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PubMed1989

Phosphatidic acid phosphatase in neonatal rat lung: effects of prenatal dexamethasone or terbutaline treatment on basal activity and on responsiveness to beta adrenergic stimulation.

Phosphatidic acid phosphatase (PAPase) is a key enzyme in the synthesis of lung surfactant. This study compares the effects of prenatal exposure (gestational days 17, 18 and 19) to two drugs which enhance surfactant synthesis: dexamethasone (0.2 mg/kg) and terbutaline (2 or 10 mg/kg). Maternal dexamethasone treatment did not cause an initial stimulation of lung PAPase but did eventually evoke a small increase after the 1st postnatal week. The effect was selective in that brain PAPase activity was generally unaffected; liver PAPase was stimulated during the early neonatal period only. Dexamethasone also prolonged the developmental period of peak reactivity of lung PAPase to beta developmental period of peak reactivity of lung PAPase to beta adrenergic stimulation (tested with acute isoproterenol challenge), which ordinarily accompanies genesis of alveoli in the 2nd to 3rd postnatal week. Significant growth retardation was present even at this low dose of dexamethasone. In contrast, maternal administration of the beta adrenergic agonist, terbutaline, resulted in a large increase in basal enzyme activity in the lung during the immediate perinatal period and enhanced the responsiveness to isoproterenol challenge. The effect of terbutaline was accompanied by little or no growth impairment. Thus, although prenatal administration of either glucocorticoids or beta adrenergic agonists can enhance lung PAPase activity and reactivity to stimulation, the two classes of drugs differ substantially in time course of effect and in the propensity to retard growth.

Aging↗
PubMed1988

Activation of NADPH-dependent superoxide production in plasma membrane extracts of pig neutrophils by phosphatidic acid.

Phosphatidic acid (PA), a molecule that is rapidly produced by the stimulated turnover of phospholipids in a variety of cells including blood neutrophils, elicited NADPH-dependent superoxide anion (O2-) production in detergent extracts from membranes of resting pig neutrophils. The stimulatory effect of PA was independent of cytosolic factors, differing from arachidonic acid and sodium dodecyl sulfate which, on the contrary, absolutely required the presence of cytosol to elicit the same result. The O2(-)-forming activity of the detergent extract activable by PA, as that by sodium dodecyl sulfate and arachidonic acid plus cytosol, was found in the chromatographic fractions containing cytochrome b558 and presented a chromatographic profile identical to that of the activated NADPH oxidase, which was obtained from neutrophils prestimulated with phorbol 12-myristate 13-acetate. The PA-induced NADPH-dependent O2(-)-forming activity showed kinetic properties and sensitivity to the inhibitors similar to the classical ones of the activated neutrophil NADPH oxidase. The data suggest that, in this cell-free system, PA may stimulate O2- formation by direct interaction with latent NADPH oxidase of neutrophils or with some of its regulatory components.

Animals↗
PubMed1975

Phosphatidate phosphohydrolase and palmitoyl coenzyme A hydrolase in cardiac subcellular fractions.

The characteristics of the two enzymes related to fatty acid esterifaction were studied in order to provide fundamental information leading to further understanding of the control of myocardial glyceride formation. Palmitoyl-CoA hydrolase and phosphatidate phosphohydrolase are both distributed unevenly among heart subcellular fractions. The activity of the latter enzyme in subcellular fractions changes independently in response to Mg2+ addition and in response to thyroid hormone treatment of animals.

Animals↗
PubMed1985

Relative importance of diacylglycerol, phosphatidate, lysophosphatidate, inositol trisphosphate and arachidonate metabolism in platelet receptor signalling.

Activation of platelets is correlated with phospholipase C-induced degradation of phosphatidylinositol 4,5-bisphosphate and the rapid formation of 1,2-diacylglycerol and myo-inositol 1,4,5-trisphosphate. Both products are considered second messengers and they, respectively, stimulate protein kinase C and Ca2+ mobilization. Mobilization of Ca2+ leads to activation of a Ca2+/calmodulin-dependent myosin light chain kinase and phospholipases A2 which liberate arachidonic acid from phospholipids. Arachidonate is then immediately converted to active endoperoxides and thromboxanes which are released and activate further platelets again through phospholipase C. The levels of phosphatidic acid and lysophosphatidic acid are also increased following receptor-stimulated hydrolysis of the inositol phospholipids. Lysophosphatidic acid might have a direct action on the opening of Ca2+-channels.

Arachidonic Acid↗
PubMed1987

Phosphatidic acid may stimulate membrane receptors mediating adenylate cyclase inhibition and phospholipid breakdown in 3T3 fibroblasts.

Incubation of 3T3 fibroblasts with phosphatidic acid (PA) from egg lecithin or with thrombin resulted in decreases in cellular cAMP due to inhibition of adenylate cyclase, in rapid increases in inositol 1,4,5-tris-,1,4-bis-, and 1-monophosphates probably due to activation of phospholipase C, and in arachidonic acid release. Synthetic PAs consisting of unsaturated fatty acid diesters were as effective as PA from egg lecithin, whereas PAs with saturated fatty acids were only slightly effective and antagonized the effect of active PAs selectively, despite the fact that both types of PA analogues (sodium salts) were apparently dissolved in the incubation medium. PA-induced decreases in cAMP were not affected by omission of Ca2+ from incubation medium but were abolished by prior exposure of cells to islet-activating protein (pertussis toxin). This islet-activating protein treatment of cells was without effect on PA- or thrombin-induced generation of inositol phosphates. Thus, PA-induced inhibition of adenylate cyclase was (but activation of phospholipase C was not) mediated by an islet-activating protein substrate GTP-binding protein. Homologous desensitization was observed with thrombin-, bradykinin-, and PA-induced decreases in cAMP in 3T3 cells; prior exposure of the cells to any one of these agents abolished or greatly diminished the subsequent response to the same agent but did not affect the responses to others. The effects of PA were cell-specific; it failed to decrease cAMP in rabbit platelets in which labeled PA rapidly increasing in response to thrombin or A23187 was mostly outside the cells. Based on these results, it is proposed that PA interacts with its own specific membrane receptors, thereby triggering multiple effector systems in 3T3 cells.

Adenylyl Cyclase Inhibitors↗
PubMed1987

Regulation of arachidonic acid metabolism in resident and BCG-activated alveolar macrophages: role of lyso(bis)phosphatidic acid.

To dissect mechanisms of arachidonic acid (20:4) metabolism in pulmonary alveolar macrophages (PAM), two distinct cell populations were investigated, resident and BCG-activated rabbit alveolar macrophages. After purified resident PAM were labeled overnight with [3H]20:4, radioactivity was localized primarily within lyso(bis)phosphatidic acid (L(bis)PA) (13.1% +/- 1.7), phosphatidylethanolamine (PE) (22.8% +/- 0.8), and phosphatidylcholine (PC) (26.7% +/- 1.7), with lesser amounts recovered in phosphatidylserine plus phosphatidylinositol (PS/PI) (9.2 +/- 0.8%). By contrast, analysis of the phospholipid classes from prelabeled BCG-activated PAM revealed that the amount of [3H]20:4 contained in L(bis)PA was profoundly decreased (4.7% +/- 0.4), p less than 0.003), whereas [3H]20:4 contained within other BCG phospholipids remained unchanged. Moreover, L(bis)PA, which composed 18.6% +/- 1.2 of the total phospholipid phosphorus of resident PAM, was reduced to 4.1% +/- 0.1 in BCG-activated macrophages (p less than 0.01). Phospholipase A2 from snake venom or from pancreas failed to release 20:4 from L(bis)PA, and lipase (phospholipase A1) from Rhizopus delmar liberated no more than one-third of this arachidonate. These results suggest that much of the arachidonate is not mobilized by classical phospholipases A1 and A2. When [3H]20:4-labeled PAM were stimulated with 1 microM 12-O-tetradecanoyl-phorbol-13-acetate (TPA), a loss of [3H]20:4 was observed from L(bis)PA, PE, PC, and PS/PI, with a concomitant increase in the synthesis of Hete and leukotriene C4. BCG-activated PAM exposed to either TPA or 3.8 microM calcium ionophore A23187 liberated [3H]20:4 solely from PE and PC, with diminished 20:4 oxidative metabolism. Analysis of the specific radioactivities of phospholipids obtained from resident PAM prelabeled with [3H]20:4 or [32P]i demonstrated that the specific activity of [32P]L(bis)PA was negligible, whereas that of [3H]20:4 was quite high. In addition, L(bis)PA deacylation induced by TPA in resident PAM was always accompanied by a corresponding loss of [3H]20:4 from phosphatidylinositol (PI), suggesting that metabolism of this novel phospholipid proceeded by a deacylation-reacylation reaction rather than by de novo synthesis. BCG-activated PAM, which exhibited depressed eicosanoid formation, consistently failed to deacylate [3H]20:4 from L(bis)PA or PI. These studies demonstrate that, unlike 20:4 derived from PE and PC by BCG-activated PAM, L(bis)PA may indeed provide a novel source of 20:4 that is tightly coupled to the lipoxygenase pathway.

Animals↗
PubMed1987

Relation of lung fatty acid binding protein to the biosynthesis of pulmonary phosphatidic acid and phosphatidylcholine.

The activities of glycerophosphate and lysophosphatidylcholine (LPC) acyltransferases were determined using lung microsomes in the presence of lung fatty acid binding protein (FABP). The synthesis of phosphatidic acid (PA) was increased two- to fourfold in the presence of FABP as compared to albumin. Lung FABP did not increase the incorporation of palmitoyl CoA into phosphatidylcholine. The results indicate that FABP-bound fatty acyl CoA may be a preferred substrate for glycerophosphate acyltransferase.

1-Acylglycerophosphocholine O-Acyltransferase↗
PubMed1984

Substance P: binding to unilamellar and multilamellar liposomes made from mixtures of phosphatidylcholine and phosphatidic acid.

Binding of the undecapeptide substance P to unilamellar and multilamellar lipid vesicles, made from mixtures of phosphatidylcholine and phosphatidic acid, was investigated, because liposomes may be supposed to become a useful pharmaceutical tool for the delivery of low molecular mass peptide hormones. It is demonstrated that binding is largely electrostatic in nature, and that the amount of bound peptide may be varied within rather broad limits by changing the lipid matrix and/or the aqueous medium conditions. Concerning the distribution of the peptide between inner and outer surfaces of the liposomes, large differences may be realised too, as revealed by enzymatic hydrolysis of the outside bound portions of substance P. But additionally, electrostatic binding is demonstrated also to bring about peculiar, unexpected properties of the system. These imply special relevance to a potential pharmaceutical application of substance P liposomes as well as some general relevance to in vivo application of liposomes as drug carriers.

Drug Stability↗
PubMed1984

Maturation of the fetal lung II. Effect of hyperoxia on phosphatidic acid phosphatase, pyruvate kinase and superoxide dismutase activity in the newborn rat lung.

Oxygen-induced lung toxicity was studied in newborn rats. Three-day-old rats were exposed to 85-90% oxygen or air for 48 h. The activity of pulmonary antioxidant defenses, as measured by the activity of superoxide dismutase (SOD), showed a progressive increase in activity. The activity of phosphatidic acid phosphatase (PAPase) showed a statistically significant decrease in the oxygen-poisoned lung. In the activity of pulmonary pyruvate kinase no significant change occurred. After two days of oxygen exposure (FiO2 085-0.9) marked histological changes appeared including an increased number of interstitial cells, atelectasis, pulmonary oedema, diminution of lamellar content, loose lamellar bodies and increasing tubular myelin in the alveolar space.

Animals↗
PubMed1984

Maturation of the fetal lung III. Effect of transplacental TRH and 2'-thiourea treatment on phosphatidic acid phosphatase and pyruvate kinase activity in rat lung.

The activity of pyruvate kinase (PK), an enzyme playing a key role in glycolysis, was studied in the lung of Wistar R/A rats in the prenatal, postnatal and adult periods of life. The highest level was measured on the 20th gestational day, a value nearly double the adult mean. In order to elicit fetal hypothyroidism, pregnant rats were treated with 0.1% thiourea solution from the 14th day of gestation up to delivery. The animals were killed on the 21st or 22nd gestational day or on the 2nd postnatal day. A significant increase in PK activity was seen in the treated animals as compared to the control group, while the activity of phosphatidic acid phosphatase (PAPase) remained unchanged. Fetal hyperthyroidism was induced by intravenous injections of TRH to the pregnant mother rat. This resulted in an increase of PAPase and a decrease of PK activity as compared to the control group. The difference was statistically significant in all instances, the level of significance, however, depended on the time when treatment had been initiated.

Administration, Oral↗
PubMed1980

Phosphatidic acid inhibition of PGE1-stimulated cAMP accumulation in WI-38 fibroblasts: similarities with carbachol inhibition.

To test the hypothesis that phosphatidic acid (PhA) is involved in the carbachol inhibition of hormone stimulated accumulation of cAMP we observed the effects of PhA on PGE1-stimulation of cAMP in WI-38 fibroblasts. PhA inhibited PGE1-stimulated cAMP accumulation of WI-38 fibroblasts; maximum inhibition (approximately 50-80%) occurred at a PhA concentration of 1.0 microM and significant inhibition was observed with a concentration of 0.1 microM. The full effects of PhA were evident within 15 sec after the co-addition of PGE1 and PhA. Addition of PhA to cells which had been pre-stimulated with PGE1 resulted in the rapid decay of cAMP levels to a new steady state level with a t 1/2 of approximately 65 sec. The inhibition produced by PhA did not appear to be simply attributable to a depolarization or increased intracellular Ca2+, since addition of either KCl or the Ca2+ ionophore A23187 did not lower PGE1-stimulated cAMP accumulation. When intact cells were pretreated with PhA then lysed and adenylate cyclase immediately assayed, no detectable changes in broken cell adenylate cyclase activities were observed. Also, PhA added directly to adenylate cyclase assays at concentrations as high as 100 microM produced no detectable inhibition of the membrane fraction adenylate cyclase activities. Nonetheless, our results suggest that adenylate cyclase activity in intact cells may be directly affected by physiological levels of PhA . Further, the similarities of carbachol [Butcher, R. W., Journal of Cyclic Nucleotide Research, 4:411 (1978)] and PhA inhibition support the hypothesis that carbachol (acetylcholine) exerts its effect on adenylate cyclase through alterations of the plasma membrane phospholipid composition.

Adenylyl Cyclases↗
PubMed1980

An improved procedure for the synthesis of 14C-labeled phosphatidylserine from cerebral phosphatidic acid.

A complete procedure to prepare a highly labeled phosphatidyl-L-[U-14C]serine possessing the same fatty acid composition of brain phospholipids is reported. CDP-diglyceride was synthesized by reaction between phosphatidic acid and CMP-morpholidate as the dicyclohexylcarboxamidium salt. The reaction between CDP-diglyceride and L-[U-14C]serine to produce the labeled phosphatidylserine was catalyzed by the CDP-diglyceride: L-serine phosphatidyl transferase (EC 2.7.8.8) from E. coli. A selective inhibition of phosphatidylserine decarboxylase activity, present as contaminant in the enzyme extract, was introduced in order to avoid a low yield of product. Traces of phosphatidylethanolamine (about 1%) were easily removed by preparative thin-layer chromatography. The yield of the labeled product was as high as 87% and it specific radioactivity was 170 mCi/mmol.

Animals↗
PubMed1983

Maturation of the fetal lung. I. Phosphatidic acid phosphohydrolase in the fetal and newborn rat.

Phosphatidic acid phosphohydrolase (PAPase) activity was measured in the lungs, brain, liver and kidneys of fetal, newborn and adult rats. The highest activity was found in the kidneys. In one-day-old rats pulmonary enzyme activity was nearly as high as in the renal tissue. In four-days-old rats the highest activity was found in the 10% homogenate of the lung, the highest PAPase specific activity could be demonstrated in the mitochondria. In the fetal lung, the enzyme activity moderately increases from the 18th day of gestation up to birth; at birth 39-77% of the normal adult value was measured. Immediately after birth 150% activity is attained, thereafter a slow decrease can be shown throughout the first week of life but the values remain above the average adult value.

Animals↗
PubMed1983

Arachidonate release and phosphatidic acid turnover in stimulated human platelets.

We have examined the temporal relationship between arachidonate release and phosphatidic acid (PA) metabolism in human platelets stimulated with thrombin. Within 1 min of stimulation at 37 degrees C, platelets released up to 16 nmol of arachidonate/10(9) cells from membrane phospholipids and exhibited an increase of severalfold in PA mass. At 23 degrees C, arachidonate release was half-maximal by 10-30 s, but PA remained near control levels for 10-30 s, indicating that increased PA is not necessary for release. [3H]Glycerol-labeled platelets synthesized phospholipids from [3H]PA at a rate of 0.08-0.3 nmol/min/10(9) cells at 37 degrees C. This rate of [3H]glycerol-PA turnover was not enhanced by thrombin stimulation; thus, PA did not turn over rapidly enough to be an intermediate in the release of several nanomoles of arachidonate from phosphatidylinositol in the first few seconds of stimulation. When aspirin-treated platelets were prelabeled with [14C]- or [3H]arachidonate, the specific activity of phospholipid-bound arachidonate pools remained constant after thrombin stimulation. Released arachidonate had specific activity intermediate to that in phosphatidylcholine and phosphatidylinositol. [14C]arachidonate in phosphatidylethanolamine had specific activity 6-fold less than released [14C]arachidonate; this phospholipid could therefore contribute only a small fraction of released fatty acid.

Arachidonic Acid↗
PubMed1983

A role for cyclooxygenase products in the formation of phosphatidic acid in stimulated human platelets. Differential mechanisms of action of thrombin and collagen.

Human platelets prelabeled with (32P)orthophosphate or [14C]arachidonic acid (AA) were stimulated with collagen or thrombin, and platelet activation (shape change, aggregation, and release of serotonin) was determined in parallel to the formation of 32P- or 14C-labeled phosphatidic acid (PA). The results show a close correlation between the degree of platelet activation and the amount of PA formed. Activation of platelets and formation of PA induced by collagen (2 to 20 micrograms/ml) was blocked by pretreatment of platelets with trifluoperazine, indomethacin, aspirin, or N-methylimidazole. This suggests that the formation of AA by phospholipase A2 and its subsequent metabolism by cyclooxygenase and thromboxane synthetase are required for the collagen-induced formation of PA. Endoperoxide analog U-44069 induces formation of PA in human platelets that have been pretreated with or without aspirin. The action of thrombin does not follow the same pattern of collagen. Low concentrations of thrombin (0.05 units/ml) induce only platelet shape change and a small stimulation of PA, changes which are only minimally inhibited by indomethacin. However, a small increase in the thrombin concentration (to 0.1 unit/ml) induces platelet aggregation, release of serotonin, and a sharp increase in PA accumulation which are effectively inhibited by indomethacin. Even higher thrombin concentrations (0.4 to 0.8 units/ml), however, result in a further stimulation of PA formation, platelet aggregation, and release of serotonin which are insensitive to inhibition by indomethacin. The data show that cyclooxygenase metabolites of AA, produced after platelet activation, may be differentially involved in the formation of PA in platelets stimulated with collagen or thrombin. Formation of PA following collagen or intermediate concentrations of thrombin (0.1 to 0.2 units/ml) is dependent on the cyclooxygenase pathway. However, formation of PA by very low or by high concentrations of thrombin is not mediated by cyclooxygenase metabolites of AA.

Blood Platelets↗
PubMed1983

Arachidonic acid stimulates the formation of 1,2-diacylglycerol and phosphatidic acid in human platelets. Degree of phospholipase C activation correlates with protein phosphorylation, platelet shape change, serotonin release, and aggregation.

Exogenous unlabeled arachidonic acid (AA) added to human platelets prelabeled with [3H]AA induces breakdown of [3H]phosphatidylinositol and the rapid and transient formation of [3H]1,2-diacylglycerol and [3H]phosphatidic acid (PA), indicating activation of phosphatidylinositol-specific phospholipase C. Formation of [3H]1,2-diacylglycerol and [3H]PA is inhibited by pretreatment of platelets with aspirin, which suggests that endoperoxides or thromboxane A2 are responsible for AA-induced stimulation of phospholipase C. Exogenous unlabeled AA also induces the formation of [32P]PA or [14C]PA in platelets that have been prelabeled with 32Pi or [14C]AA, respectively. Increased radioactivity in PA reflects increased content of PA as measured by the fatty acid composition of PA. The relation of PA production, which reflects stimulation of phospholipase C, to specific platelet responses was further investigated. Low concentrations of AA (0.05-0.2 microM) induces platelet shape change in parallel to formation of 50-100% PA and phosphorylation of a 40,000 molecular weight protein. Higher concentrations of AA (0.5-50 microM) stimulate the formation of a further amount of PA (200-250%), and phosphorylation of 40,000 molecular weight protein, platelet aggregation, and serotonin release. Indomethacin inhibits all these observed changes by inhibiting the conversion of AA by platelet cyclooxygenase. In contrast, prostacyclin blocks these responses without affecting conversion of AA by platelet cyclooxygenase and thromboxane synthetase. We conclude that formation of endoperoxides and thromboxane A2 is necessary but not sufficient for platelet activation by AA. Only if PA is formed are platelets activated. The results indicate a central role for the phospholipase C pathway in the process of platelet activation.

Arachidonic Acid↗
PubMed1981

The initial action of thrombin on platelets. Conversion of phosphatidylinositol to phosphatidic acid preceding the production of arachidonic acid.

Measurements of phosphatidylinositol (PI) and phosphatidic acid (PA) by phosphorus assays and by radioactivity ([14C]arachidonate) indicate that thrombin induces the degradation of a given fraction of the total PI to PA. The maximal conversion of PI to PA represents approximately one-third of the total PI which can be degraded by thrombin. This same amount of PI is converted to PA even in the presence of 1 mM quinacrine, which completely inhibits the release of arachidonic acid from phospholipids and which reduces by two-thirds the loss of labeled PI. In this case the fall in PI is equal to the amount of PA formed. If thrombin is added to platelets previously maximally stimulated by ionophore A23187, PA is produced from PI in amounts equal to those produced by thrombin in the absence of other stimuli. Furthermore, the resynthesis of PI from PA is also unaffected by quinacrine, and thus the entire thrombin-stimulated PI-cycle is maintained. The data thus indicate the existence of a quinacrine-insensitive phospholipase C which can initially convert a given amount of PI to PA and which is closely associated to the thrombin receptor. The further breakdown of PI and production of arachidonic acid might result from the action of quinacrine-sensitive activities (i.e. phospholipase A2). The simplest scheme is one in which thrombin specifically produces an active fraction of PA which in some way results in the subsequent production of arachidonic acid from various phospholipids (including PI), perhaps by activation of quinacrine-sensitive phospholipase A2.

Arachidonic Acids↗
PubMed1981

Fatty acid composition of phosphatidylinositol and phosphatidic acid in stimulated platelets. Persistence of arachidonyl-stearyl structure.

The fatty acid composition of phosphatidylinositol (PI), phosphatidic acid (PA), and the free fatty acid pool of human platelets was studied as a function of time following thrombin stimulation. Upon addition of thrombin, the total amount of fatty acids in PI decreased sharply, then rose toward basal levels, while that of PA showed an inverse pattern. However, the percentage distribution of fatty acids in stimulated as well as unstimulated PI and those in stimulated PA remained relatively constant: stearic and arachidonic acids accounted for 90 and 80% of the total in PI and PA, respectively. These data suggest that in stimulated human platelets PI and PA are interconverted via the "PI cycle." The time course of changes in PI and PA may suggest that the levels of arachidonyl-stearyl PA are involved in regulation of the resynthesis of arachidonyl-steryl PI. In contrast to PI and PA, the free fatty acid pool showed sharp increases in the five major platelet fatty acids: arachidonate, stearate, palmitate, oleate, as well as linoleate. These data suggest that most of the fatty acids liberated upon platelet stimulation are not derived via PI metabolism but by other mechanisms.

Arachidonic Acid↗