Evidence for existence of various homologues and analogues of platelet activating factor in a lipid extract of bovine brain

Tokumura, Akira; Kamiyasu, Koumei; Takauchi, Kenkichi; Tsukatani, Hiroaki

doi:10.1016/0006-291x(87)91338-6

Cited by 104 publications

(27 citation statements)

References 17 publications

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“…In analogy to previous in vitro studies (25)(26)(27)(28)44), we propose that these compounds are formed by attack of cigarette smoke-derived radicals or reactive oxygen species on plasma or membrane phospholipids. The oxidative modification of phosphatidylcholine to PAF-like lipids is not due to fragmentation of the sn -2 fatty acyl residue to an acetyl residue to create PAF or its acyl analog.…”

Section: Discussionsupporting

confidence: 52%

Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking.

Lehr¹,

Weyrich²,

Saetzler³

et al. 1997

J. Clin. Invest.

156

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Cigarette smoking within minutes induces leukocyte adhesion to the vascular wall and formation of intravascular leukocyte-platelet aggregates. We find this is inhibited by platelet-activating factor (PAF) receptor antagonists, and correlates with the accumulation of PAF-like mediators in the blood of cigarette smoke-exposed hamsters. These mediators were PAF-like lipids, formed by nonenzymatic oxidative modification of existing phospholipids, that were distinct from biosynthetic PAF. These PAF-like lipids induced

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Section: Discussionsupporting

confidence: 52%

Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking.

Lehr¹,

Weyrich²,

Saetzler³

et al. 1997

J. Clin. Invest.

156

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“…The activity ratio of oxidized 1-O-hexadecyl-2-arachidonoyl-sn-glycero-3-phosphocholine to its sn-1 acyl homolog in stimulating Ca 2ϩ flux in PMN cells was approximately 800, suggesting that highly potent diacyl oxidation products are not present in abundance. Lipoproteins transport small amounts of alkyl acyl phosphatidylcholines (21), which varies with LDL subtype (22) not affect the types of oxidative reactions that fragment unsaturated acyl residues, so oxidation of diacyl and alkylacyl phosphatidylcholines produce homologous species (20). Thus we expect that LDL oxidation should produce homologous fragmented diacyl and alkyl acyl phosphatidylcholine products in relation to the abundance of their precursors, which is approximately 150 to 1.…”

Section: Discussionmentioning

confidence: 99%

“…Oxidation of phosphatidylcholines generates a plethora of chemically related phosphatidylcholines and, as sn-1 alkyl or acyl phosphatidylcholines oxidize in a similar fashion (20), there is heterogeneity at both the sn-1 and sn-2 position. Only some of these will stimulate the PAF receptor, but identification of the biologically active species in the mix of similar oxidation products has been complicated by this heterogeneity.…”

Section: Platelet-activating Factor (Paf)mentioning

confidence: 99%

Inflammatory Platelet-activating Factor-like Phospholipids in Oxidized Low Density Lipoproteins Are Fragmented Alkyl Phosphatidylcholines

Marathe¹,

Davies²,

Harrison³

et al. 1999

Journal of Biological Chemistry

184

196

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Oxidation of human low density lipoprotein (LDL)generates proinflammatory mediators and underlies early events in atherogenesis. We identified mediators in oxidized LDL that induced an inflammatory reaction in vivo, and activated polymorphonuclear leukocytes and cells ectopically expressing human platelet-activating factor (PAF) receptors. Oxidation of a synthetic phosphatidylcholine showed that an sn-1 ether bond confers an 800-fold increase in potency. This suggests that rare ether-linked phospholipids in LDL are the likely source of PAF-like activity in oxidized LDL. Accordingly, treatment of oxidized LDL with phospholipase A 1 greatly reduced phospholipid mass, but did not decrease its PAF-like activity. Tandem mass spectrometry identified traces of PAF, and more abundant levels of 1-Ohexadecyl-2-(butanoyl or butenoyl)-sn-glycero-3-phosphocholines (C 4 -PAF analogs) in oxidized LDL that comigrated with PAF-like activity. Synthesis showed that either C 4 -PAF was just 10-fold less potent than PAF as a PAF receptor ligand and agonist. Quantitation by gas chromatographymass spectrometry of pentafluorobenzoyl derivatives shows the C 4 -PAF analogs were 100-fold more abundant in oxidized LDL than PAF. Oxidation of synthetic alkyl arachidonoyl phosphatidylcholine generated these C 4 -PAFs in abundance. These results show that quite minor constituents of the LDL phosphatidylcholine pool are the exclusive precursors for PAF-like bioactivity in oxidized LDL. Platelet-activating factor (PAF)1 is a phospholipid autacoid with a wide variety of actions, primarily on cells and events that comprise the inflammatory system. PAF initiates the rapid inflammatory response as it is the leukocyte activating molecule produced and displayed by stimulated endothelial cells (1). PAF does not induce the bactericidal effector functions of leukocytes, but rather stimulates their adhesive and migratory behavior that allows them to transit the endothelial barrier. Leukocytes (polymorphonuclear leukocytes or PMN), monocytes, and eosinophils, as well as platelets, express the PAF receptor and accordingly are activated by PAF in concentrations ranging from picomolar to nanomolar levels. The potency of PAF, its broad actions, and the potentially deleterious events it invokes rationalize the tight regulation of PAF synthesis (2).PAF is recognized by a single, specific receptor that is a member of the family of seven-transmembrane-spanning, Gprotein-linked receptors (3, 4). Alone among this large family of receptors and related orphan sequences, the PAF receptor recognizes an intact phospholipid, and does so with a marked specificity. The PAF receptor shows a several hundredfold selectivity for the sn-1 ether bond of PAF, and complete specificity for the sn-2 acetyl residue compared with the long chain fatty acyl residue of most alkyl phosphatidylcholines (5, 6). The choline headgroup confers a several thousandfold advantage over the related phosphatidylethanolamine analog (7). Thus, compared with Edg-2 and Edg-4 receptors for lysophosphatidic...

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“…Phosphatidylcholines with short sn-2 residues were originally identified in extracts of bovine brain (15,16) that were similar to products expected from phospholipid oxidation (17). This large family of oxidation products has now also been observed in oxidized LDL (14, 18 -20), human plasma (21), and food products (22).…”

Section: Lipid Oxidationmentioning

confidence: 97%

Biologically Active Oxidized Phospholipids

McIntyre¹,

Zimmerman²,

Prescott³

1999

Journal of Biological Chemistry

145

105

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Oxidants and free radicals are deleterious in many ways, and organisms employ numerous approaches to block their production or limit their damage. Hydrogen atoms adjacent to olefinic bonds are susceptible to oxidative attack and those between unconjugated olefinic bonds especially so. Lipids are a rich source of these bonds and so are a primary target for oxidative reactions. Lipid oxidation is problematic as the many oxidative chemical reactions are not controlled and constrained by enzymes and may show exponential reaction rates, and some of the products of the attack are highly reactive species that modify proteins and DNA. This review summarizes current information about another outcome of the uncontrolled attack on cellular and circulating phospholipids, the generation of potent biologically active compounds that activate components of the immune and inflammatory systems.The biologically active species discussed here include oxidized phosphatidylcholines with biologic activity similar to platelet-activating factor (PAF), 1 oxidized phosphatidylcholines that stimulate responses through ways other than the PAF receptor, and the lysophosphatidylcholines that result from the enzymatic metabolism of these modified phospholipids. Oxidation products that mimic the properties of a wide variety of arachidonate metabolites are discussed in a separate review in this series (FitzGerald et al. (85)), as is a study of the effects of cholesterol oxidation (Chisolm et al. (86)). We will briefly mention the role of PAF acetylhydrolase in the catabolism of oxidized phospholipids. With the structures of some biologically active oxidation products deciphered, there is physical evidence to show that oxidatively modified phospholipids accumulate in vivo. This suggests that potent biologic mediators can arise from uncontrolled chemical reactions when the antioxidant defenses of the organism are overwhelmed. One area where such newly formed species subvert physiologic events is atherogenesis, but exposure to cigarette smoke, reperfusion injury, and stroke are also likely candidates for inappropriate events initiated or propagated by biologically active oxidized phospholipids. Lipid OxidationOxidative reactions of free fatty acids have been defined (e.g. Refs. 1-3), and oxidation of fatty acyl residues esterified in phospholipids appears to proceed in a similar fashion. The initial oxidative attack on polyunsaturated fatty acids generates alkyl radicals and then with the addition of oxygen, alkoxy radicals and peroxides. Arachidonate when oxidized enzymatically generates hydroperoxyeicosatetraenoates, hydroxyeicosatetraenoates, prostaglandins, and leukotrienes. A larger series of stereo and positional isomers known as isoprostanes, isothromboxanes, and isoleukotrienes (4, 5) is produced when arachidonate is nonenzymatically oxidized by a series of competing chemical reactions.

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Evidence for existence of various homologues and analogues of platelet activating factor in a lipid extract of bovine brain

Cited by 104 publications

References 17 publications

Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking.

Vitamin C blocks inflammatory platelet-activating factor mimetics created by cigarette smoking.

Inflammatory Platelet-activating Factor-like Phospholipids in Oxidized Low Density Lipoproteins Are Fragmented Alkyl Phosphatidylcholines

Biologically Active Oxidized Phospholipids

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