platelet-activating factor

血小板活性化因子、PAF

WordNet

1. be a contributing factor; "make things factor into a companys profitability"
2. any of the numbers (or symbols) that form a product when multiplied together
3. an independent variable in statistics
4. anything that contributes causally to a result; "a number of factors determined the outcome"
5. consider as relevant when making a decision; "You must factor in the recent developments" (同)factor in, factor out
6. resolve into factors; "a quantum computer can factor the number 15" (同)factor in, factor out
7. an event known to have happened or something known to have existed; "your fears have no basis in fact"; "how much of the story is fact and how much fiction is hard to tell"
8. a concept whose truth can be proved; "scientific hypotheses are not facts"
9. a piece of information about circumstances that exist or events that have occurred; "first you must collect all the facts of the case"
10. a statement or assertion of verified information about something that is the case or has happened; "he supported his argument with an impressive array of facts"
11. tiny bits of protoplasm found in vertebrate blood; essential for blood clotting (同)blood_platelet, thrombocyte
12. causing motion or action or change (同)actuating

PrepTutorEJDIC

1. (…の)『要因』,(…を生み出す)要素《+『in』+『名』(do『ing』)》 / 囲数,約数 / 代理人,《おもに英》仲買人 / =factorize
2. 〈C〉『事実』,実際にある(あった)事 / 〈U〉真相,真実(truth) / 《the~》(法律用語で)犯行

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/06/08 01:06:15」(JST)

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Platelet-activating factor

Identifiers
CAS Number	74389-68-7 Y
ChEBI	CHEBI:44811 N
ChemSpider	97241 N
IUPHAR/BPS	1833 1831
Jmol 3D model	Interactive image
MeSH	Platelet+Activating+Factor
PubChem	108156
InChI InChI=1S/C26H54NO7P/c1-6-7-8-9-10-11-12-13-14-15-16-17-18-19-21-31-23-26(34-25(2)28)24-33-35(29,30)32-22-20-27(3,4)5/h26H,6-24H2,1-5H3/t26-/m1/s1 N Key: HVAUUPRFYPCOCA-AREMUKBSSA-N N InChI=1/C26H54NO7P/c1-6-7-8-9-10-11-12-13-14-15-16-17-18-19-21-31-23-26(34-25(2)28)24-33-35(29,30)32-22-20-27(3,4)5/h26H,6-24H2,1-5H3/t26-/m1/s1 Key: HVAUUPRFYPCOCA-AREMUKBSBE
SMILES CCCCCCCCCCCCCCCCOC[C@H](COP(=O)([O-])OCC[N+](C)(C)C)OC(=O)C
Properties
Chemical formula	C26H54NO7P
Molar mass	523.683
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Platelet-activating factor, also known as PAF, PAF-acether or AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a potent phospholipid activator and mediator of many leukocyte functions, platelet aggregation and degranulation, inflammation, and anaphylaxis. It is also involved in changes to vascular permeability, the oxidative burst, chemotaxis of leukocytes, as well as augmentation of arachidonic acid metabolism in phagocytes.

PAF is produced by a variety of cells, but especially those involved in host defense, such as platelets, endothelial cells, neutrophils, monocytes, and macrophages. PAF is continuously produced by these cells but in low quantities and production is controlled by the activity of PAF acetylhydrolases. It is produced in larger quantities by inflammatory cells in response to specific stimuli.

History

It was discovered by French immunologist Jacques Benveniste in the early 1970s. PAF was the first phospholipid known to have messenger functions. Jacques Benveniste made significant contributions in the role and characteristics of PAF and its importance in inflammatory response and mediation. Using lab rats and mice, Jacques Benveniste found that ionophore A23187 (a mobile ion carrier that allows the passage of Mn²⁺, Ca²⁺ and Mg²⁺ and has antibiotic properties against bacteria and fungi) caused the release of PAF. These developments led to the finding that macrophages produce PAF and that macrophages play an important function in aggregation of platelets and liberation of their inflammatory and vasoactive substances.

Further studies on PAF were conducted by Constantinos A. Demopoulos in 1979. Demopoulos found that PAF plays a crucial role in heart disease and strokes. His experiment’s data found that atherosclerosis (hardening of the arteries) can be attributed to PAF and PAF-like lipids and a diet with lipids that have antagonistic PAF properties can inhibit the development of heart disease. During the course of his studies, he also determined the chemical structure of the compound.

Evolution

The production of PAF can be found in the fossil records of protozoans, yeasts, plants, bacteria, and mammals. The oldest example of PAF being used in a regulatory role was found in protozoans. The regulatory role is thought to diverge from that point and be maintained as living organisms started to evolve. During evolution, functions of PAF in the cell have been changing and enlarging.

PAF has been found in plants but its function has not yet been determined.

Fungal PAF

The antifungal protein PAF from Penicillium chrysogenum exhibits growth-inhibitory activity against a broad range of filamentous fungi. Evidence suggests that disruption of Ca2+ signaling/homeostasis plays an important role in the mechanistic basis of PAF as a growth inhibitor.

PAF also elicits hyperpolarization of the plasma membrane and the activation of ion channels, followed by an increase in reactive oxygen species in the cell and the induction of an apoptosis-like phenotype

Cumulative evidence reveals that diabetes is a condition in which cell Ca2+ homeostasis is impaired. Defects in cell Ca2+ regulation were found in erythrocytes, cardiac muscle, platelets, skeletal muscle, kidney, aorta, adipocytes, liver, osteoblasts, arteries, lens, peripheral nerves, brain synaptosomes, retinal tissue, and pancreatic beta cells, confirming that this defect in cell Ca2+ metabolism is a basic pathology associated with the diabetic state.

The defects identified in the mechanical activity of the hearts from type 1 diabetic animals include alteration of Ca2+ signaling via changes in critical processes.

Function

PAF is used to transmit signals between neighboring cells and acts as a hormone, cytokines, and other signaling molecules. The PAF signaling system can trigger inflammatory and thrombotic cascades, amplify these cascades when acting with other mediators, and mediate molecular and cellular interactions (cross talk) between inflammation and thrombosis. Unregulated PAF signaling can cause pathological inflammation and has been found to be a cause in sepsis, shock, and traumatic injury. PAF can be used as a local signaling molecule and travel over very short distances or it can be circulated throughout the body and act via endocrine.

PAF initiates an inflammatory response in allergic reactions. This has been demonstrated in the skin of humans and in the paws and skin of lab rabbits and rodents. The inflammatory response is enhanced by the use of vasodilators, including prostaglandin E1 (PGE,) and PGE2 and inhibited by vasoconstrictors.

PAF also induces apoptosis in a different way that is independent of the PAF receptor. The pathway to apoptosis can be inhibited by negative feedback from PAF acetylhydrolase (PAF-AH), an enzyme that catabolizes platelet-activating factor.

It is an important mediator of bronchoconstriction.

It causes platelets to aggregate and blood vessels to dilate. Thus, it is important to the process of hemostasis. At a concentration of 10⁻¹² mol/L, PAF causes life-threatening inflammation of the airways to induce asthma like symptoms.

Toxins such as fragments of destroyed bacteria induce the synthesis of PAF, which causes a drop in blood pressure and reduced volume of blood pumped by the heart, which leads to shock and possibly death.

Structure

Several molecular species of platelet-activating factor that vary in the length of the O-alkyl side-chain have been identified.

• Its alkyl group is connected by an ether linkage at the C1 carbon to a 16-carbon chain.
• The acyl group at the C2 carbon is an acetate unit (as opposed to a fatty acid) whose short length increases the solubility of PAF allowing it to function as a soluble signal messenger.
• The C3 has a phosphocholine head group, just like standard phosphatidylcholine.

Studies found that PAF could not be modified without losing its biological activity. Thus, small changes in the structure of PAF could render its signaling abilities inert. Investigation led to the understanding that platelet and blood pressure response were dependent on the sn-2 propionyl analog. If the sn-1 was removed than PAF lacked any sort of biological activity. Finally, the sn-3 position of PAF was experimented with by removing methyl groups sequentially. As more and more methyl groups were removed, biological activity diminished until it was eventually inactive.

Biochemistry

Biosynthesis

PAF is produced by stimulated basophils, monocytes, polymorphonuclear neutrophils, platelets, and endothelial cells primarily through lipid remodeling. A variety of stimuli can initiate the synthesis of PAF. These stimuli could be macrophages going through phagocytosis or endothelium cells uptake of thrombin.

There are two different pathways in which PAF can be synthesized: de novo pathway and remodeling. The remodeling pathway is activated by inflammatory agents and it is thought to be the primary source of PAF under pathological conditions. The de novo pathway is used to maintain PAF levels during normal cellular function.

The most common pathway taken to produce PAF is remodeling. The precursor to the remodeling pathway is a phospholipid, which is typically phosphatidylcholine (PC). The fatty acid is removed from the sn-2 position of the three-carbon backbone of the phospholipid by phospholipase A2 (PLA2) to produce the intermediate lyso-PC (LPC). An acetyl group is then added by LPC acetyltransferase (LPCAT) to produce PAF.

Using the de novo pathway, PAF is produced from 1-O-alkyl-2-acetyl-sn-glycerol (AAG). Fatty acids are joined on the sn-1 position with 1-O-hexadecyl being the best for PAF activity. Phosphocholine is then added to the sn-3 site on AAG creating PAF.

Regulation

The concentration of PAF is controlled by the synthesis of the compound and by the actions of PAF acetylhydrolases (PAF-AH). PAF-AH are a family of enzymes that have the ability to catabolize and degrade PAF and turn it into an inactive compound. The enzymes within this family are lipoprotein-associated phospholipase A2, cytoplasmic platelet-activating factor acetylhydrolase 2, and platelet-activating factor acetylhydrolase 1b.

Cations are one form of regulation in the production of PAF. Calcium plays a large role in the inhibitation of enzymes that produce PAF in the denovo pathway of PAF biosynthesis.

The regulation of PAF is still not completely understood. Enzymes that are associated with the production of PAF are controlled by metal ions, thiol compounds, fatty acids, pH, compartimentalization, and phosphorylation and dephosphorylation. These controls on these PAF producing enzymes are believed to work in conjunction to control it, but the overall pathway and reasoning is not well understood.

Pharmacology

Inhibition

PAF antagonists is a type of receptor ligand or drug that does not provoke an inflammatory response upon binding, but blocks or lessens the effect of PAF. Examples of PAF antagonists are:

• CV-3988 is a PAF antagonist that blocks signaling events correlated to the expression and binding of PAF to the PAF Receptor.
• SM-12502 is a PAF antagonist, which is metabolized in the liver by the enzyme CYP2A6.
• Rupatadine is an antihistamine and PAF antagonist used to treat allergies.

Clinical significance

High PAF levels are associated with a variety of medical conditions. Some of these conditions include:

•Allergic reactions
•Stroke
•Sepsis
•Myocardial infarction
•Colitis, inflammation of the large intestine
•Multiple sclerosis

While the effects of PAF have on inflammatory response and cardiovascular conditions are well understood, PAF is still a hot subject for discussion. Over the past 15 years, papers written on PAF have almost doubled from approximately 7,500 in 1997 to 13,000 in 2012. PAF is not completely understood and is still a hot topic for research.

Anti-PAF drugs

Anti-PAF drugs are currently being used in cardiac rehabilitation trails. Anti-PAF drugs are used to block angiotensin II type 1 receptors to lower in the risk of atrial fibrillation in individuals with paroxysmal fibrillation. It is also used to lessen the effects of allergies.

See also

• Platelet-activating factor receptor
• Platelet-derived growth factor

References

External links

• Srf1 is Essential to Buffer Toxic Effects of Platelet Activating Factor
• Pharmacorama - PAF (Platelet Activating Factor)
• Platelet Activating Factor at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. 肥満細胞由来のメディエーター mast cell derived mediators
• 2. アナフィラキシー：急性期診断 anaphylaxis acute diagnosis
• 3. 好酸球の生物学および好酸球増多症の原因 eosinophil biology and causes of eosinophilia
• 4. アナフィラキシーの病態生理 pathophysiology of anaphylaxis
• 5. 初期肺移植片機能不全 primary lung graft dysfunction

English Journal

• PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis.

• Filgueiras LR1, Koga MM1, Quaresma PG2, Ishizuka EK1, Montes MB1, Prada PO3, Saad MJ2, Jancar S1, Rios FJ4.
• Clinical science (London, England : 1979).Clin Sci (Lond).2016 Apr 1;130(8):601-12. doi: 10.1042/CS20150538. Epub 2016 Jan 19.
• Metabolic dysfunction is associated with adipose tissue inflammation and macrophage infiltration. PAFR (platelet-activating factor receptor) is expressed in several cell types and binds to PAF (platelet-activating factor) and oxidized phospholipids. Engagement of PAFR in macrophages drives them tow
• PMID 26785675

• CYP3A5*3 and MDR1 C3435T are influencing factors of inter-subject variability in rupatadine pharmacokinetics in healthy Chinese volunteers.

• Xiong Y1, Yuan Z2,3, Yang J2, Xia C2, Li X4, Huang S2, Zhang H2, Liu M2.
• European journal of drug metabolism and pharmacokinetics.Eur J Drug Metab Pharmacokinet.2016 Apr;41(2):117-124. Epub 2014 Nov 27.
• Rupatadine (RUP) is an oral antihistamine and platelet-activating factor antagonist and is shown as the substrate of CYP3A5 and P-gp. The significant interindividual differences of CYP3A5 and P-gp often cause bioavailability differences of some clinical drugs. The present study is aimed to evaluate
• PMID 25427746

• Platelet-activating factor receptor (PAFr) is upregulated in small airways and alveoli of smokers and COPD patients.

• Shukla SD1, Muller HK1, Latham R1, Sohal SS1,2, Walters EH1.
• Respirology (Carlton, Vic.).Respirology.2016 Apr;21(3):504-10. doi: 10.1111/resp.12709. Epub 2015 Dec 10.
• BACKGROUND AND OBJECTIVE: PAFr is a cell adhesion site for specific bacteria, notably non-typeable Haemophilus influenzae (NTHi) and Streptococcus pneumoniae. We previously published that PAFr expression is significantly upregulated in the large airways of smokers, especially in COPD. We have now in
• PMID 26662379

Japanese Journal

• 免疫学的特異性に基づいたヘパリン起因性血小板減少症(HIT)の適切な診断と治療

• 臨床血液 57(3), 322-332, 2016
• NAID 130005145474

• The Responses of Pulmonary and Systemic Circulation and Airway to Allergic Mediators in Anesthetized Rats

• Biological and Pharmaceutical Bulletin 39(4), 556-563, 2016
• NAID 130005141682

• 2) 顆粒膜細胞における細胞内信号伝達系分子の活性化機序と排卵誘発への応用(シンポジウム1(生殖) 卵巣のダイナミックな変化の神秘に迫る-臨床へのフィードバックを目指して-,第67回日本産科婦人科学会学術講演会講演要旨)

• 日本産科婦人科學會雜誌 67(10), 2152-2166, 2015-10-01
• NAID 110009989072

Related Pictures

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★リンクテーブル★

リンク元	「血小板活性化因子」「PAF」
関連記事	「fact」「factor」「activating factor」

「血小板活性化因子」

　　[★]

英

platelet activating factor platelet-activating factor, PAF

関

白血球走化性因子

「PAF」

　　[★] 血小板活性化因子, platelet activating factor, platelet-activating factor

「fact」

　　[★]

• n.

• 事実、現状、実際、実態

関

actual、actually、in fact、in practice、indeed、practically

　 　 　 　 　

「factor」

　　[★]

• n.

• 因子、要因、要素、ファクター

関

element、elementary、factorial、parameter

　 　 　 　 　 　 　

「activating factor」

　　[★]

• 活性化因子

関

activator