Platelet-activating factor and its analogs: metabolic pathways and related intracellular processes

Snyder, Fred

doi:10.1016/0005-2760(94)00192-2

Cited by 190 publications

(142 citation statements)

References 237 publications

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“…PAF was identified initially as a lipid mediator of anaphylaxis which was able to induce aggregation and release of mediators, particularly thromboxanes and serotonin, from human platelets [32,33]. PAF in the heart can be released not only by mast cells but also by basophils, neutrophils, eosinophils and tissue macrophages [33,34].…”

Section: Cardiovascular Effects Of Pafmentioning

confidence: 99%

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Allergy and the cardiovascular system

Triggiani

Patella²,

Staiano

et al. 2008

Clinical and Experimental Immunology

153

147

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SummaryThe most dangerous and life-threatening manifestation of allergic diseases is anaphylaxis, a condition in which the cardiovascular system is responsible for the majority of clinical symptoms and for potentially fatal outcome. The heart is both a source and a target of chemical mediators released during allergic reactions. Mast cells are abundant in the human heart, where they are located predominantly around the adventitia of large coronary arteries and in close contact with the small intramural vessels. Cardiac mast cells can be activated by a variety of stimuli including allergens, complement factors, general anesthetics and muscle relaxants. Mediators released from immunologically activated human heart mast cells strongly influence ventricular function, cardiac rhythm and coronary artery tone. Histamine, cysteinyl leukotrienes and platelet-activating factor (PAF) exert negative inotropic effects and induce myocardial depression that contribute significantly to the pathogenesis of anaphylactic shock. Moreover, cardiac mast cells release chymase and renin that activates the angiotensin system locally, which further induces arteriolar vasoconstriction. The number and density of cardiac mast cells is increased in patients with ischaemic heart disease and dilated cardiomyopathies. This observation may help explain why these conditions are major risk factors for fatal anaphylaxis. A better understanding of the mechanisms involved in cardiac mast cell activation may lead to an improvement in prevention and treatment of systemic anaphylaxis.

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Section: Cardiovascular Effects Of Pafmentioning

confidence: 99%

“…PAF in the heart can be released not only by mast cells but also by basophils, neutrophils, eosinophils and tissue macrophages [33,34]. Studies in experimental animals have demonstrated convincingly that PAF influences several myocardial functions.…”

Section: Cardiovascular Effects Of Pafmentioning

confidence: 99%

Allergy and the cardiovascular system

Triggiani

Patella²,

Staiano

et al. 2008

Clinical and Experimental Immunology

153

147

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“…Since this first report, the enzyme activity has been detected in microsomes of rat spleen and lung as well as porcine leukocytes (14,20). Although several groups have attempted to identify and characterize the enzyme from various sources (2,4,14, 21,22), it has not yet been purified nor cDNA-cloned.PC is a major component of cellular membranes and also plays an important role as a PAF precursor. PC is formed from diacylglycerol by a de novo pathway, originally described by Kennedy (23) in 1961 but is also generated from LPC by a remodeling pathway.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…PAF is synthesized in various cells and tissues via two distinct pathways, the de novo and remodeling pathways (2,4,5), and the latter is regulated by extracellular signals and plays a critical role in stimulus-coupled PAF biosynthesis (2, 4 -6). PAF synthesis induced by extracellular signals has been reported in murine peritoneal cells stimulated by calcium ionophore (7) or by PAF (8), in human eosinophils stimulated by fMet-Leu-Phe (9), in human neutrophils stimulated by acid stress (10), and in murine peritoneal macrophages stimulated by lipopolysaccharide (LPS) (11).…”

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confidence: 99%

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A Single Enzyme Catalyzes Both Platelet-activating Factor Production and Membrane Biogenesis of Inflammatory Cells

Shindou¹,

Hishikawa²,

Nakanishi

et al. 2007

Journal of Biological Chemistry

220

239

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Platelet-activating factor (PAF) is a potent proinflammatory lipid mediator eliciting a variety of cellular functions. Lipid mediators, including PAF are produced from membrane phospholipids by enzymatic cascades. Although a G protein-coupled PAF receptor and degradation enzymes have been cloned and characterized, the PAF biosynthetic enzyme, aceyl-CoA:lyso-PAF acetyltransferase, has not been identified. Here, we cloned lyso-PAF acetyltransferase, which is critical in stimulusdependent formation of PAF. The enzyme is a 60-kDa microsomal protein with three putative membrane-spanning domains. The enzyme was induced by bacterial endotoxin (lipopolysaccharide), which was suppressed by dexamethasone treatment. Surprisingly, the enzyme catalyzed not only biosynthesis of PAF from lyso-PAF but also incorporation of arachidonoyl-CoA to produce PAF precursor membrane glycerophospholipids (lysophosphatidylcholine acyltransferase activity). Under resting conditions, the enzyme prefers arachidonoyl-CoA and contributes to membrane biogenesis. Upon acute inflammatory stimulation with lipopolysaccharide, the activated enzyme utilizes acetyl-CoA more efficiently and produces PAF. Thus, our findings provide a novel concept that a single enzyme catalyzes membrane biogenesis of inflammatory cells while producing a prophlogistic mediator in response to external stimuli.Platelet-activating factor (PAF 3 ; 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a phospholipid mediator that activates a G protein-coupled receptor (1-3) and results in pleiotropic and potent biological effects, including platelet activation, airway constriction, and hypotension (1). PAF is synthesized in various cells and tissues via two distinct pathways, the de novo and remodeling pathways (2, 4, 5), and the latter is regulated by extracellular signals and plays a critical role in stimulus-coupled PAF biosynthesis (2, 4 -6). PAF synthesis induced by extracellular signals has been reported in murine peritoneal cells stimulated by calcium ionophore (7) or by PAF (8), in human eosinophils stimulated by fMet-Leu-Phe (9), in human neutrophils stimulated by acid stress (10), and in murine peritoneal macrophages stimulated by lipopolysaccharide (LPS) (11). In the remodeling pathway, the precursor of PAF, 1-Oalkyl-sn-glycero-3-phosphocholine (lyso-PAF), is synthesized from 1-O-alkyl-2-arachidonoyl-sn-glycero-3-phosphocholine (1-alkyl-phosphatidylcholine; PC) by the action of phospholipase A 2 (2, 4, 12, 13). Subsequently, lyso-PAF is converted to PAF by acetyl-CoA:lyso-PAF acetyltransferase (lyso-PAF acetyltransferase) (EC 2.3.1.67) (14). PAF is then rapidly degraded to lyso-PAF by PAF acetylhydrolases (15). Alternatively, lyso-PAF is again transformed into PC by the action of lysophosphatidylcholine (LPC) acyltransferase (2.3.1.23) (16).A G protein-coupled PAF receptor was cloned in our laboratory (17), and PAF acetylhydrolases have been cloned and characterized by others (18,19). Lyso-PAF acetyltransferase was initially demonstrated and partially characterized by ...

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Priming Interleukin 8 Production

et al. 1999

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Platelet-activating factor (PAF) activates p38, an important intracellular signal transduction kinase, and primes human mononuclear cells for the production of interleukin 8 (IL-8), a potent chemoattractant and activator of neutrophils. Methods: Human mononuclear cells were isolated from healthy adults by Ficoll-paque density-gradient centrifugation. Interleukin-8 in the supernatant was measured by enzyme-linked immunosorbent assay. Dual phosphospecific p38 antibody was used to detect activated p38 by Western blotting. Results: Lipopolysaccharide (LPS) and PAF activated p38. There was a shorter latency to peak p38 activation with PAF vs LPS stimulation, 5 vs 30 minutes. Plateletactivating factor-induced p38 activation was calcium dependent because it was inhibited by ethyleneglycoltet-racetic acid. Lipopolysaccharide, 0.01 to 1.00 ng/mL, induced significant IL-8 production. Although PAF did not induce significant IL-8 production, it potentiated LPSinduced IL-8 production. Production of IL-8, in response to LPS alone or in combination with PAF, was inhibited by SB202190, a specific p38 inhibitor. Conclusions: Although LPS and PAF activated p38, only LPS induced IL-8 production; PAF acted as a priming agent. It seems that p38 activation is necessary but not sufficient for IL-8 production by human mononuclear cells. Identifying and evaluating the activation state of inflammatory signal transduction pathways might lead to methods for controlling and preventing neutrophilinduced tissue injury without interfering with the normal host immune response.

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Platelet-activating factor and its analogs: metabolic pathways and related intracellular processes

Cited by 190 publications

References 237 publications

Allergy and the cardiovascular system

Allergy and the cardiovascular system

A Single Enzyme Catalyzes Both Platelet-activating Factor Production and Membrane Biogenesis of Inflammatory Cells

Priming Interleukin 8 Production

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