects of prostaglandins and may help in evaluating hepatic pathology in man.

Animals↗

PubMed1993

[Molsidomine and nitric oxide in gastric cytoprotection].

The effect of Molsidomine as a gastric mucosa protector against absolute ethanol was studied in Wistar rats. It was found that Molsidomine provided an important gastric cytoprotection and it behaved in a similar way as the nitric oxide (NO), the latter verified by specific NO antagonist, namely the NG-monomethyl-L arginine. It was also demonstrated that the cytoprotector mechanism of Molsidomine, as well as of other nitroderivates was sulfhydryl and HEM dependent regarding the guanylate-cyclase enzyme. It can be concluded that both Molsidomine and the NO behaved as modulator of the gastric microcirculation, venous and arterial vasodilator and that their gastric cytoprotective mechanism was endogenous prostaglandin dependent.

Animals↗

PubMed1993

Tauroursodeoxycholate and tauro-beta-muricholate exert cytoprotection by reducing intrahepatocyte taurochenodeoxycholate content.

Cytoprotection by tauroursodeoxycholic acid and tauro-beta-muricholic acid against taurochenodeoxycholic acid-induced toxicity was examined with reference to intracellular bile acid content in primary cultured rat hepatocytes. In comparison with levels in the group administered taurochenodeoxycholic acid 1 mmol/L alone, lactate dehydrogenase levels in the culture medium decreased significantly in groups simultaneously administered taurochenodeoxycholic acid 1 mmol/L and tauroursodeoxycholic acid 0.5 to 2 mmol/L or tauro-beta-muricholic acid. Results of the trypan blue uptake test indicated that the lactate dehydrogenase release was indeed caused by cell damage. After the administration of tauroursodeoxycholic acid 2 mmol/L or tauro-beta-muricholic acid 2 mmol/L, intracellular taurochenodeoxycholic acid content was consistently reduced to half of that after administration of taurochenodeoxycholic acid alone. Simultaneous administration of dibutyl cyclic AMP also reduced intracellular taurochenodeoxycholic acid content and lactate dehydrogenase release. Being rinsed with tauroursodeoxycholic acid and tauro-beta-muricholic acid after being precultured in taurochenodeoxycholic acid 1 mmol/L also markedly reduced their taurochenodeoxycholic acid content. Taurocholic acid caused limited reduction of intracellular taurochenodeoxycholic acid but not suppression of lactate dehydrogenase release. Taurodehydrocholic acid showed no reduction of taurochenodeoxycholic acid content and no decrease of lactate dehydrogenase release. Although only small amounts of tauroursodeoxycholic acid or tauro-beta-muricholic acid were found to accumulate in hepatocytes, taurocholic acid increased as if replacing taurochenodeoxycholic acid. The results suggest that tauroursodeoxycholic acid or tauro-beta-muricholic acid may exert cytoprotective effects by lowering intracellular taurochenodeoxycholic acid levels associated with their optimal hydrophilicity.

Animals↗

PubMed1993

Cytoprotective drugs in the prevention of ethanol-induced experimental gastric mucosal damage: a morphological study.

Various so-called "cytoprotective" agents (sucralfate, carbenoxolone, 16,16-dimethyl-PGE2, sulglycotide and Maalox TC) have been tested on rats, with the aim of quantifying their capability to prevent ethanol-induced gastric mucosal damage. Rats fasted for 48 hours received 1 ml of 80% ethanol by oral gavage, after prior oral treatment with placebo or one of the above-mentioned drugs u.i.d. for 5 consecutive days. Six hours after ethanol administration, the animals were sacrificed and the stomach was removed and processed for computerized macroscopic assessment of the damaged surface and for structural (light microscopy) and ultrastructural (scanning and transmission electron microscopy) studies. The results obtained demonstrate that ethanol injury caused extensive mucosal necrosis of the glandular region of the stomach, an event that was effectively reduced in rats treated with 16,16-dm-PGE2, carbenoxolone or sulglycotide. These drugs appeared to preserve the mucosa, with morphology comparable to that of normal noninjured rats - in contrast to the other drugs investigated. These data confirm the cytoprotective properties of sulglycotide in particular, which was the most potent agent for preventing the development of ethanol-induced acute lesions of the gastric mucosa.

16,16-Dimethylprostaglandin E2↗

PubMed1996

Amifostine: the preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies.

Administered prior to cytotoxic chemotherapy or radiation, the aminothiol amifostine provides broad-spectrum cytoprotection of various normal tissues without attenuating antitumor response. The basis for the selectivity of action resides in the anabolism of amifostine at the normal tissue site by membrane-bound alkaline phosphatase. Dephosphorylation to the free thiol WR-1065 is followed by rapid uptake into normal tissues by a carrier-mediated facilitated diffusion process. In contrast, uptake into tumor tissues is slow to negligible. Pretreatment with amifostine provides protection of normal tissues from the cytotoxic effects of alkylating agents, organoplatinums, anthracyclines, taxanes, and radiation. Additionally, the mutagenic and carcinogenic effects of these modalities are also attenuated. Preclinical studies show significant protection of marrow progenitor cells that give rise to the red blood cells, white blood cells, and platelets. Protection of kidneys and neural tissues from cisplatin toxicity has been shown, along with protection of the heart, intestinal crypt cells, and pulmonary tissues from chemotherapy and radiation, as well as vasculoconnective and musculoconnective tissue in an irradiated field. Comparative in vitro and in vivo studies using murine and human tumor xenografts show no attenuation of antitumor effects of these same therapies despite the protection of normal organs. The unique preclinical profile of amifostine serves as the basis for the clinical development program for this important new broad-spectrum cytoprotective agent.

Amifostine↗

PubMed1996

Amifostine cytoprotection with chemotherapy for advanced ovarian carcinoma.

To determine the efficacy of pretreatment with amifostine in diminishing the hematologic and nonhematologic toxicities of cyclophosphamide and cisplatin in previously untreated patients with stage III/IV ovarian cancer, a multicenter randomized controlled trial of cyclophosphamide (1,000 mg/m(2)) and cisplatin (100 mg/m(2) with or without amifostine (910 mg/m(2)) was performed. Two hundred forty-two patients with stage III/IV epithelial ovarian cancer were enrolled. Following primary surgery, patients were stratified and randomized to either cyclophosphamide/cisplatin (CP; 120 patients) or amifostine plus CP (122 patients) every 3 weeks for six cycles. Patient characteristics were similar in both groups. Cytoprotective end points and tumor response were evaluated, including the need to delay or discontinue therapy because of toxicity and the incidence of febrile neutropenia with associated complications. Fourteen patients treated with CP discontinued protocol therapy because of hematologic or renal toxicity (eight hematologic and six renal). In contrast, only one patient treated with amifostine plus CP discontinued protocol therapy for hematologic or renal toxicity (P < .001). Forty-three percent of CP patients compared with 22% of amifostine plus CP patients had grade 4 neutropenia (P = .001); total days in hospital were reduced from 258 in the CP arm to 11 in the amifostine plus CP arm (P = .009, two-sided). Sixty-five percent of the CP patients and 41% of the amifostine plus CP patients (P = .004) had the next cycle of CP delayed because of an absolute neutrophil count below 1,500/microL at day 22. Platelet and red blood cell transfusion support were substantially reduced in the group that received amifostine. The serum creatinine failed to return to < or = to 1.5 mg/dL by day 22, requiring a delay in chemotherapy in 15% and 5%, respectively, of the CP and amifostine plus CP groups (P = .014). Over the six cycles, the incidence and severity of peripheral neuropathy were also significantly reduced in the amifostine-treated group (P = .029). Pathologic response rates and survival curves were equivalent. The significant reduction in the CP-induced acute and cumulative hematologic, renal, and neurologic toxicities by amifostine pretreatment with equivalent response and survival indicates selective cytoprotection. This selective effect has the potential to affect quality of life and medical economic considerations.

Amifostine↗

PubMed1996

Adaptive cytoprotection against ethanol-induced small intestinal mucosal injury.

Exposure of the small intestinal mucose to 6% ethanol (which is found in human jejunum during alcohol consumption) causes morphological alterations, and increased permeability of the mucosa and histamine release from intestinal mast cells. The released histamine is shown to mediate a significant component of the increased mucosal permeability (i.e., mucosal injury). In the present study, we have investigated whether adaptive cytoprotection occurs against the increased mucosal permeability and histamine release induced by 6% ethanol. Rabbits were used. In each animal, three adjacent segments of upper small intestine were pre-perfused for 30 min, and then perfused for 90 min in the following order control solution followed by control solution (control segment); control solution followed by 6% ethanol (ethanol segment); 1% ethanol followed by 6% ethanol (pretreated ethanol segment). During the 90-min perfusion, mucosal permeability of each segment was measured by analyzing the effluent for intraluminal clearance of i.v. administered 51Cr-labelled ethylenediaminetetraacetic acid (51Cr-EDTA) and 125I-labelled bovine serum albumin (125I-BSA). Mast cell histamine release was assessed by determining histamine concentration of the gut effluent. All measurements were higher in the ethanol segments than in the controls. These ethanol effects were significantly lower in the pretreated ethanol segments, indicating that adaptive cytoprotection occurs against the mucosal injury induced by 6% ethanol. These findings are discussed in relation to the literature on mucosal effects of intestinal intraluminal ethanol.

Animals↗

PubMed1996

[Cytoprotective effect of epidermal growth factor on cultured rabbit airway epithelial cells exposed to ozone].

In this study, it was observed that ozone (O3) exposure has cytotoxic effects on cultured airway epithelial cells, which was positively related with exposure duration. Both the production of malondialdehyde (MDA) and the 3H release in the exposure group were much higher than the control (P < 0.01), suggesting that lipoperoxidation occurring in the cell membrane was responsible for the cellular injury observed under O3 attack. EGF at low concentration (5 ng/ml) showed cytoprotective effect on airway epithelial cells exposed to O3 as shown by attenuated MDA production and decrease of 3H release and cytotoxic index (P < 0.01). Pretreatment with EGF could reverse the depletion of intracellular GSH content as a result of O3 exposure and increase the total glutathionein the cells. The above results suggest that the cytoprotection of EGF on airway epithelial cells may be related to its promotive effect on GSH synthesis.

Animals↗

PubMed1998

Testing the gonadal regression-cytoprotection hypothesis.

Germinal damage is an almost universal accompaniment of cancer treatment as the result of bystander damage to the testis from cytotoxic drugs and/or irradiation. Cancer treatment for the most common cancers of the reproductive age group in men has improved such that most are now treated with curative intent, and many others are treated with likelihood of prolonged survival, so that the preservation of fertility is an important component of posttreatment quality of life. This has led to the consideration of developing adjuvant treatments that may reduce the gonadal toxicity of cancer therapy. One dominant hypothesis has been based on the supposition that the immature testis was resistant to cytotoxin damage. Hence, if hormonal treatment were able to cause spermatogenic regression to an immature state via an effective withdrawal of gonadotrophin secretion, the testis might be maintained temporarily in a protected state during cytotoxin exposure. However, clinical studies have been disappointing but have also been unable to test the hypothesis definitively thus far, due to the inability to completely suppress gonadotrophin secretion. Similarly, experimental models have also given conflicting results and, at best, a modest cytoprotection. To definitively test this hypothesis experimentally, we used the fact that the functionally hpg mouse has complete gonadotrophin deficiency but can undergo the induction of full spermatogenesis by testosterone. Thus, if complete gonadotrophin deficiency were an advantage during cytotoxin exposure, then the hpg mouse should exhibit some degree of germinal protection against cytotoxin-induced damage. We therefore administered three different cytotoxins (200 mg/kg procarbazine, 9 mg/kg doxorubicin, 8 Gy of X irradiation) to produce a range of severity in testicular damage and mechanism of action to either phenotypically normal or hpg mice. Testis weight and homogenization-resistant spermatid numbers were measured to evaluate the potential protective effects on spermatogenesis. Although the three cytotoxins produced a range of severity of spermatogenic damage, there was no evidence of cytoprotection in the hpg mice that were completely gonadotrophin deficient at the time of treatment. These findings cast doubt on the validity of the hypothesis that spermatogenic regression via gonadotrophin withdrawal can protect the mouse testis against cytotoxin-mediated spermatogenic damage.

Animals↗

PubMed1999

Cytoprotection in the treatment of pediatric cancer: review of current strategies in adults and their application to children.

BACKGROUND: The protection of patients from the acute and/or chronic toxicity of antineoplastic therapy has become a major concern of oncology centers around the world. However, most of the effort has been directed toward the adult population, and limited studies have been performed in the group that may gain the most from such strategies, namely, children. PROCEDURES: The MedLine and CancerLit databases were surveyed, and the relevant biomedical literature on cytoprotection during antineoplastic treatment was analyzed. RESULTS: Cytotoxicity from antineoplastic therapy customarily is addressed by altering dosing schedules, a technique that can seriously impact the efficacy of the therapy. Colony stimulating factors have been used posttherapy to stimulate recovery from neutropenia, and various agents have been proposed as pretherapy cytoprotectors. Trials in adults have produced mixed results, and, to date, only amifostine and dexrazoxane have been approved as cytoprotectors for very narrow indications. Few trials have been performed in children, although these patients often can look forward to long-term remission. CONCLUSIONS: To prevent permanent toxicities from antineoplastic therapies that impact long-term pediatric survivors, the experience gained in adults should be extended more aggressively to children, and formal, randomized trials should be performed to determine the type of protection most suitable for the pediatric population.

Antineoplastic Agents↗

PubMed2001

Induction of endothelial cell decay-accelerating factor by vascular endothelial growth factor: a mechanism for cytoprotection against complement-mediated injury during inflammatory angiogenesis.

OBJECTIVE: Decay-accelerating factor (DAF) is a widely expressed, multifunctional cell surface protein involved in complement regulation and cell signaling. Previous studies have demonstrated that endothelial cell (EC) DAF is up-regulated by tumor necrosis factor alpha and inhibits complement binding. Because vascular endothelial growth factor (VEGF) is cytoprotective to endothelium and is expressed at sites of chronic inflammation, we hypothesized that VEGF may induce DAF expression during inflammatory angiogenesis. METHODS: Human umbilical vein and dermal microvascular EC were isolated using routine procedures, and the regulation and function of DAF, as well as other complement-regulatory proteins (membrane cofactor protein and CD59), were analyzed following stimulation with VEGF. RESULTS: Incubation of large- or small-vessel EC with VEGF led to increased expression of DAF, with maximal expression after 48-72 hours of stimulation. This effect depended on the activation of protein kinase C (PKC) and required increased steady-state messenger RNA levels and de novo protein synthesis. Although VEGF-induced EC proliferation was inhibited by both p38 and p42/44 mitogen-activated protein kinase (MAPK) antagonists, DAF up-regulation in response to VEGF was only sensitive to inhibition of p38 MAPK. VEGF-stimulated EC showed a 60% reduction in C3 deposition following complement activation, and this resulted in a marked reduction in complement-mediated EC lysis. These protective effects were abolished by anti-DAF monoclonal antibody 1H4. CONCLUSION: This study confirms the importance of PKC for the regulation of DAF expression by EC and reveals VEGF to be a physiologic agonist for this pathway. The up-regulation of DAF expression by VEGF may represent an important mechanism for the protection of EC from complement-mediated injury during angiogenesis in inflammatory rheumatic diseases.

CD55 Antigens↗

PubMedDate not supplied

MRP1/GS-X pump ATPase expression: is this the explanation for the cytoprotection of the heart against oxidative stress-induced redox imbalance in comparison to skeletal muscle cells?

Striated muscle activity is always accompanied by oxidative stress (OxStress): the more intense muscle work and/or its duration, the more a redox imbalance may be attained. In spite of cardiac muscle functioning continuously, it is well known that the heart does not suffer from OxStress-induced damage over a broad physiological range. Although the expression of antioxidant enzymes may be of importance in defending heart muscle against OxStress, a series of combined antioxidant therapeutic approaches have proved to be mostly ineffective in avoiding cellular injury. Hence, additional mechanisms may be involved in heart cytoprotection other than antioxidant enzyme activities. The strong cardiotoxic effect of doxorubicin-induced cancer chemotherapy shed light on the possible role for multidrug resistance-associated proteins (MRP) in this context. Muscle activity-induced 'physiological' OxStress enhances the production of glutathione disulfide (GSSG) thus increasing the ratio of GSSG to glutathione (GSH) content inside the cells, which, in turn, leads to redox imbalance. Since MRP1 gene product (a GS-X pump ATPase) is a physiological GSSG transporter, adult Wistar rats were tested for MRP1 expression and activity in the heart and skeletal muscle (gastrocnemius), in as much as the latter is known to be extremely sensitive to muscle activity-induced OxS. MRP1 expression was completely absent in skeletal muscle. In contrast, the heart showed an exercise training-dependent induction of MRP1 protein expression which was further augmented (2.4-fold) as trained rats were challenged with a session of acute exercise. On the other hand, inducible expression of the 70-kDa heat shock protein (HSP70), a universal marker of cellular stress, was completely absent in the heart of sedentary and acutely exercised rats, whereas skeletal muscle showed a conspicuous exercise-dependent HSP70 expression, which decreased by 45% with exercise training. This effect was paralleled by a 58% decrease in GSH content in skeletal muscle which was even higher (an 80%-fall) after training thus leading to a marked redox imbalance ([GSSG]/[GSH] raised up to 38-fold). In the heart, GSH contents and [GSSG]/[GSH] ratio remained virtually unchanged even after exercise challenges, while GS-X pump activity was found to be 20% higher in the heart related to skeletal muscle. These findings suggest that an intrinsic higher capacity to express the MRP1/GS-X pump may dictate the redox status in the heart muscle thus protecting myocardium by preventing GSSG accumulation in cardiomyocytes as compared to skeletal muscle fibres.

Adenosine Triphosphatases↗

PubMed1998

Mitochondrial dysfunction and cytoskeletal disruption during chemical hypoxia to cultured rat hepatic sinusoidal endothelial cells: the pH paradox and cytoprotection by glucose, acidotic pH, and glycine.

We investigated mechanisms underlying death of cultured rat liver sinusoidal endothelial cells exposed to chemical hypoxia with KCN (2.5 mmol/L) to simulate the adenosine triphosphate (ATP) depletion and reductive stress of anoxia. During chemical hypoxia, acidotic pH prevented cell death. Glucose (0.3-10 mmol/L) also prevented cell killing. Cytoprotection by glucose but not acidosis was associated with prevention of ATP depletion. After 4 hours of chemical hypoxia at pH 6.2 (simulated ischemia), rapid cell death occurred when pH was restored to pH 7.4 with or without washout of KCN (simulated reperfusion). This pH-dependent reperfusion injury (pH paradox) was prevented after KCN washout at pH 6.2. Glycine (0.3-3 mmol/L) also prevented the pH paradox, but glucose did not. The initial protection by acidotic pH and glycine during simulated reperfusion was lost when pH was later restored to 7.4 or glycine was subsequently removed. Mitochondria depolarized during chemical hypoxia. After washout of cyanide, mitochondrial membrane potential (delta psi) did not recover in cells that subsequently lost viability. Conversely, those cells that repolarized after cyanide washout did not subsequently lose viability. The actin cytoskeleton and focal adhesions became severely disrupted during chemical hypoxia at both pH 6.2 and 7.4 and did not recover after cyanide washout under any condition. Glucose during chemical hypoxia prevented cytoskeletal disruption. In conclusion, endothelial cell damage during simulated ischemia/reperfusion involves mitochondrial dysfunction, ATP depletion, and ATP-dependent cytoskeletal disruption. Glycine and acidotic pH prevented cell killing after reperfusion but did not reverse mitochondrial injury or the profound disruption to the cytoskeleton.

Adenosine Triphosphate↗

PubMed2002

Chronic electromagnetic field exposure decreases HSP70 levels and lowers cytoprotection.

Electromagnetic field (EMF) exposures have been shown to induce heat shock proteins (HSPs), which help to maintain the conformation of cellular proteins during periods of stress. We have previously reported that short-term exposure of chick embryos to either 60 Hz (extremely low frequency: ELF), or radio-frequency (RF: 915 MHz) EMFs induce protection against hypoxia. Experiments presented in the current report are based on a study in which long-term (4 days), continuous exposure to ELF-EMFs decreased protection against ultraviolet radiation. Based on this result, it was hypothesized that de-protection against hypoxia should also occur following long-term, continuous, or daily, repeated exposures to EMFs. To test this hypothesis, chick embryos were exposed to ELF-EMFs (8 microT) continuously for 4 days, or to ELF or RF (3.5 mW incident power)-EMFs repeated daily (20, 30, or 60 min once or twice daily for 4 days). Several of the exposure protocols yielded embryos that had statistically significant decreases in protection against hypoxic stress (continuous and 30 or 60 min ELF twice daily; or 30 or 60 min once daily RF). This is consistent with our finding that following 4 days of ELF-EMF exposure, HSP70 levels decline by 27% as compared to controls. In addition, the superposition of ELF-EMF noise, previously shown to minimize ELF-EMF induced hypoxia protection, inhibited hypoxia de-protection caused by long term, continuous ELF or daily, repeated RF exposures. This EMF-induced decrease in HSP70 levels and resulting decline in cytoprotection suggests a mechanism by which daily exposure (such as might be experienced by mobile phone users) could enhance the probability of cancer and other diseases.

Animals↗