Prostaglandin E1 Treatment Research Articles

Prostaglandin E1-associated pathology of pulmonary microvasculature in newborn pups: similarity to findings in prostaglandin E1-treated human newborns.

Prostaglandin E1 (PGE1) administration is a useful therapeutic measure for short-term maintenance of ductal patency in patients with obstructions to pulmonary or systemic blood flow. Such treatment is not without complications, however, and a report of three infants from our institution with abnormalities of the pulmonary microvasculature after varying periods of PGE1 therapy was recently published (Heffelfinger et al., Pediatr Pathol 1987;7:165-73). The vascular abnormalities appeared to be temporally related to the PGE1 administration. To test this hypothesis, we investigated the effects of PGE1 in newborn beagles by infusing PGE1 for periods of up to 21 days in four experimental pups. Two control pups were infused with saline for the same period of time. Five of the animals developed respiratory infection during the course of the infusions. One PGE1-treated pup was not infected. Both the PGE1- and saline-treated pups had bronchopneumonias of similar severity; however, pulmonary arteritis occurred only in the PGE1-treated pups. The severity of the arteritis varied with the amount of pulmonary parenchymal inflammation and not with the duration of PGE1 administration. Inflammatory and vascular lesions were found in organs other than the lung only in two pups receiving longer courses of PGE1 treatment. We conclude that systemic PGE1 infusion at therapeutic levels plays a role in the development of arterial lesions in small muscular arteries and that this is potentiated by the presence of infection.

PGE1 inhibits neutrophil adherence and neutrophil-mediated injury to cultured endothelial cells.

Prostaglandin E1 (PGE1) has been shown to inhibit acute inflammatory reactions involving vascular permeability changes and subsequent tissue damage caused by immune complex deposition and other inflammatory mediators. These effects have been postulated to be due to functional changes induced in circulating neutrophils by PGE1. We evaluated the ability of PGE1 (1 to 100 microM) to protect endothelial cells (EC) from neutrophil injury induced by C5a or phorbol myristate acetate (PMA). The injury to endothelial monolayers was quantitated by 51Cr loss after an 18-h incubation. In the presence of PGE1, there was a concentration-dependent inhibition of C5a- or PMA-stimulated human neutrophil injury to EC. The protective effect was more effective by pretreatment of neutrophils than EC. Since neutrophil adherence to endothelial cells is thought to be an early event in the sequence resulting in injury to vascular endothelium, we next evaluated the effect of PGE1 on neutrophil adherence to plastic surfaces and EC. In a similar fashion, there was a concentration-dependent inhibition of neutrophil adherence to plastic and EC following stimulation with PMA (10 ng/ml), human C5a (5 micrograms/ml) or formyl-met-leu-phe (FMLP, 2 x 10(-7) M). To investigate a possible mechanism of inhibition of neutrophil adherence to plastic surfaces or EC, expression of the neutrophil surface protein Mo1, previously shown to be associated with increased granulocyte adherence, was measured by fluorescence flow cytometry. Although basal levels of Mo1 expression by unstimulated neutrophils were diminished by PGE1 treatment, there was no significant inhibition of PMA- or FMLP-stimulated Mo1 expression in PGE1-treated neutrophils compared with neutrophils stimulated in the absence of PGE1.(ABSTRACT TRUNCATED AT 250 WORDS)

Tetralogy of Fallot with absent ductus arteriosus and absent collateral pulmonary circulation: Diagnostic and surgical implications during the neonatal period

A newborn infant with tetralogy of Fallot and presumed agenesis of the ductus arteriosus presented without the expected associated pulmonic regurgitation and aneurysmal pulmonary arteries. The presumption of agenesis of the ductus arteriosus was made because there was no reduction in cyanosis following prostaglandin E1 treatment and no remnant of ductus arteriosus could be demonstrated by angiography at 19 h of age. The fetal hemodynamics inferred in this infant are discussed with reference to the absence of aneurysmal pulmonary arteries. Closed transventricular pulmonary valvulotomy is recommended as emergency palliation for symptomatic newborns with this variant of tetralogy of Fallot because further reduction of pulmonary vascular bed, even temporarily, as in unilateral pulmonary artery cross-clamping for systemic-pulmonary anastomosis, may not be tolerated without the use of cardiopulmonary bypass.

Incubation of bovine thyroid slices with thyrotropin is associated with a decrease in the ability of pertussis toxin to adenosine diphosphate-ribosylate guanine nucleotide regulatory component(s).

Pretreatment of bovine thyroid slices with TSH resulted in desensitization of TSH-sensitive adenylyl cyclase activity but no change in stimulatory nucleotide binding regulatory component of adenylyl cyclase (Gs) activity assessed by reconstitution of the Gs-defective cyc-S49 adenylyl cyclase system. Possible changes in substrates for pertussis toxin (PT)-induced ADP ribosylation due to TSH treatment and/or in endogenous ADP ribosylation of membrane proteins were explored. Using 10 microM [32P]NAD+ as substrate, endogenous ADP ribosylation was not observed in membranes from control or TSH-treated slices. ADP ribosylation of alpha-subunits of Gs by cholera toxin was also unaffected by incubation of thyroid slices with TSH. In contrast, ADP ribosylation of 40 kilodalton (kDa) substrates for PT was decreased between 40% and 60% by TSH treatment. This effect of TSH was dependent on its concentration and the time of incubation of the slices and was specific for labeling of the 40 kDa PT substrate. Prostaglandin E1 treatment of thyroid slices, which results in a much smaller homologous desensitizing effect, did not result in changes in ADP ribosylation by PT. The effect of incubation of slices with TSH was abolished by pretreatment of the membranes with 0.3-1.0% Lubrol PX, which increased the labeling of the 40 kDa polypeptides. The data suggests that TSH induces in thyroid tissue a redistribution of 40 kDa polypeptides changing their availability to PT.

Prostaglandin E1 inhibits effector T cell induction and tissue damage in experimental murine interstitial nephritis.

Immunosuppressive effects of E-series prostaglandins have been demonstrated in many in vitro assays of immune responsiveness as well as in autoimmune diseases. To explore the mechanisms underlying prostaglandin E1 (PGE1)-associated immunosuppression in autoimmunity, we treated SJL mice immunized to produce immune-mediated interstitial nephritis with PGE1, PGF2 alpha, or vehicle alone. Mice receiving PGE1 treatment do not develop interstitial nephritis, nor do they display delayed-type hypersensitivity (DTH) to the immunizing renal tubular antigen preparation. The observed immunosuppression is critically dependent on PGE1 administration during the period of effector T cell induction. We therefore investigated the effect of PGE1 on the in vitro induction of DTH effector T cells reactive to renal tubular antigens (SRTA). PGE1 inhibits effector T cell induction in a dose-dependent, reversible manner, but has no inhibitory effect on fully differentiated DTH effector cells or SRTA-reactive cell lines. The PGE1 effect is indirect and mediated via nonspecific suppressor lymphokines. This suppression can be overcome by recombinant interleukin 1 (IL-1), which suggests a mechanism related to either diminished IL-1 secretion or target cell sensitivity to IL-1.

Pulmonary Vascular Changes Associated with Prolonged Prostaglandin E1 Treatment

Prostaglandin E's (PGEs) are used therapeutically in newborn infants to maintain an open ductus arteriosus when there is obstruction to systemic or pulmonary arterial blood flow. These prostaglandins have been shown to have other systemic physiologic effects, such as vasodilation, inhibition of platelet aggregation, and enhancement of chemotactic-factor-mediated polymorphonuclear leukocyte infiltration, with resultant loss of lysosomal granules and possibly the generation of free radicals. We have recently seen previously unreported vascular lesions in 3 infants with hypoplastic left heart syndrome treated with usual therapeutic doses of PGE1 for prolonged periods. At autopsy, pulmonary vascular changes reflecting increased flow were present in each infant. One infant had a necrotizing vasculitis, sometimes associated with infarcts, in the lungs and in small muscular arteries in other organs. The form and severity of the vascular changes appear to be related to the duration of PGE1 administration.

Effects of intra-arterial prostaglandin E1 in patients with peripheral arterial occlusive disease.

The effects of intraarterially administered prostaglandin E1 (PGE1) on macrocirculatory, microcirculatory and metabolic parameters in patients with peripheral arterial occlusive disease were studied. Nutritive calf muscle blood flow, as determined with the xenon-clearance technique, and muscle tissue oxygen pressure increased markedly in patients with obliterations of the femoral artery. Transcutaneous PO2 as indicator for cutaneous blood flow increased in prestenotic regions dose-dependently whereas there was a clear poststenotic decrease during the infusion period. High lactate/pyruvate ratios in the femoral vein were significantly decreased by PGE1 treatment. PO2 in the femoral vein increased significantly. Thus, PGE1 has some beneficial effects on muscle circulation in these patients.

Suppression of cellular immunity to Listeria monocytogenes by activated macrophages: mediation by prostaglandins.

We previously demonstrated the suppression of cell-mediated immunity to Listeria monocytogenes by Pseudomonas aeruginosa-induced, macrophage-like cells. The present study was undertaken to evaluate the mechanism for this suppression. P. aeruginosa supernatant was shown to activate macrophages by the criteria of increased bactericidal capacities and increased attachment to glass surfaces. Acquired cellular resistance to L. monocytogenes could also be inhibited by macrophages from L. monocytogenes-pretreated mice. The depression of acquired immunity by P. aeruginosa- or L. monocytogenes-activated macrophages did not appear to be due to a reduction of antigenic stimulus after nonspecific macrophage activation. In contrast, our findings suggest that suppression is mediated by activated macrophages through a prostaglandin-dependent mechanism. In vivo administration of aspirin blocked the immunosuppressive effect of P. aeruginosa- or L. monocytogenes-activated cells. Moreover, the suppressive activity of supernatants of macrophages from Listeria-infected mice was reversed when indomethacin was present during supernatant generation. Finally, prostaglandin E1 treatment in vivo profoundly inhibited the induction of cell-mediated immunity to L. monocytogenes. The possible role and mechanism of prostaglandin in suppressing cellular immunity to intracellular bacteria are discussed.

閉塞性動脈硬化症における赤血球変形能とpentoxifylline投与の効果

Red cell deformability is very important for microcirculation in arteriosclerosis obliterans (ASO). RBC deformability in ASO patients was measured by a modification of Reid's method using a 5-μm pore Nuclepore Micro Filter and a 20% Ht red cell suspension. The flow rate of a 20% Ht suspension through the filter was calculated, and red cell filtration rate (RFR) was used as an estimate of red cell deformability.RBC deformability in 34 ASO patients (mean age: 64.2 years) was reduced (RFR=32.32 pl/sec) significantly, compared with 17 age-matched controls (mean age: 59.0 years RFR=50.01μl/sec) (p<0.001). RBC deformability in ASO was also analyzed by allotting the patients into a claudication group and an ulcer group. The mean RFR in the claudication group (n=23) was 35.33μl/sec while that in the ulcer group (n=5) was 5.74μl/sec. The RBC deformability in the ulcer group was thus singificantly lower than that in the claudication group (p<0.001).Pentoxifylline was given orally to 9 patients in a dose of 600mg per day for 6 weeks. The mean RFR pre-treatment was 32.18μl/sec. The mean RFR post-treatment increased to 59.40μl/sec (p<0.01). Pentoxifylline was proven to be very effective for improving not only reduced RBC deformability but also clinical signs and symptoms.Ehrly pointed out that one of the factors governing the microcirculatory blood maldistribution was the reduced red cell deformability in occlusive arterial disease. The cause of this reduced RBC deformability in ASO, however, is still unknown. We have shown that reduced red cell deformability was improved after prostaglandin E1 and PGI2 analogue treatment. On the other hand, the productivity of PGI2 in ASO was proven to be lowered. These findings indicate that there may be some relationship between PGI2 and RBC deformability in ASO.Because red cell deformability was reduced significantly in the ulcer group, this lowered deformability might be a cause and a consequence of the ulcer in ASO patients. On the other hand, the ATP level in poorly deformable RBC is known to be below normal. Furthermore in vascular disease, the ATP level in RBC is reportedly lower than in normal controls. Pentoxifylline is thought to improve reduced RBC deformability in ASO by increasing the ATP level in RBC.

Prostaglandin E1 treatment in experimental acute pancreatitis in the rat.

Prostaglandin E1 (PGE1) was tested for cytoprotective activity against the development of experimental acute pancreatitis in the rat induced by the closed duodenal loop technique. Sham-operated, untreated and PGE1-treated pancreatic rats were investigated. All rats received an initial bolus of 3 ml 5% dextrose in normal saline (D5NS) via jugular catheter 30 min prior to surgery, and a continuous subcutaneous infusion of 35 ml D5NS over 24 h. Each treated rat received 10 micrograms/kg PGE1 in the initial bolus and a maintenance dosage of 10 micrograms/kg/h via the infusate. Serum amylase rose significantly in all pancreatic rats with no significant difference between treated and untreated. Pancreatic edema was more pronounced in PGE1-treated than in untreated rats. The ischemic and autolytic damage to acinar cells and vascular endothelial cells typical of untreated pancreatitis was delayed by PGE1. Mortality rates were unaffected by PGE1.

Morphometric Effect of Prostaglandin E1 and F2α on Lactating Bovine Mammary Tissue In Vitro

Mammary explants from six lactating cows were incubated for .17, 4, 8, and 12h in medium containing prostaglandin E1 or prostaglandin F2α tromethamine salt at 0, 1, 10, or 50 μ/ml to determine if prostaglandins alter tissue structure. Explants were fixed, dehydrated, embedded in plastic resins, and sectioned at .5 to 1.0 μ. Tissue area was partitioned by light microscopy into normal, damaged, or debris epithelial; normal or debris lumenal; or stromal areas. All tissue samples exhibited signs of deterioration as incubation progressed. Prostaglandin E1 treatment maintained more secretory epithelium and resulted in less epithelial debris and lumenal debris than controls. Prostaglandin F2α-treated tissue had less epithelial debris and normal lumenal area than tissue receiving no prostaglandin during the limited incubation. The three concentrations of prostaglandins studied did not identify optimal prostaglandins for mammary tissue incubated but indicated concentrations below 1μg prostaglandin E1 or F2α/ml should be studied. The response of mammary tissue to prostaglandin was affected by donor milk production. Increases of normal epithelial area were correlated with decreases of damaged and debris areas. Prostaglandins E1 and F2α appeared to be beneficial to healthy mammary tissue incubated under limited conditions.

Elevated Cyclic Adenosine 3′, 5′ Monophosphate Enhances Lactic Acid Production by Streptococcus lactis

Elevation of cyclic adenosine 3′, 5′ monophosphate levels induced by prostaglandin E1 enhanced growth of Streptococcus lactis C2 in a medium supplemented with lactose. The prostaglandin E1-induced enhancement of growth did not appear to result from stimulation of the phosphoenolpyruvate phosphotransferase system because o-nitrophenol-β-D-galactopyranoside phosphorylation was not elevated by prostaglandin E1, treatment. Measurement of the extracellular proteolytic activity revealed increased activity in prostaglandin E1-treated cultures suggesting that an increase in the organic nitrogen source contributed to increased growth rate. Moreover, elevations in intracellular cyclic adenosine 3’, 5’ monophosphate induced by prostaglandin E1 treatment increased lactic acid production at the cellular level.

Effect of prostaglandin E1 in collagen disease patients with inflammatory skin ulcer

Clinical, physiological and biochemical studies of PGE1 were done, in a series of collagen diseas patients with skin ulcer, foot varix patient with skin ulcer as non-inflammatory skin ulcer control, and 2 diabetics without skin ulcer as no skin ulcer control. Intra-venous infusions of prostaglandin E1 (PGE1) was given continuously in the dose of 1 ng/kg/min for 72 hours. Blood samples were collected from cubital vein, before, during, right after and at 7 days after PGE1 therapy. Platelet aggregations were studied by light transmittance (PRP: modified by Born's method, whole blood: modified by Tohjima's method) . Platelet iPG E (immunoreactive PG E like material) levels were assayed by radio-immunoassay. Essintial fatty acids compositions of plasma, pltelet and red cell were analyzed by gas chromatography.Results were as follows:(1) In all of cases, complete healing of skin ulcers was observed.(2) In most cases, skin temperature increased during PGE1 treatment.(3) Platelet aggregation was increased during PGE1 treatment than before one, and was higher in PRP than in whole blood, during PGE1 treatment.(4) The platelet basal iPGE levels were significantly decreased by PGE1 (p<0.025) .(5) The plasma and platelet linoleic acids levels were significantly higher than before PG E1 treatment (plasma: p<0.05, platelet: p<0.025) .(6) Thrombocytosis of one case of MRA was healed by the second PGE1 treatment.Conclusion:The inflammatory skin ulcers in collagen diseases had healed completly by continued intravenous infusion of PGE1. This effect might be brought by the supression of PG metabolism, especially in platelet.

Effect of prostaglandin E1-induced elevation of cyclic AMP on glucose repression in the lactic streptococci.

Cyclic adenosine 3', 5' -monophosphate (cAMP) activity was observed in Streptococcus lactis C2, Streptococcus cremoris C10, Streptococcus diacetlactis 18-16, and Streptococcus thermophilus C3. In vitro assays of cell-free extracts obtaianed from S. lactis C2 showed that the cAMP-associated enzymes adenyl cyclase and phosphodiesterase were also present. In vitro experiments showed that prostaglandin E1 (PGE) stimulation of adenyl cyclase increased cAMP concentrations approximately fivefold, and in vivo studies showed that PGE treatment of S. lactis C2 increased intracellular cAMP concentrations twofold. Futhermore, PGE-induced elevation of intracellular cAMP levels was shown to prevent the repression of ss-D-phosphogalactoside galactohydrolase synthesis by glucose.

Endogenous cyclic AMP does not modulate transport of hexoses, nucleosides, or nucleobases in chinese hamster ovary cells

In a previous study we have demonstrated that neither extracellular nor intracellular cyclic adenosine monophosphate (AMP) levels directly affect the uptake of nucleosides, nucleobases, or hexoses by various types of cultured mammalian cells. Uptake of these nutrients into cells, however, involves two processes operating in tandem: facilitated transport across the membrane and intracellular phosphorylation; and uptake rates generally reflect the rates of substrate phosphorylation rather than of transport. In the present study we have examined the question of whether substrate transport per se is regulated by intracellular cyclic AMP. Initially various cell lines, grown both in suspension and monolayer culture, were screened for their cyclic AMP response to prostaglandin E1, isoproterenol, and inhibitors of cyclic AMP phosphodiesterase. Prostaglandin E1 treatment of Chinese hamster ovary cells was selected as the system giving the largest and most consistent (50-fold to 100-fold) elevation of cyclic AMP. Rapid kinetic techniques were used to measure the transport of 3-O-methylglucose, thymidine, adenosine, hypoxanthine, and adenine in wild-type cells and in mutant sublines incapable of phosphorylating these substrates. In no case was an increase in intracellular cyclic AMP accompanied by a significant change in the rate of transport of these substrates, although prostaglandin E1 slightly inhibited the transport of various substrates.

Prostaglandin E1 treatment of NZB/NZW F1 hybrid mice. II. Prevention of glomerulonephritis.

The F1 hybrid of New Zealand black and New Zealand white mice--the NZB/NZW mouse--spontaneously develops a disease similar to human systemic lupus erythematous, characterized by impaired cell-mediated and enhanced humoral immune responses, development of antibodies to nuclear antigens, and immune complex glomerulonephritis. Because there is experimental evidence that prostaglandin E1 (PGE1) can enhance T-cell function and cell-mediated responses and suppress B-cell activity, NZB/NZW mice were treated with 200 microgram PGE1 subcutaneously once or twice daily from 6 weeks of age. PGE1 treatment of female and male mice prevents giomerular deposition of immunoglobulins and complement (monitored by immunofluorescence), and development of the proliferative glomerulonephritis (determined by light and electron microscopy) characteristic of untreated NZB/NZW mice. After 1 year of treatment, 18 of 19 female mice survived, whereas only 2 of 19 untreated control mice were alive. Male mice treated with 200 microgram PGE1 daily were also protected: 9 of 11 versus 2 of 9 untreated mice were alive at 65 weeks. PGE1 treatment did not prevent development of antibodies to nuclear material in any of the treated groups.

Prostaglandin E1 treatment of NZB/NZW mice

NZB/NZW F1 hybrid mice were treated with pharmacologic doses of prostaglandin E1 (PGE1) (200 microng subcutaneously either once or twice daily) from 6 through 52 weeks of age. PGE1-treated mice were protected against development anemia, clinical nephritis, and death. At 52 weeks 18 of 19 treated mice were alive, wherase only 2 of 19 untretreated control mice were alive. None of the 10 mice treated with PGE1 twice daily exhibited significant (greater than 2+) proteinuria at 1 year of age. PGE1 treatment did not prevent development of antibodies to nuclear antigens. The data also suggest that survival of NZB/NZW mice is prolonged when treatment with PGE1 is begun at 24 weeks, an age at which mice already show evidence of nephritis. Thus all 6 mice treated with PGE1 (200 microng sc twice daily) from 24 weeks were alive at 52 weeks, whereas only 2 of 6 untreated control mice were alive. The mechanisms whereby PGE1 treatment influences the course of disease in NZB/NZW mice are not known.

The action of prostaglandin E1 on frog skeletal muscle.

The effects of prostaglandin E1 (PGE1) were investigated in frog semitendinosus and sartorius muscle preparations in vitro, PGE1 augmented and prolonged the twitch response, and the effect was equally developed in preparations stimulated through the nerve or directly. The threshold concentration was between 0.03 and 0.14 mM, and definite changes occurred with concentrations between 0.7 and 1.4 mM. Enhancement of twitch responses developed gradually, and a peak was reached within 5–20 min following PGE1 application. Prolonged exposure of the tissue to PGE1 showed that the twitch height increases first to a maximum and then declines to control values and below, despite the continuous presence of the compound in the bath. This decrease of twitch height was coupled with a progressive lengthening of the response. Twitch depression and prolongation were not reversible after transfer to normal Ringer but 2 mM caffeine consistently restored the depressed response to control levels, or above. PGE1, unlike caffeine, did not elicit sarcomeric oscillations. No substantial changes of membrane potentials at junctional or extrajunctional regions resulted from PGE1 treatment. It is concluded that PGE1 acts at a muscle site possibly by lowering the mechanical threshold of the contracting element.

Prostaglandin E 1 (PGE 1 ) suppression of adjuvant arthritis. Histopathology.

AbstractHistopathologic studies of tibiotarsal joints from rats with adjuvant disease show complete suppression of arthritis in animals treated with prostaglandin E1 (PGE1) from time of adjuvant injection. Established synovitis is improved by PGE1 treatment and progression of arthritis and cartilage destruction is halted.