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PubMed1988

Metabolism and function of skin lipids.

It is apparent from this review that the skin is an organ displaying a highly active metabolism of PUFA's. It possesses the capacity to biosynthesize, metabolize and interconvert a variety of lipids as outlined in the review. Its inability to desaturate the essential fatty acids underscores the significance of these PUFAs in cutaneous biology. For instance, increases in the concentrations of 20:4n6 as well as certain autacoids are associated with many inflammatory-hyperproliferative dermatoses. However, the origin of 20:4n6, which is found complexed to skin phospholipids, has until recently remained a mystery. Studies undertaken in our laboratory designed to delineate the origin of epidermal 20:4n6, and to elucidate the effects of EFA deficiency and crossover replenishment with dietary oils on epidermal lipid metabolism have demonstrated: (i) that microsomal preparations from rat and guinea pig epidermis lack the capacity to transform 18:2n6 into 18:3n6 (catalyzed by the enzyme delta 6 desaturase) and 20:3n6 into 20:4n6 (catalyzed by the enzyme delta 5 desaturase). This observation implies that 20:4n6, a component of epidermal phospholipids, is biosynthesized elsewhere endogenously and transported to the epidermis for esterification into the phospholipids. In an extension of this work, epidermal microsomal preparations from normal human and diseased human epidermis (clinically uninvolved and involved psoriatic epidermis) were examined in order to determine the activities of the delta 6 and the delta 5 desaturases as well as the elongase, respectively. Our data revealed that normal, uninvolved and involved human epidermal preparations lack the capacity to desaturate 18:2n6 to 18:3n6 and 20:3n6 to 20:4n6. These results are interesting in view of the fact that 20:4n6 metabolites participate in the phlogistic and hyperproliferative processes in psoriasis. It is likely that the increases in the 20:4n6-derived eicosanoids, which are prominent in uninvolved and involved psoriatic skin, are the result of an enhanced epidermal phospholipase A2 activity. The heightened lipase activity would lead to an elevated concentration of free 20:4n6 which, in turn, would result in the reported increase of epidermal eicosanoid levels. (ii) Incubation of 18:3n6 with microsomal preparations from skin specimens from normal, uninvolved and involved psoriatic epidermis revealed the presence of elongase activity capable of converting 18:3n6 into 20:3n6. This activity was markedly elevated (5-fold) in involved hyperproliferative psoriatic preparations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

The biochemical role of platelet-activating factor in reproduction.

The presence of Co-A independent transacylase activity in amnion cells and the preferential transfer of arachidonic acid to acceptor-ethanolamine plasmalogen provide a satisfactory explanation to the questions raised by the observation that arachidonate-enriched ethanolamine plasmalogen increases in amnion late in gestation without alteration in the total amount of ethanolamine glycerophospholipids. The proposed mechanism also serves as a link between the observed changes in glycerophospholipid composition and the generation of PAF. We have emphasized a role for PAF in fetal lung maturation, the initiation and maintenance of parturition, and in certain complications associated with a premature delivery. Although PAF is known to be the most potent lipid mediator yet described and its importance in reproductive biology is well documented, it is our view that these events cannot be attributed solely to PAF and in all likelihood a number of autacoids participate in these processes.

Amnion↗
PubMed1992

Platelet-activating factor-mediated synthesis of prostaglandins in rat Kupffer cells.

Synthesis of prostaglandins was stimulated in rat Kupffer cells upon challenge with platelet-activating factor (PAF). PAF-mediated synthesis of prostaglandins was inhibited by the Ca2+ ion chelator (EGTA), the Ca2+ channel antagonist (nifedipine) and U66985, a structural analogue and antagonist of the biological effects of PAF in other cellular systems. Inhibitors of protein kinase C, staurosporine and polymixin B, did not affect PAF-induced prostaglandin synthesis. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, stimulated synthesis of prostaglandins in Kupffer cells; PAF and PMA exerted additive actions on this process. Both PAF- and PMA-stimulated prostaglandin production was inhibited by TMB-8. PAF-stimulated synthesis of prostaglandins also was inhibited upon treatment of Kupffer cells with pertussis toxin. Cholera toxin, in contrast, stimulated the production of prostaglandins in a concentration-dependent manner; cholera toxin and PAF together had an additive effect. These results suggest that PAF-induced synthesis of prostaglandins is stimulated via a specific receptor coupled to a pertussis toxin-sensitive G-protein, is dependent upon extracellular Ca2+ and is not influenced by protein Kinase C activation. Since PAF and prostaglandins are produced in the liver under conditions such as endotoxemia, PAF-mediated synthesis of these lipid autacoids may be of importance in the regulation of hepatic function during pathophysiological episodes.

Animals↗
PubMed1994

Platelet-activating factor induced calcium mobilization and phosphoinositide metabolism in cultured bovine cerebral microvascular endothelial cells.

Platelet-activating factor (PAF) is a powerful lipid autacoid with a variety of biological activities. More and more evidence suggests that PAF might play an important role in modulation of cerebrovascular system function, particularly during ischemia-induced cerebrovascular damage. However, the mechanisms involved in PAF actions on cerebrovascular or other brain cells are virtually unknown. Therefore, this study was designed to investigate PAF receptor-mediated cellular signal transduction in bovine cerebral microvascular endothelial (CME) cells with the aid of a potent PAF antagonist, WEB 2086. PAF induced an immediate and concentration-dependent increase in [Ca2+]i with an EC50 of 4.75 nM. PAF-induced [Ca2+]i mobilization was inhibited by PAF antagonist WEB 2086, in a dose-dependent manner (IC50 = 15.53 nM). The calcium channel blockers diltiazem (10 microM) and verapamil (10 microM) had no effect on the PAF-induced increase in [Ca2+]i, but depletion of Ca2+ from the incubation buffer caused a 45.26% reduction of PAF-induced [Ca2+]i elevation. PAF stimulated phosphoinositide metabolism in a dose-dependent manner with an EC50 of 12.4 nM for IP3 formation, which was also inhibited by the PAF antagonist WEB 2086 in a dose-dependent manner with IC50 value of 16.97 nM for IP3 production. These data indicate that bovine CME cells respond to biologically relevant concentrations of PAF and this response involves activation of phospholipase C and increase in [Ca2+]i via specific PAF receptors. Our results may contribute to further understanding of the mechanism behind PAF actions on cerebrovascular cells.

Animals↗
PubMed1996

PAF and haematopoiesis. X. Macrophage colony-stimulating factor and granulocyte macrophage colony-stimulating factor enhance platelet-activating factor acetylhydrolase production by human blood-derived macrophages.

Platelet-activating factor (PAF), a phospholipid autacoid with potent regulatory functions, is synthesized by stimulated monocytes. Macrophages are a source of the plasma acetylhydrolase activity (AHA) which regulates PAF concentrations. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are involved in the differentiation and functions of cells from the monocytic/macrophagic lineage. This work reports that M-CSF and GM-CSF stimulated AHA production by human blood monocyte-derived macrophages in a time- and dose-dependent manner. After 7 days of culture without serum, a 6- and 4-fold increase was found in cells treated with M-CSF (1000 U/ml) and GM-CSF (50 ng/ml), respectively. M-CSF (up to 1000 U/ml) and GM-CSF (up to 10 ng/ml) did not induce PAF production by human blood monocytes. While GM-CSF (10 ng/ml) and interleukin-1 (10 U/ml) stimulated M-CSF production from monocyte-derived macrophages, PAF did not. These results indicate that M-CSF and GM-CSF enhance AHA production by human blood-derived macrophages cultured in low serum concentrations. Clearly the effects of growth factors on AHA production in vivo deserve to be assessed.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1984

Biological consequences of fatty acid oxygenase reaction mechanisms.

Fatty acid oxygenases catalyze the insertion of molecular oxygen into polyunsaturated fatty acids. The enzymic reactions that have been studied in detail exhibit a continuous requirement for a hydroperoxide activator and appear to proceed by a free radical chain reaction. The self-limiting nature of fatty acid oxygenase-catalyzed reactions appears to be due to enzyme self-inactivation during the reaction rather than to product inhibition. Thus "suicide" substrates are potential regulators of overall enzyme activity, although linoleate is a much weaker inactivator than the highly unsaturated fatty acids. Inhibition by added glutathione peroxidase has demonstrated the need for hydroperoxide activator in the cyclooxygenase reaction catalyzed by prostaglandin H synthase and the lipoxygenase reactions catalyzed by lung, leukocyte, and soybean enzyme preparations. The regulation of cellular hydroperoxide levels may influence the formation of prostaglandins and other autacoids by fatty acid oxygenases.

Animals↗
PubMed1986

Hemofiltration in septic ARDS. The artificial kidney as an artificial endocrine lung.

Twenty-four patients with high microvascular permeability pulmonary edema were initially treated by means of conventional supportive therapy for 1-12 days. Continued deterioration was treated by predilutional hemofiltration and induced a dramatic improvement in 22/24 patients. Survival was 92%. Sieving coefficients for autacoids and middle molecular weight vasoactive peptides involved in the development of high microvascular permeability pulmonary edema were higher than 0.88 indicating that clearing from blood of these peptides during one pass through the hemofilter is similar to that obtained during one pass through the pulmonary normal microvasculature. Hemofiltration seems to be a significant breakthrough in the treatment of ARDS secondary to severe sepsis.

Acute Kidney Injury↗
PubMed1989

Platelet-activating factor and cytokine interactions in shock.

Many types of shock are characterized by profound hemodynamic alterations and depression of immune processes. Among the various mediators implicated in shock conditions, there is much evidence to suggest that, together with various cytokines, the inflammatory and chemotactic autacoid, platelet-activating factor (PAF), plays an important role. Studies on several animal models have shown that infusion of PAF mimicks the shock state, that markedly increased levels of PAF are produced in shock and that PAF antagonists afford significant protection against diverse forms of shock. The precise mechanism by which PAF antagonists protect against shock remains unclear; however, it is becoming apparent that in traumatic states a complex interaction occurs between PAF and cytokines, which leads to the acute phase reaction and circulatory collapse. We propose that PAF antagonists may be effective in counteracting shock because of their antiprotease activity and their ability to inhibit deleterious PAF/cytokine auto-generated feedback processes.

Animals↗
PubMed1989

Extraneuronal localization of acetylcholine and its release upon nicotinic stimulation in rabbits.

A study was undertaken to examine the origin of plasma acetylcholine (ACh). The ACh content of blood cells was about 25 times higher than that of plasma in normal rabbits (3,722 vs 140 pg/ml blood, n = 7). Plasma ACh content in rabbits having antibody against ACh was about 80 times higher than in normal rabbits, while no difference was observed in the ACh content of blood cells between the groups. Nicotine (100 micrograms/kg, i.v.) produced a significant increase in plasma ACh content and a decrease in the ACh content of blood cells in normal rabbits. These data demonstrate that a large amount of ACh is localized in blood cells and that a considerable proportion of plasma ACh originates from blood cells, suggesting that ACh acts not only as a neurotransmitter but also as an autacoid.

Acetylcholine↗
PubMed1990

Synthesis and release of acetylcholine by cultured bovine arterial endothelial cells.

Using cultured endothelial cells prepared from bovine carotid artery, and a specific radioimmunoassay for acetylcholine (ACh), the synthesis and release of ACh by vascular endothelial cells were investigated directly. ACh content in the culture medium after 24 h of incubation in the presence of isoflurophate, a nonspecific cholinesterase inhibitor, was about 16 times higher than that in endothelial cells, indicating that ACh synthesized inside the cells was released rapidly. The presence of ACh in the culture medium was further confirmed qualitatively using high-performance liquid chromatography with an electrocapture detection. These results represent the first direct evidence that endothelial cells can synthesize and release ACh, suggesting the possibility that ACh acts not only as a neurotransmitter but also as an autacoid under certain conditions.

Acetylcholine↗
PubMed1991

Rat heart anaphylaxis: influence of mediator antagonists.

1. Parameters of isolated hearts from rats which were actively sensitized to ovalbumin were found to be impaired on ovalbumin challenge: the heart rate increased whereas the contractility force and coronary flow decreased significantly. 2. Treatment in vivo or in vitro with histamine receptor antagonists (promethacine and cimetidine), the leukotriene antagonist FPL 55712, the PAF antagonist BN 52021, the combined prostaglandin endoperoxide receptor antagonist/thromboxane A2 synthesis inhibitor R 68070, the thromboxane synthetase inhibitor HOE 944, the lipoxygenase inhibitor ZIMET 47/79, the antioxidant sodium hyposulfite or with dexamethasone caused a different improvement of the parameters to a different degree. 3. Consequently, histamine, leukotrienes, PAF, activated oxygen, thomboxane A2 and possibly further autacoids might be involved in mediating the described anaphylactic reaction.

Adamantane↗
PubMed1990

Effects of endotoxin infusion on circulating levels of eicosanoids, progesterone, cortisol, glucose and lactic acid, and abortion in pregnant cows.

The effects of Escherichia coli endotoxin infusions (1.0 or 2.5 micrograms kg-1 over 6 h) on pregnancy were investigated in cows in the first, second and third trimester of gestation. Endotoxin increased the plasma levels of prostaglandins (PGs), thromboxane B2 and cortisol, and decreased progesterone. The severity of the clinical signs and the magnitude of the increases in plasma PGs, thromboxane B2 and cortisol tended to depend on the dose of endotoxin, but were independent of the gestation period. There was hyperglycemia followed by hypoglycemia and lactic acidemia. Hyperglycemia and lactic acidemia were significant only at the high dose of endotoxin. Endotoxin infusion at both doses caused a preferential mobilization of oleic acid from adipose tissue, and also had some effects on the mobilization of palmitic and stearic acids during the post-infusion period. The cows in the first trimester of gestation were more sensitive to the abortifacient effect of endotoxin than cows in the second and third trimester of gestation. The results of this study indicate that the mechanism of endotoxin-induced abortion in cows initially involves a prolonged release of PGF2 alpha and its subsequent stimulant effect on uterine smooth muscle contraction and luteolytic effect leading to a gradual decline in the plasma levels of progesterone. It was concluded that pregnancy terminates in the absence of an adequate level of progesterone, especially during the first trimester of gestation, when progesterone of extraluteal origin is not yet available, coupled with the PGF2 alpha-induced propulsive contraction of the uterus. In addition, the metabolic and circulatory failures in severe cases of endotoxemia, especially at the high dose of endotoxin, resulting either directly or indirectly via the release of various autacoids, catecholamines and cortisol, may also contribute to the termination of pregnancy at any stage of gestation.

Abortion, Veterinary↗
PubMed1991

Effects of endothelin-1 on vascular tension in human umbilical vessels.

The effect of endothelin-1 on vascular tension has been investigated in human umbilical cord vessels perfused in vitro and compared to that of serotonin. Both autacoids induced vasoconstrictions in the arteries and in the veins, all responses being clearly dose-dependent. Endothelin-1 was found to be most potent, eliciting visible pressure changes in concentrations of 10(-11)-10(-10) M. The responses to 10(-9) M endothelin-1 in the veins increased markedly at repeated stimulations. In the arteries a potentiating effect on the serotonin response was observed after exposure to 10(-11) M of endothelin-1. The results signal that the peptide may be of significance in the regulation of umbilicoplacental blood flow.

Dose-Response Relationship, Drug↗
PubMed1991

Ethnopharmacology and the development of natural PAF antagonists as therapeutic agents.

Ginkgolides are unique twenty-carbon terpenes, occurring naturally only in the roots and leaves of Ginkgo biloba. The molecules incorporate a tert-butyl group and six 5-membered rings, and are specific and potent antagonists of platelet-activating factor (PAF), a potent inflammatory autacoid. Studies in animal models with the most potent ginkgolide, BN 52021, and other specific PAF antagonists have demonstrated that PAF plays an important role in pathologies such as asthma, shock, ischemia, anaphylaxis, graft rejection, renal disease, CNS disorders and numerous inflammatory conditions. Ginkgolides are now being developed as therapeutic agents and very promising results have been obtained in clinical trials on shock, organ preservation and thermal injury. In addition to ginkgolides, several other types of natural PAF antagonists have been identified from various medicinal plants. These compounds have not only helped to explain the pharmacological basis of several traditional medicines, but have also provided man with a valuable new class of therapeutic agents.

Diterpenes↗
PubMed1990

Endothelial control of vascular tone in large and small coronary arteries.

The endothelium modulates coronary vascular tone by the release of endothelium-derived relaxing or contracting substances. The endothelium-derived relaxing factor has been identified as nitric oxide synthesized in endothelial cells from L-arginine. The endothelium can release other relaxing substances such as prostacyclin and a hyperpolarizing factor. Endothelin-1 is a potent vasoconstrictor peptide formed by endothelial cells, and is likely to be the physiologic antagonist of endothelium-derived relaxing factor. Other putative contracting factors include superoxide anions and products of arachidonic acid metabolism. Endothelium-derived relaxing factor is released spontaneously and in response to flow, platelet-derived products (that is, serotonin, thrombin and adenosine diphosphate) and certain autacoids (that is, acetylcholine, bradykinin, histamine, substance P, vasopressin, alpha-adrenergic agonists). A considerable heterogeneity of responses exists among vessels of different size from different anatomic origin and different species. Hypercholesterolemia, atherosclerosis, hypertension and myocardial ischemia or reperfusion, or both, impair endothelium-dependent relaxation. Under normal conditions, endothelium-derived relaxing factor appears to dominate the control of vascular tone of large and small coronary vessels, whereas in disease states, endothelium-derived contracting factors are released. Impairments of endothelial function may be important in the development of various forms of cardiovascular disease.

Animals↗
PubMed1993

Long-term potentiation in the hippocampus induced by platelet-activating factor.

Platelet-activating factor (PAF) is an ether phospholipid that serves as an autacoid in a wide range of biological processes. We found that when PAF was added to hippocampal slices, it induced a stable and concentration-dependent increase in excitatory postsynaptic potential and population spike recordings (long-term potentiation [LTP]). The PAF effect was blocked by the PAF receptor antagonists BN 52021 and WEB 2086 and the N-methyl-D-aspartate receptor antagonists MK 801 and 2-amino-5-phosphonovalerate. However, these PAF receptor antagonists did not block LTP induced by high frequency stimulation. The facilitation induced by PAF could not be reversed by PAF receptor antagonists. Induction of either PAF-or tetanus-triggered facilitation occluded the subsequent expression of the other, suggesting a common pathway. LTP is a type of synaptic plasticity associated with the formation of memory, and PAF may play an important modulatory role in this process.

Action Potentials↗
PubMed1996

A pharmacophore for high affinity PAF antagonists. I. Electronic model using molecular electrostatic potential.

PAF is a powerful phospholipid-derived autacoid involved in many physio-pathological mechanisms. Many PAF antagonists have been synthesized and assayed for therapeutic purposes. In this study, molecular electrostatic potential is used to compare the electronic properties of 48 'heterocyclic sp2 nitrogen' highly potent PAF antagonists, belonging to six series (nine hetrazepines, five pyrrolo[1,2-c]thiazoles, 14 carboxamides, nine dihydropyridines, nine pyridinylthiazolidines and two imidazo[4,5-c]pyridines). Their common features consist of three main electronegative zones (A, B1 and B2) describing the electronic pharmacophore of these ligands. The high affinity of these PAF antagonists seems to be related to this electronegative system A-B(x), which is characterized by three distances A-B1 (9.3 +/- 1.0 A), A-B2 (13.4 +/- 0.7 A) and B1-B2 (4.9 +/- 0.9 A). Moreover, B1 and B2 may surround a common anchorage point in the binding site of the receptor.

Models, Chemical↗
PubMed1992

Influence of nitrovasodilators on bovine pulmonary histamine release.

The organic nitrates and related nitrovasodilators are relaxants of vascular and airway smooth muscle. Very little information is currently available regarding the influence of nitrates and related nitrovasodilators on pulmonary autacoid release. This study examined the influence of glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside on histamine release from bovine lung mince. Spontaneous histamine release from bovine lung mince was not altered by 0.1 nM to 1 microM glyceryl trinitrate, isosorbide dinitrate or sodium nitroprusside. Glyceryl trinitrate, isosorbide dinitrate and sodium nitroprusside produced a concentration-dependent decrease in A23187 (10 microM) stimulated histamine release. Glyceryl trinitrate also inhibited histamine liberation following the addition of compound 48/80. Further studies indicated that the inhibitory action of glyceryl trinitrate was reversed by coincubation with the guanylate cyclase inhibitor, methylene blue (10 microM). These findings indicate that glyceryl trinitrate, sodium nitroprusside and isosorbide dinitrate inhibit non-immunologically stimulated pulmonary histamine release and suggest that alterations in guanylate cyclase activity may influence pulmonary histamine release.

Animals↗