Protective Effects Of Prostaglandins Research Articles

EP-2270: Novel protective effect of prostaglandin for timely hair follicle regeneration from radiation injury

EP-2270: Novel protective effect of prostaglandin for timely hair follicle regeneration from radiation injury

Protective Effect of Prostaglandin E<sub>1</sub> on Radiation-Induced Proliferative Inhibition and Apoptosis in Keratinocytes and Healing of Radiation-Induced Skin Injury in Rats

We examined the effects of prostaglandin E₁ (PGE₁) on radiation-induced proliferation inhibition and apoptosis in keratinocytes and healing of radiation-induced skin injury in a rat model. PGE₁ had a protective effect on radiation-induced growth inhibition in keratinocytes in vitro, but not in fibroblasts. Varying concentrations of PGE₁ were subcutaneously administered into the posterior neck region. X-irradiation at a dose of 20 Gy was administrated to the lower part of the back using a lead sheet with two holes 30 min to 1 h before or after the administration of PGE₁. Although X-irradiation induced epilation, minor erosions, or skin ulcers in almost all rats, PGE₁ administration prior to irradiation reduced these irradiation injuries. Staining with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling showed that proportions of apoptotic keratinocytes in the X-irradiated skin of PGE₁-administered rats were significantly lower than for those in the skin of rats which did not receive PGE₁. Cutaneous full-thickness defective wounds were then formed in X-irradiated areas to examine the time course of wound healing. Wound healing was significantly delayed because of X-irradiation, but PGE₁ administration prior to irradiation led to a significantly shorter delay in wound healing compared with controls. Decreasing delay in wound healing was correlated with concentration of PGE₁ administrated. Thus, PGE₁-administration may potentially alleviate the radiation-induced skin injury.

Hypoxia–reoxygenation‐induced apoptosis in cultured neonatal rat cardiomyocyets and the protective effect of prostaglandin E1

The aim of the present study was to investigate the effect of prostaglandin (PG) E1 on hypoxia/re-oxygenation (H/R) apoptosis and the expression of bcl-2 and bax in cultured neonatal rat cardiomyocytes. The H/R model was made using the first generation of cultured neonatal rat cardiomyocytes. Hypoxia/re-oxygenation apoptosis was studied by electron microscopy and agarose gel electrophoresis. The percentage of apoptotic cells was measured by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL). The expression of bcl-2 and bax was detected by in situ hybridization and immunohistochemical staining. Most cells of the H/R group tested by electron microscopy showed cytoplasmic concentration, nuclear chromatin condensation and margination. Prostaglandin E1 (5, 15 and 45 microg/L) relieved the injury. The results of DNA electrophoresis in the H/R group showed a typical DNA ladder and the DNA ladder decreased gradually corresponding with increasing doses of PGE1. The TUNEL staining showed that the total number of apoptotic cells in the H/R group was much more than that in the PGE1 (45 microg/L) group. The results of in situ hybridization and immunohistochemical staining showed that the bcl-2 content in the H/R group was lower than that in the control group; bax content showed the reverse. Compared with the H/R group, bcl-2 content was significantly higher in the PGE1 (5, 15 and 45 microg/L) groups. However, bax content in the PGE1 (5, 15 and 45 microg/L) groups was significantly lower than that in the H/R group. 6. In conclusion, H/R injury can induce cardiomyocyte apoptosis. Prostaglandin E1 obviously has anti-apoptotic effects on cardiomyocytes and the mechanisms probably involve the inhibition of bax expression and increased expression of bcl-2.

Protective effects of prostaglandins in the isolated gastric mucosa of the eel, Anguilla anguilla.

The protective effect of endogenous prostaglandins on the fish gastric mucosa was evaluated by studying the effect of indomethacin and aspirin, known cyclooxigenase inhibitors, on the mucosal ulceration in the isolated gastric sacs of Anguilla anguilla. Gastric sacs devoid of muscle layers were incubated in the presence of indomethacin (10(-4) mol x l(-1)) or aspirin (10(-4) mol x l(-1)) in different experimental conditions. Both the antiinflammatory drugs produced ulcers, but the effects were more severe in the presence of histamine and in the absence of HCO3- in the incubation bath. The effects of prostaglandin E2 (PGE2) on acid secretion rate (J(H)) and on alkaline secretion rate (J(OH)) were evaluated (with the aid of the pH stat method) in isolated gastric mucosa mounted in Ussing chambers. We found that PGE2 (10(-8)-10(-5) mol x l(-1)) increased JH in a dose-dependent manner. In tissues pretreated with luminal omeprazole (10(-4) mol x l(-1)), PGE2 stimulated gastric alkaline secretion. It was nullified by serosal removal of HCO3- or Na+ and by serosal ouabain (10(-4) mol x l(-1)). These results suggested that prostaglandins also exert their protective effects in fish gastric mucosa. This protection seems partially due to a stimulation of exogenous HCO3- transport from the serosal to the mucosal side. It is likely that this transport is an active transcellular mechanism coupled to Na+ transport.

Prostaglandins protect human intestinal cells against ethanol injury by stabilizing microtubules: role of protein kinase C and enhanced calcium efflux.

Prostaglandins (PG) protect gastrointestinal cells against damage induced by ethanol (EtOH) and other noxious agents, a process termed cytoprotection. The present study investigated the relationships between microtubule (MT) stability, protein kinase C (PKC) activation, and calcium efflux as a possible mechanism of PG's protective action using a human colonic cell line (Caco-2) exposed to known damaging concentrations of EtOH (7.5% and 10%). Preincubation of Caco-2 cells with 16,16-dimethyl-PGE2 (PG, 2.6 microM) significantly increased PKC activity in these cells. Pretreatment of Caco-2 cells with 50 microM OAG (a synthetic diacylglycerol and PKC activator) or 30 nM TPA (a direct PKC activator) prior to exposure to 7.5% or 10% EtOH for 5 min significantly reduced cell injury, as determined by trypan blue exclusion, and increased MT stability, as confirmed by confocal microscopy. Pretreatment of Caco-2 cells with 4 alpha-PDD (an inactive phorbol ester, 20 nM) failed to prevent cell injury and disruption of the MT cytoskeleton. Preincubation with staurosporine (a PKC inhibitor, 3 nM) abolished the protective effects of PG in cells exposed to 7.5% and 10% EtOH. Incubation of Caco-2 cells with A23187 (a Ca2+ ionophore), similar to 10% EtOH, caused a significant reduction in cell viability and MT stability. Preincubation with A23187 in combination with PG or OAG prior to subsequent exposure to EtOH significantly abolished the protective effects of PG or OAG pretreatment. Finally, pretreatment with OAG, TPA, or PG resulted in significant increases in calcium-45 efflux, which correlated with increased stability of the MT cytoskeleton. These data suggest that PG possesses direct protective effects against EtOH injury in Caco-2 cells and may act by stabilizing MT through the PKC signal transduction pathway and/or stimulation of calcium efflux from the cells.

Lack of biochemical correlation between the protective effect of prostaglandins and nitric oxide pathway on NSAID-induced gastric injury

Lack of biochemical correlation between the protective effect of prostaglandins and nitric oxide pathway on NSAID-induced gastric injury

Protective effect of prostaglandin E 2 on glutamate-induced cytotoxicity in cultured cortical neurons

Protective effect of prostaglandin E 2 on glutamate-induced cytotoxicity in cultured cortical neurons

Role of superoxide dismutase in mechanism of diethyldithiocarbamate-induced gastric antral ulcer in rats: protective effect of prostaglandin, cimetidine and pirenzepine.

The role of superoxide radicals and the protective effects of superoxide dismutase (SOD), allopurinol, 16,16-dimethyl-prostaglandin E2 (dmPGE2), cimetidine and pirenzepine in diethyldithiocarbamate (DDC)-treated rats were evaluated. Pretreatment with Cu,Zn-SOD (superoxide radical scavenger) 60,000 units/kg, allopurinol (competitive inhibitor of xanthine oxidase) 50 mg/kg, dmPGE2 (prostaglandin analogue) 10 micrograms/kg, cimetidine (H2-receptor antagonist) 10 mg/kg or pirenzepine (selective antimuscarinic drug) 10 mg/kg all significantly reduced the DDC-induced (800 mg/kg) gastric antral ulcer formation in rats. DDC treatment substantially decreases the gastric mucosal Cu,Zn-SOD activity. In this study treatment with DDC and SOD, DDC and dmPGE2, DDC and cimetidine, and DDC and pirenzepine were demonstrated significantly to prevent the decrease of gastric mucosal Cu,Zn-SOD activity. However, allopurinol did not have this effect. The results suggest that SOD and/or superoxide radicals may play an important role in the mechanism of DDC-induced gastric antral ulcer. The protective property against ulcer formation of these drugs studied might be due to the action of SOD in the gastric mucosa.

Prostaglandins protect against murine hair injury produced by ionizing radiation or doxorubicin.

Several years ago we showed that prostaglandins (PGs) are potent radioprotective agents. To investigate further the potential use of these compounds we employed quantitative measures of murine hair loss and regrowth to assess the effects of PG administration before multi-dose fractionated radiation exposures. We compared these results with findings utilizing the thiol compounds WR-2721 or WR-1065, the "gold standard" laboratory radioprotectors. Three weeks after systemic administration of 16-16 dm PGE2 (Upjohn Company) or WR-2721, given 1 h before each dose of 2-4.5 Gy per fraction for 10-15 fractions, regrowing hair counts increased up to 100% compared to irradiated-only skin sites. The thiol compound effects were slightly superior to the PG effects in these studies. Local applications of 16-16 dm PGE2 or WR-1065 given 15 min before each radiation fraction also enhanced post-radiation hair regrowth, although systemic administration of either agent was more effective than the topical route. We also evaluated possible protective effects of PGs given before doxorubicin, measuring murine hair loss 1 week after parenteral injections of the drug. Five daily doses of doxorubicin, 0.1 mg/25 g animal, reduced the number of hairs in a 4.42 mm2 area of skin from 241 +/- 5 (controls) to 144 +/- 3. Misoprostol (G.D. Searle & Co.), 25 micrograms/mouse, applied locally 2 h before each dose of doxorubicin, resulted in 213 +/- 8 residual hairs. We conclude that clinical use of these compounds may provide significant protection of hair follicles and possibly other normal tissues (skin; oral, rectal, and bladder mucosa) lying within a radiation field or in patients treated with chemotherapeutic agents. Further assessment of possible tumor protection effects are needed, however.

Prostaglandins protect against murine hair injury produced by ionizing radiation or doxorubicin

everal years ago we showed that prostaglandins (PGs) are potent radioprotective agents. To investigate further the potential use of these compounds we employed quantitative measures of murine hair loss and regrowth to assess the effects of PG administration before multi-dose fractionated radiation exposures. We compared these results with findings utilizing the thiol compounds WR-2721 or WR-1065, the “gold standard” laboratory radioprotectors. Three weeks after systemic administration of 16-16 dm PGE2 (Upjohn Company) or WR-2721, given 1 h before each dose of 2–4.5 Gy per fraction for 10–15 fractions, regrowing hair counts increased up to 100% compared to irradiated-only skin sites. The thiol compound effects were slightly superior to the PG effects in these studies. Local applications of 16-16 dm PGE2 or WR-1065 given 15 min before each radiation fraction also enhanced post-radiation hair regrowth, although systemic administration of either agent was more effective than the topical route. We also evaluated possible protective effects of PGs given before doxorubicin, measuring murine hair loss 1 week after parenteral injections of the drug. Five daily doses of doxorubicin, 0.1 mg/25 g animal, reduced the number of hairs in a 4.42 mm2 area of skin from 241 ± 5 (controls) to 144 ± 3. Misoprostol (G.D. Searle & Co.), 25 μg/mouse, applied locally 2 h before each dose of doxorubicin, resulted in 213 ± 8 residual hairs. We conclude that clinical use of these compounds may provide significant protection of hair follicles and possibly other normal tissues (skin; oral, rectal, and bladder mucosa) lying within a radiation field or in patients treated with chemotherapeutic agents. Further assessment of possible tumor protection effects are needed, however.

Epithelial Renewal in Protection and Repair of Gastroduodenal Mucosa

The constant, rapid renewal of the gastroduodenal epithelium is an important mechanism of mucosal protection because it maintains the functional integrity of the epithelium. It also is necessary for the repair of mucosal injury. Aspirin, indomethacin, and ethanol all have been shown to stimulate epithelial proliferation in the experimental setting. The stimulatory effects of these agents may be a compensatory reaction to mild injury and may contribute to the process of mucosal adaptation. On the other hand, corticosteroids, physiologic stress, and smoking appear to depress epithelial proliferation, which could render the mucosa susceptible to the effects of other ulcerogens as well as retard the healing of existing mucosal lesions. Epithelial proliferation in mucosa adjacent to active duodenal ulcers as well as from nonulcerated duodenitis is increased when compared to normal-appearing mucosa. This stimulation of epithelial proliferation may be caused by inflammation; it is not known whether ulcer patients have a defect in epithelial proliferation that precedes ulceration. Although prostaglandins (PGs) protect ulceration. Although prostaglandins (PGs) protect the gastroduodenal mucosa, the weight of evidence indicates that PGs do not have a primary effect on epithelial proliferation but rather retard senescence and loss of epithelial cells. The result is thickening of the mucosa, which may contribute to the protective effects of PGs. Ulcerogenic agents or conditions may either depress epithelial proliferation, which predisposes to ulceration or the ulcerogenic effects of other ulcerogens, or result in a hyperproliferative response, which may contribute to the process of mucosal adaptation and protection.

Protective effect of prostaglandin E2 on ethanol-induced injury of chief cells isolated from guinea pig

Protective effect of prostaglandin E₂ on ethanol-induced injury of chief cells isolated from guinea pig

Protective effect of prostaglandin A 2 against menadione-induced cell injury in cultured porcine aorta endothelial cells

Prostaglandine A 2 (PGA 2) stimulates the biosynthesis of γ-glutamylcysteine synthetase and elevates glutathione (GSH) contents in cultured mammalian cells. To clarify the importance of γ-glutamylcysteine synthetase induction in the defence of endothelial cells against oxidative stress, the effect of PGA 2 on menadione (2-methyl-1,4-naphthoquinone)-induced cell injury was examined. Incubation of porcine aorta endothelial cells with menadione produced marked loss of cellular GSH and protein sulfhydryl groups, followed by leakage of lactic dehydrogenase (LDH) into the culture medium. The LDH leakage and modification of protein thiol was, however, completely prevented by pretreatment of the cells with PGA 2. The protective effect of PGA 2 was more potent than that of cysteine delivery agents such as methionine, N-acetylcysteine or 2-oxo-4-thiazolidine carboxylic acid (OTC). The results suggest that cellular GSH plays an important role in the defence against oxidative stress, and induction of γ-glutamylcysteine synthetase is effective for protecting vascular endothelial cells.

Alteration in gastric mucosal acid protease activity induced by necrotizing agents and prevention by prostaglandin E2.

Tissue levels of two gastric mucosal acid proteases, pepsinogen and cathepsin D-like acid proteinase, were determined in rat gastric mucosa damaged by various necrotizing agents and the protective effects of prostaglandins against these biological alterations were investigated. Gastric mucosal damage by each necrotizing agent used was associated with a marked decrease in tissue level of cathepsin D-like acid proteinase. Particularly, ethanol ingestion caused its significant reduction parallel to the production of gastric lesions in a time-dependent manner. On the other hand, mucosal pepsinogen level increased markedly only in ethanol-damaged gastric mucosa, indicating that this change was mediated by a different mechanism from that for cathepsin D-like enzyme. In rats pretreated with prostaglandin E2 and prostaglandin inducers before ethanol administration, these biological alterations of two enzymes were effectively prevented as were gastric lesions. However, ethanol ingestion caused these changes to occur to the same degree in both the necrotic and non-necrotic areas of glandular mucosa. It was considered that cathepsin D-like acid proteinase was released from damaged gastric mucosa through a direct action on cellular membrane different from vasoconstrictor and platelet aggregating actions mediated by arachidonic acid metabolites.

N-acetyl-cysteine and prostaglandin. Comparable protection against experimental ethanol injury in the stomach independent of mucus thickness.

The role of barrier mucus in mediating the protective effects of 16,16 dimethyl PGE2 (dm PGE2) against ethanol-induced gastric injury, with and without concomitant treatment with N-acetyl-cysteine (NAC), a potent mucolytic agent, was evaluated. Fasted rats were orally administered either saline, 10 micrograms/kg dm PGE2, 20% NAC, or 10 micrograms/kg dm PGE2 plus 20% NAC. In the first study, the rats were killed 15 minutes later and their stomachs were removed and assayed for barrier mucus adherent to the gastric wall using the Alcian blue technique. In the second study, the rats were orally given 2 mL of absolute ethanol (EtOH) after receiving one of these pretreatment regimens, and 5 minutes later they were killed and their stomachs were evaluated histologically by light microscopy for the magnitude of EtOH injury. Although NAC significantly reduced the thickness of barrier mucus by 76% when compared with control animals, it did not adversely affect the ability of dm PGE2 to spare the deep epithelium from injury by EtOH. In fact, NAC was as effective a protective agent as dm PGE2. Neither agent prevented damage to the surface epithelium by EtOH, verifying previous studies regarding the protective effects of prostaglandins. These results indicate that both dm PGE2 and NAC prevent EtOH-induced damage to the deeper layers of the gastric mucosa independent of mucus gel layer thickness, suggesting that other mechanisms than mucus are involved in mediating this protection.

Protective effect of prostaglandins D2, E1 and I2 against cerebral hypoxia/anoxia in mice.

The protective effect of prostaglandins (PGs) against cerebral hypoxia/anoxia was investigated with a variety of experimental models in relation to their CNS depressant effects in mice. Furthermore, the effect of PGs on the changes of cerebral energy metabolites and cyclic nucleotide was examined in hypoxic mice. Mice were given s.c. doses of PGs 30 min before tests. Among the PGs tested, treatment with PGD2, PGE1 and PGI2 Na showed a consistent and dose-dependent protection against cerebral anoxia induced by all models studied: histotoxic anoxia by KCN, hypobaric hypoxia, normobaric hypoxia and decapitation-induced gasping. However, PGA1, PGA2, PGB1, PGB2, PGE2, PGF1 alpha, PGF2 alpha and 6-keto-PGF1 alpha at a dose of 3 mg/kg were without effect against normobaric hypoxia and gasping duration. The three PGs, i.e. PGD2, PGE1 and PGI2 which showed anti-hypoxic effects decreased locomotor activity and potentiated hexobarbital-induced sleep. On the other hand, PGE2, PGA1, PGA2 and PGB2 also caused a decrease in locomotor activity. Similarly, PGE2 and PGA1 caused a potentiation of hexobarbital-induced sleep, but interestingly they did not cause clear-cut increase in cerebral resistance to hypoxia, in contrast with the former three PGs. Thus general depression of CNS function appears not to be responsible for the PGD2-, PGE1- and PGI2-induced increase in cerebral resistance to hypoxia. The levels of Cr-P and ATP were significantly reduced and those of ADP and AMP were markedly elevated in hypoxic brain, resulting in a decrease in a calculated energy charge potential. The lactate level and lactate/pyruvate ratio increased and the glucose level decreased markedly.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructural effects of ulcerogens.

Agents such as ethanol, aspirin, bile acids, and hypertonic urea and glucose, are capable of breaking the physiological gastric mucosal barrier and may cause ultrastructural injury to the epithelial cells within several minutes of exposure. Ethanol at any pH, and aspirin and bile acids at acid pH, are lipid soluble and diffuse rapidly into surface epithelial cells where a sequence of injury can be documented by electron microscopy. First, the nuclear chromatin becomes clumped and the density of the cytoplasmic ground substance decreases. Second, mitochondria become swollen and the apical cell membrane is distorted. Finally, the apical cell membrane ruptures and the cell disintegrates. Throughout this sequence, the tight junctions between cells appear morphologically intact. In contrast to lipid soluble agents, hypertonic urea and glucose do not diffuse well into surface epithelial cells. Although these agents also cause rapid changes in transmucosal potential difference and ion fluxes, their ultrastructural effects are quite different. Hypertonic urea and glucose initially cause small blebs within the tight junctions and larger vacuoles within the cytoplasm of surface epithelial cells, while the remainder of the cell structure appears normal. More severe injury is characterized by more vacuolization and eventual disruption of epithelial cells. These changes presumably are secondary to osmotic shifts of fluid and electrolytes. Although the 'cytoprotective' effects of prostaglandins have been well described, there is virtually no information at the ultrastructural level concerning the protective effects of prostaglandins with regard to these ulcerogenic agents.

Protective effects of prostaglandins against ulcerogenic activity of indomethacin during different stages of erosion development in rat stomach. Role of acid and bicarbonate secretion.

Prostaglandin E2 (PGE2) and PGF2 beta decreased the gastric erosive activity of orally administered indomethacin in a dose-dependent manner, when given as a continuous intravenous infusion in the conscious rat. PGE2 protected both during the initial stage of erosion induction and during the later outgrowth to larger erosions. Moreover PGE2 was able to stop the eroding process at any stage as long as the infusion continued. Both PGs were protective only in doses which also reduced the histamine-stimulated acid secretion. PGE2 protected the stomach against indomethacin-induced erosions even in the presence of exogenously administered acid. An infusion of PGE2 stimulated the secretion of bicarbonate in the stomach during some minutes but had no effect during prolonged infusion. These results suggest that, although effects on secretion of acid and bicarbonate were found, these effects cannot be the (only) explanation for the cytoprotective effects observed. Furthermore the protective effect of PGE2 is not confined to any specific stage of the development of indomethacin-induced gastric injury.

Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms.

Recent evidence indicates that prostaglandins (PGs) possess potent gastric antiulcer properties independent of their known inhibitory effects on acid secretion. The mechanism underlying this cytoprotective property, as it has been called, has remained elusive. Although exogenously administered PGs can prevent disruption of the gastric mucosal barrier, enhance gastric mucosal blood flow, and stimulate mucus and bicarbonate secretion, as well as a number of cellular transport processes, evidence for and against each of these proposed mechanisms for cytoprotection has been demonstrated. Thus, it is doubtful whether any of these effects of PGs on gastric epithelium is the mechanism responsible for cytoprotection, if indeed a single, common mechanism exists. In addition, an association between alterations in endogenous PGs and gastric mucosal injury induced by a variety of damaging agents has also been observed, but the importance of this association in terms of mediating gastric damage needs further clarification. Finally, the phenomenon of adaptive cytoprotection in which mild irritants protect the gastric mucosa against the damaging effects of various necrotizing agents may also be PG mediated since it can be blocked by indomethacin, an inhibitor of PG synthesis, but a clear association between changes in endogenous PGs and adaptive cytoprotection remains to be demonstrated. Despite being inconclusive, these findings suggest that PGs may play a significant role in the pathogenesis of gastric ulceration and may serve an important function in maintaining normal gastric mucosal integrity.

The effect of orally administered prostaglandins on gastric mucus secretion in the rat

The secretion of gastric mucus may play a role in the protective effect of prostaglandins against gastric ulcers. To investigate the effect of prostaglandins E 1, E 2, F 1α, F 2α, A l, A 2 and 15(S)15 methyl prostaglandin E 2, F 1α, ester on gastric mucus secretion, these prostaglandins were given orally to rats at doses of 0.1, 1.0 and 4.0 mg/kg. The anthrone method was used to analyze the amount of mucus washed from the stomach with 2 M NaCl. Gastric secretory volume effects were also observed. All of the compounds tested increased both gastric mucus and secretory volume. The most. active compound was 15(5)15 methyl PGE 2 Me ester. The mucus stimulating effect of these prostaglandins, when administered locally, may be relevant to the understanding of the anti-ulcer effects of prostaglandins.